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SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms
Molecular Medicine volume 30, Article number: 46 (2024)
Abstract
Effective therapeutic targets and early diagnosis are major challenges in the treatment of gastrointestinal tract (GIT) cancers. SALL4 is a well-known transcription factor that is involved in organogenesis during embryonic development. Previous studies have revealed that SALL4 regulates cell proliferation, survival, and migration and maintains stem cell function in mature cells. Additionally, SALL4 overexpression is associated with tumorigenesis. Despite its characterization as a biomarker in various cancers, the role of SALL4 in GIT cancers and the underlying mechanisms are unclear. We describe the functions of SALL4 in GIT cancers and discuss its upstream/downstream genes and pathways associated with each cancer. We also consider the possibility of targeting these genes or pathways as potential therapeutic options for GIT cancers.
Introduction
Gastrointestinal tract (GIT) cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), liver cancer, and pancreatic cancer, are major causes of morbidity and mortality globally (Shoji et al. 2022; Abdul-Latif et al. 2020). In 2020, CRC, GC, and EC ranked fifth, sixth, and seventh, respectively, among 36 cancers in terms of new deaths (Sung et al. 2021). Although multiple nonsurgical treatment strategies have been employed, they are limited because of side effects (Johdi and Sukor 2020) and cancer resistance (Huang and Yu 2018; Sahin et al. 2019). Therefore, developing new therapeutic targets is essential.
Spalt-like transcription factor 4 (SALL4), a cancer stem cell (CSC) marker (Islam et al. 2015), has been identified as a promising biomarker and diagnostic/therapeutic target owing to its overexpression in various cancers, including GIT cancers, with adverse progression and poor outcomes (Zhang et al. 2015; Sun et al. 2022; Dirican and Akkiprik 2016; Yong et al. 2013). SALL4 is excessively expressed in various malignant tumors, such as esophageal cancer (He et al. 2016), gastric cancer (Wang et al. 2021a; Yang et al. 2021a; Shao et al. 2020), colorectal cancer (Ardalan Khales et al. 2015), hepatocellular carcinoma (HCC) (Yong et al. 2013), breast cancer (Dirican and Akkiprik 2016; Yang et al. 2022), lung cancer (Kobayashi et al. 2011; Li et al. 2020) and acute myeloid leukemia (AML) (Wang et al. 2016). SALL4 plays a vital role in regulating the cell cycle and apoptosis, as well as in the formation and development of malignant tumors, but its role in different tumors is regulated by different mechanisms (Sun et al. 2022; Hwang et al. 2020; Liao et al. 2018). The function and mechanism of SALL4 in gastrointestinal tract cancers require further investigation, which may provide new insights into tumor therapy.
In this review, we summarize current research data on the roles of SALL4 in gastrointestinal tract cancers and the underlying mechanisms. We also describe the upstream regulatory genes (Table 1) and downstream target genes/pathways (Table 2) of SALL4 in each GIT cancer.
Functions of SALL4 in gastrointestinal tract cancers
SALL4 was first described in humans as an oncogene in 2006 (Ma et al. 2006), after which it was extensively studied and discussed (Zhang et al. 2015; Sun et al. 2022; Dirican and Akkiprik 2016; Moein et al. 2022; Liu et al. 2021; Abouelnazar et al. 2023b; Nicolè et al. 2017; Tatetsu et al. 2016; Yang 2018; Oikawa et al. 2013). It is known that SALL4 has 2 isoforms, SALL4A and SALL4B. SALL4A originates from the full-length transcript, while the spliced isoform SALL4B lacks a part of exon 2 (Milanovich et al. 2015). In murine embryonic stem (ES) cells, SALL4A and SALL4B have different binding sites, with few overlapping sites, playing distinct roles in the maintenance of the pluripotent state (Rao et al. 2023). As SALL4B is the predominant isoform in murine hematopoietic stem cells and progenitors, its overexpression results in a failure of engrafting transplanted bone marrow and reconstituting hematopoiesis (Milanovich et al. 2015). The OCT4 promoter and KRLR sequence have been identified as the transcriptional target and bona fide nuclear localization signal for SALL4B, respectively (Wu et al. 2014). In addition, massive expansion of CD34+ cells has been considered one function of SALL4B (Shen et al. 2016). SALL4A interacts with JARID2, PRDM14 and ESRRB, achieving rapid and effective somatic reprogramming (Iseki et al. 2016). In mouse ES cells, SALL4A occupies enhancers and regulates the expression of developmental genes as a 5-formylcytosine binder (Xiong et al. 2016).
Currently, there are extremely limited studies on the exact roles of SALL4A and SALL4B in cancers. In acute lymphoblastic leukemia (ALL), SALL4A may be correlated to the poor prognosis (Peng et al. 2017). SALL4B transgenic mice develop acute myeloid leukemia (AML), which indicates SALL4B contribution to leukemia development and maintenance (Li et al. 2013). SALL4B may be involved in angiogenesis in GC cells by targeting VEGF (Abouelnazar et al. 2023a). Considering the important role of SALL4 in GIT cancers, additional in-depth studies can be performed to explore the functions of the different SALL4 isoforms in cancers.
Since being discovered, SALL4 has been considered to be a biomarker and to play a vital role in the proliferation, apoptosis, invasive migration, epithelial-mesenchymal transition (EMT), chemoresistance, and the maintenance of cancer stem cells (CSCs) through various pathways, such as the NOTCH, Wnt/β-catenin, ERK, STAT3, NF-κB, TGF-β/SMAD, and PTEN/AKT signaling pathways (Zhang et al. 2015; Dirican and Akkiprik 2016; Ma et al. 2006; Nicolè et al. 2017; Tatetsu et al. 2016; Yang 2018; Oikawa et al. 2013). In recent years, an increasing number of studies have focused on the carcinogenicity of SALL4 and its corresponding mechanisms in GIT cancers (Sun et al. 2022; Moein et al. 2022; Liu et al. 2021; Abouelnazar et al. 2023b), and new functions and regulators/targets of SALL4 have been discovered. A recent study has found that SALL4 plays an important role in angiogenesis by transcriptionally regulating VEGF expression (Abouelnazar et al. 2023a). SALL4 is associated with clinicopathological features related to GC progression, and it functions via the Wnt/β-catenin pathway (Yang et al. 2021a), which can be mediated by dual regulation of SALL4 by EZH2 and KDM6A (Ren et al. 2023). Nicotine promotes the stabilization and expression of SALL4 by upregulating the RNA-binding protein interleukin enhancer binding factor 2 (ILF2), which facilitates tumor initiation in esophageal cancer cells (Li et al. 2021). SALL4 induces the invasion and metastasis of colon adenocarcinoma (COAD) and is significantly correlated with TNM grading, histological grading, and lymphatic metastasis in tumor tissues (Zhang et al. 2022). SALL4 activates the PI3K/AKT signaling pathway by targeting PTEN, thereby facilitating the migration, invasion and proliferation of HCC cells (Tang et al. 2022).
There are reviews demonstrating the functions and regulatory mechanisms of SALL4 (Zhang et al. 2015; Sun et al. 2022; Moein et al. 2022; Liu et al. 2021; Abouelnazar et al. 2023b; Nicolè et al. 2017), many of which show that each pathway is involved in many different types of cancers. In the next section, we will focus on GIT cancers, including the most recent findings regarding the role of SALL4 and its mechanisms. We will separately summarize the identified upstream regulators and downstream targets/pathways of SALL4 in each type of GIT cancer, which may help gain an insight into the regulatory mechanisms of SALL4 in each GIT cancer.
Regulators and targets of SALL4 in gastrointestinal tract cancers
Esophageal cancer
In 2020, it was estimated that 604,100 people were diagnosed with esophageal cancer (EC) globally, which resulted in approximately 544,100 deaths (Thrift and El-Serag 2020). Esophageal squamous cell carcinoma (ESCC) is much more common than esophageal adenocarcinoma (EAC). We focused on summarizing research on ESCC, since it accounts for 90% of all cases (Smyth et al. 2017). SALL4 is overexpressed in ESCC tissues (He et al. 2016; Zargari et al. 2020; Yang et al. 2007; Forghanifard et al. 2014), which indicates its involvement in ESCC progression and reveals the underlying function of SALL4 as a predictor in the early diagnosis and therapy of ESCC (Fig. 1).
Upstream regulatory genes
Previous research has shown that nuclear receptor-binding protein 1 (NRBP1) downregulates SALL4 protein expression by driving its ubiquitination and proteasomal degradation (Hwang et al. 2020). TSC22 homologous gene-1 (THG-1) interrupts the ubiquitination of SALL4 by competitive binding to NRBP1 (Hwang et al. 2020). Knockdown of THG-1 limits the growth of TE13 cells, a human ESCC cell line, and induces downregulation of SALL4. Conversely, exogenous SALL4 expression significantly restores the growth of the knockdown cell line (Hwang et al. 2020).
By analyzing gene expression patterns and conducting clinicopathological tests on tumor and adjacent tumor-free tissues from 50 ESCC patients, researchers have shown that SALL4 expression positively correlates with that of MEIS1, a homeobox transcription factor (Zargari et al. 2020). Silencing of MEIS1 induces a striking decline in SALL4 expression (Zargari et al. 2020). These results reveal the role of MEIS1 as an upstream regulatory gene of SALL4, and further exploration is needed to determine the downstream pathway of MEIS1/SALL4 in ESCC.
Nicotine-induced upregulation of the RNA-binding protein interleukin enhancer-binding factor 2 (ILF2) promotes the stabilization and expression of SOX2, NANOG, and SALL4 by facilitating nuclear mRNA export and inhibiting hMTR4-mediated degradation, which enhances the stemness and tumor-initiating capacity of esophageal cancer cells (Li et al. 2021).
Downstream signaling pathways
Esophageal tumor tissues exhibit elevated expression of both SALL4 and SOX2, which function as stemness markers (Forghanifard et al. 2014). A study has demonstrated the interaction between SOX2 and SALL4 in nuclear protein complexes (Cox et al. 2010). The SOX2/SALL4 stemness axis has been shown to modulate the Notch pathway (Forghanifard et al. 2021). The Notch cascade cell signaling pathway contributes to the pathological process of ESCC, which is modulated by ligands binding to Notch receptors (NOTCH1, 2, and 3), a Notch ligand (DLL1), Notch target genes (C-MYC and HEY2) and a Notch signaling pathway transcription activator (MAML1) (Forghanifard et al. 2015). The expression of these molecules is associated with various pathological properties, such as tumor progression, lymph node metastasis and invasion to the adventitia (Forghanifard et al. 2021).
The Wnt/β-catenin pathway promotes transcriptional changes, driving epithelial-mesenchymal transition (EMT) in cancer and contributing to metastasis (Tang et al. 2020; Yu et al. 2021). Applying the Wnt agonist HLY78 has been shown to improve the motility of ESCC cells (Chen et al. 2022). Previous research has indicated that SALL4 knockdown attenuates EMT and downregulates the expression of Wnt3a and β-catenin in ESCC (He et al. 2016). These findings suggest that SALL4 may be involved in ESCC oncogenesis via the Wnt/β-catenin pathway.
Aldehyde dehydrogenase 1A1 (ALDH1A1) is a CSC marker that is highly expressed in ESCC tissues. ALDH1A1 could activate the AKT signaling pathway via stimulation of AKT phosphorylation, further increasing cancer stem cell-like properties (Wang et al. 2020). Bioinformatics analysis has shown an interaction between the SALL4 and ALDH1A1 genes, and high coexpression of SALL4/ALDH1A1 in serous ovarian carcinoma is significantly associated with distant metastasis and aggressive tumor behavior (Sharbatoghli et al. 2022). These findings may provide a new idea for exploring potential targets of the SALL4/ALDH1A1/AKT signaling pathway.
Caspase-8 overexpression is considered a predictor of worse prognosis of ESCC (Chai et al. 2023). SALL4 regulates multiple caspase family members in tumor cells (Sun et al. 2022; Yong et al. 2013; Chai et al. 2023). The activity of caspase-3/8 in SALL4 knockout cells is elevated in acute B-cell lymphoblastic leukemia (Ueno et al. 2014), indicating that SALL4 maintains the survival of tumor cells by inhibiting caspase family members.
These results reveal roles of the Notch, Wnt/β-catenin, AKT, and caspase-induced apoptosis signaling pathways as potential targets of SALL4 in esophageal cancer. However, their exact functions in this cancer and the underlying mechanisms require further investigation.
Gastric cancer
There were over one million new cases of gastric cancer (GC) reported in 2020 (Sung et al. 2021). Advanced-stage GC, lymph node metastasis, noncardia localization, and vascular invasion are associated with a higher SALL4-positive rate (Yang et al. 2021a). Together with alpha-fetoprotein (AFP) and glypican-3 (GPC3), SALL4 is a proven indicator of poor prognosis in GC (Wang et al. 2021a). Both the serum level and immunohistochemical expression of AFP can be used to indicate the poor prognosis for gastric adenocarcinoma, while the SALL4 immunohistochemistry can also be an indicator of adverse prognosis for such cancer (Wang et al. 2021a). Recently, SALL4 helps to identify clinically and molecularly distinct genomic consensus subtypes (CGSs) (Jeong et al. 2023). Besides, positivity of SALL4 can aid in the diagnosis of hepatoid adenocarcinoma of stomach (HAS), a special subtype of gastric cancer with poor prognosis (Yang et al. 2024). Current treatments for GC, including conventional therapy, immunotherapy and targeted therapy, show some curative effects, and clarifying the molecular pathogenesis and regulatory genes underlying GC is necessary for developing novel and personalized treatments for patients. In this section, we will discuss the regulatory genes of SALL4 in GC and its downstream signaling pathways (Fig. 2).
Upstream regulatory genes
Yes-associated protein 1 (YAP) expression increases in GC spheroid cells and promotes cell self-renewal (Bie et al. 2020). Immunofluorescence staining has revealed the colocalization of YAP and SALL4 (Bie et al. 2020), and interfering with YAP expression significantly suppresses the mRNA level of SALL4 in MGC-803 cells (Bie et al. 2020). It is necessary to confirm the correlation between YAP and SALL4 in vivo and determine whether the regulatory effect of YAP on SALL4 expression is direct.
The microRNA (miRNA) family modulates biological processes in cancer by targeting different genes (Ishiguro et al. 2014; Ali Syeda et al. 2020; Peng et al. 2021). miR-188-5p is highly expressed in various GC cell lines and promotes the expression of SALL4, thereby facilitating the proliferation and migration of GC cells (Wang et al. 2019a). In contrast, another in vitro study has revealed the anticancer effect of miR-188-5p by targeting ZFP91 (Peng et al. 2018), suggesting that the precise function of miR-188-5p still needs to be confirmed. As a tumor suppressor, miR-16 is expressed at low levels in GC tissues and specifically targets SALL4 at both the RNA and protein levels in GC cells (Jiang and Wang 2018).
According to a study on hepatocellular carcinoma (HCC) (Zhao et al. 2019), miR-497 directly targets SALL4 and negatively regulates its expression, contributing to the stemness properties and metastatic potential of HCC cells (Zhao et al. 2019). Although miR-497 suppresses GC tumorigenesis and progression (Zhang et al. 2021), it is still unknown whether SALL4 participates in the regulation of miR-497 in gastric cancer. Based on these findings, SALL4 is the only potential target gene of miR-497 in gastric cancer, as has been revealed in HCC cells.
Downstream signaling pathways
The Wnt/β-catenin signaling pathway, which has been shown to play a role in the regulation of SALL4 in ESCC, may also be involved in this process in GC (Yang et al. 2021a). A study of 1815 GC patients found that SALL4 expression was positively correlated with TRIB3, a core gene in the Wnt/β-catenin pathway (Yang et al. 2021a). The expression of CTNNB1 (also known as catenin beta 1 or β-catenin) is directly upregulated by SALL4 in cervical cancer cells (Chen et al. 2019). Activation of CTNNB1 transcription may give rise to anoikis resistance and enhance the metastatic ability of GC cells (Ye et al. 2020).
Overexpressing the SALL4 gene upregulates the expression of EMT inducer genes, thereby promoting EMT in GC cells (Zhang et al. 2018; Du et al. 2023). Further research has shown that SALL4 modulates EMT by regulating TGF-β1 expression and SMAD phosphorylation (Zhang et al. 2018). These results indicate that SALL4 may activate the TGF-β/SMAD signaling pathway to induce EMT. A recent study has also shown that SALL4 facilitates EMT (Du et al. 2023). SALL4 overexpression promotes the proliferation and invasiveness of GC cells through EMT-related genes, while the knockdown of SALL4 inhibits this process (Du et al. 2023). In addition, the HDAC inhibitor entinostat partially targets SALL4 and suppresses the proliferation, migration, and invasion of gastric cancer cells by regulating the expression of EMT-associated proteins (Du et al. 2023).
SALL4 knockdown downregulates the expression of stemness- and EMT-related genes (OCT4, SOX2, NANOG, C-MYC and CD44) and suppresses the activation of the ERK, STAT3 and NF-κB pathways, thus inhibiting the proliferation and migration of gastric cancer cells (Yuan et al. 2016). As CD44 is a cell adhesion molecule, its overexpression antagonizes SALL4 knockdown-induced inhibition of proliferation, migration, invasion and growth of GC (Yuan et al. 2016). These results suggest that CD44 is partially responsible for the oncogenic roles of SALL4 in GC.
In addition to these signaling pathways, there are other genes and molecules that are considered targets of SALL4 in GC. For example, SALL4 knockdown eliminates the suppressive effect of miR-188-5p on PTEN expression (Wang et al. 2019a), indicating that SALL4 is a key regulatory factor through which miR-188-5p inhibits PTEN.
Abnormal glycolysis contributes to tumorigenesis, metastasis, and drug resistance of cancers, including GC (Ma et al. 2015; Rosa et al. 2015). SALL4 overexpression promotes glycolysis in GC, leading to cell proliferation. SALL4 knockdown or overexpression downregulates or upregulates, respectively, the activity of the HK-2 gene, which is involved in glycolysis (Shao et al. 2020). In addition, knockdown of HK-2 inhibits the promotional effect of SALL4 on glycolysis and its effects on GC cells (Shao et al. 2020), confirming the role of HK-2 as a target gene of SALL4 in GC.
In addition to tumorigenesis, metastasis, and drug resistance of cancers, SALL4 transcriptionally regulates the expression of VEGF to promote angiogenesis (Abouelnazar et al. 2023a). Overexpression of SALL4B increases VEGF-A, −B, and −C gene expression, while SALL4B knockdown reduces their expression (Abouelnazar et al. 2023a).
Colorectal cancer
Colorectal cancer (CRC) is ranked second in terms of mortality and third in terms of the incidence as of 2020 (Sung et al. 2021). People with a family history of CRC among first-degree relatives are usually considered high-risk populations (Siegel et al. 2020). This suggests the important role of genetic factors in CRC. It is usually considered that the pathological transformation of CRC results from molecular events involving various pathways (Gryfe et al. 1997). SALL4 expression in CRC tissue and serum correlates with the degree of lymph node metastasis (LNM), differentiation degree, and staging, and patients with high SALL4 expression usually have a shorter mean survival time than those with low SALL4 expression (Hao et al. 2016; Moein et al. 2022; Liu et al. 2021; Abouelnazar et al. 2023b; Wu et al. 2017; Forghanifard et al. 2013). These findings reveal the potential of SALL4 for developing antitumor targets in CRC. The activated pluripotency transcriptional network, consisting of SALL4/OCT4/DPPA2/Nanog in CRC, plays essential roles in the maintenance of the stemness state, self-renewal characteristics, and progression of tumor cells, leading to an increased depth of invasion (Ghodsi et al. 2015). Colorectal adenocarcinoma with enteroblastic differentiation (CAED), a rare malignancy, is also SALL4 positive (Murakami et al. 2019; Abada et al. 2022; Minato et al. 2023). According to a study that examined 46 normal colonic and small intestinal mucosal samples, no SALL4 expression was detected in the normal intestinal epithelium (Inaguma et al. 2017). Therefore, SALL4 has been considered a potential diagnostic and prognostic marker of colorectal cancer (Ardalan Khales et al. 2015; Wu et al. 2017; Yamashiro et al. 2020; Sajadi et al. 2022). In contrast to the above studies, one study showed negative expression of SALL4 in 20 cases of AFP-producing colorectal cancer (Ren et al. 2019), which indicates that the use of SALL4 as a biomarker in this type of CRC needs to be further validated. An immunohistochemistry study on clinical samples revealed that the regulatory transcriptional network of SALL4/OCT4/DPPA2/NANOG had an essential role in the maintenance of the stemness state and self-renewal of CRC cells (Ghodsi et al. 2015). Although the mechanism underlying SALL4 regulation in CRC is not well defined, some clues have been partially uncovered (Fig. 3).
Upstream regulatory genes
microRNAs participate in the upstream regulation of SALL4 in CRC (Chang et al. 2020; Cheng et al. 2015a; Yan et al. 2018). In vitro studies have identified miR-3622a-3p as a tumor suppressor by targeting SALL4 (Chang et al. 2020). Researchers have validated that miR-3622a-3p is a microRNA with the lowest expression in 619 CRC specimens and is negatively correlated with worse prognosis using the TCGA database and tumor tissues (Chang et al. 2020). Similarly, miR-219-5p is reduced in malignant tissues with SALL4 overexpression and can interact with the 3' UTR sequence of SALL4 (Cheng et al. 2015a). Research has also shown that miR-219-5p suppresses cell growth, induces apoptosis of CRC, and decreases drug resistance to fluorouracil and oxaliplatin by inhibiting the oncogene SALL4 (Cheng et al. 2015a). Additionally, miR-508 has been shown to decrease the expression of stemness genes in CRC, with SALL4 being one of the genes most downregulated by miR-508 (Yan et al. 2018).
NRBP1 overexpression in CRC cells leads to caspase-dependent intrinsic apoptosis, inhibiting cell proliferation and colony formation (Liao et al. 2018). Whether this inhibitory effect on tumor cells is due to SALL4 targeting, as observed in ESCC (Hwang et al. 2020), requires further exploration.
In addition to the high expression of SALL4, a high frequency of methylation is found in colorectal laterally spreading tumors (LSTs) and protruding adenomas. However, it is unclear whether inactivation of the SALL4 gene by methylation contributes to the development of colorectal adenomas (Sugai et al. 2016). Another study has shown that the SALL4 gene is more frequently hypermethylated in aneuploid cancers (8 of 16, 50%) than in diploid cancers (3 of 18, 17%) (Habano et al. 2007). These results indicate that epigenetic silencing of SALL4 may be associated with tumor cell aneuploidy, which affects the chromosomal stability in intestinal epithelial cells (Habano et al. 2007).
Downstream signaling pathways
The Sonic Hedgehog (SHH) signaling pathway regulates tumor origination and cell growth, and Gli-1 is considered the downstream transcription factor of this pathway (Cheng et al. 2015b). The knockdown of SALL4 downregulates the expression of Gli-1 and inhibits oncogenesis in CRC cells, which is antagonized by upregulating Gli-1, suggesting that Gli-1 may be a target gene of SALL4 in CRC (Cheng et al. 2015b). Aberrant activation of the SHH signaling is also responsible for the tumorigenesis in medulloblastoma (MB) (Wang et al. 2018). By forming a trimeric complex with Gli-1 and HDAC1, SALL4 potentiates Gli-1 transcriptional activity therefor sustains SHH-MB cells proliferation (Lospinoso Severini et al. 2024). These findings highlight SALL4 as a crucial role in SHH pathway and promising therapeutic target in SHH-dependent cancers.
SALL4 mediates EMT in CRC cells (Zhang et al. 2022), as in other gastrointestinal tract cancers (He et al. 2016), with the Wnt/β-catenin pathway potentially involved in this process (Chang et al. 2020). SALL4 expression correlates with the levels of TRIB3 (Yang et al. 2021a), which directly binds to β-catenin in CRC (Hua et al. 2019). The enhancement of canonical Wnt signaling in CRC cells increases SNAIL expression (a zinc finger transcription factor family that drives EMT), which regulates EMT by inhibiting E-cadherin and promotes local invasion (Goossens et al. 2017). Immunofluorescence and coimmunoprecipitation show the colocalization of SALL4 and β-catenin and indicate their interaction in human CRC tissues and cell lines (Hao et al. 2016). In addition, the function of SALL4 in promoting lymph node metastasis and an advanced TNM stage may be partly related to its interaction with β-catenin and subsequent aberrant activation of the Wnt/β-catenin signaling pathway (Hao et al. 2016). These studies suggest that the Wnt/β-catenin pathway is a downstream target of SALL4 in CRC.
In the regulation of cancer cell apoptosis, the interaction among Bcl-2 family members, for example, Bcl-2 and Bax, plays a significant role (Chipuk et al. 2010). Bcl-2 overexpression suppresses cell apoptosis and downregulates Bax expression, ultimately promoting cell proliferation and impeding programmed cell death. Knockdown of SALL4 effectively inhibits Bcl-2 expression, leading to the induction of cell apoptosis in CRC cells (Hesari et al. 2019). Therefore, SALL4 could promote oncogenesis and inhibit apoptosis in CRC cells by targeting Bcl-2.
Liver cancer
Owing to its limited therapeutic interventions, liver cancer is the second leading cause of cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Since most HCC patients can only receive palliative treatments (Galle et al. 2018), studying new targets of chemotherapy drugs is of great significance. As a stem cell-associated gene, SALL4 is highly expressed in fetal liver progenitor cells but not in adult hepatocytes (Yong et al. 2013) and is considered a stem cell biomarker in liver cancers (Oikawa et al. 2013). By examining 124 samples of HCC tissues, 44 samples of adjacent noncancerous cirrhotic tissues and 10 samples of liver hemangioma tissues, researchers found high expression of SALL4 and its relevance to the adverse prognosis of patients with HCC (Yin et al. 2016). PD-L1-positive HCC frequently shows positive expression of SALL4 (Nishida et al. 2020). Additional studies have also shown that SALL4 mRNA and protein levels are elevated in HCC tissues compared with adjacent tissues (Wang et al. 2017a, 2021b; Moeini et al. 2017; Tanaka et al. 2015). Clinicopathological analysis has revealed that patients with high SALL4 expression in HCC have a worse prognosis than those with low expression (Zeng et al. 2014; Wang et al. 2017; Leake 2013; Jung et al. 2022). SALL4-positive HCC patients exhibit higher HBs antigen positivity and higher levels of tumor markers (Wang et al. 2017). Activated SALL4 has been found in HCC with high metabolic activity, which displays the features of poor survival, the strongest stem cell signature, high genomic instability, and low potential for benefiting from immunotherapy (Jung et al. 2022). SALL4 regulates the stemness of EpCAM-positive HCC as a transcription factor and is associated with high values of serum alpha-fetoprotein, a high frequency of hepatitis B virus infection, and poor prognosis after surgery (Zeng et al. 2014). Another study has shown that EpCAMhigh liver cancer stem cells can resist NK cell–mediated cytotoxicity (Park et al. 2020). In hepatoblastoma, high expression of SALL4 is also associated with poor prognosis (Zhou et al. 2016). To treat HCC, small-molecule drugs targeting SALL4 have been developed. Competitive inhibitors of SALL4 have been shown to block its carcinogenic effects both in vitro and in vivo (Jones 2013). Information on the underlying mechanisms of SALL4 regulation in HCC has been reported (Fig. 4).
Upstream regulatory genes
miR-15a inhibits the expression of SALL4, which in turn accelerates apoptosis and suppresses the oncogenic potential of HCC cells, such as proliferation, migration, and invasion (Ma et al. 2021). miR-497 also inhibits SALL4 expression and suppresses the self-renewal and metastasis of HCC cells by directly targeting SALL4 (Zhao et al. 2019). Upstream TNF-α downregulates miR-497 expression, upregulates SALL4 expression, and promotes the metastatic phenotype of HCC cells (Zhao et al. 2019). miR-296-5p inhibits the stemness potency of HCC cells through the BRG1/SALL4 axis. miR-296-5p directly targets brahma-related gene-1 (BRG1), which binds to the SALL4 promoter and enhances SALL4 transcription, thereby inhibiting the stemness potency of HCC cells (Shi et al. 2020).
As only a few genes regulating SALL4 have been studied in liver cancer, further research is needed to explore more upstream regulatory genes of SALL4 in this cancer.
Downstream signaling pathways
As a tumor suppressor, PTEN (phosphatase and tensin homolog) is considered a target gene of SALL4 (Tang et al. 2022). SALL4 activates PI3K/AKT signaling pathway by mediating PTEN silencing, promoting the development of HCC and leading to a poor prognosis (Tang et al. 2022).
In addition to the PI3K signaling pathway, SALL4/Wnt/β-catenin signaling has been shown to be associated with the clinicopathological features and prognosis of HCC patients (Wang et al. 2019b). Significantly upregulated mRNA and protein expression of SALL4, Wnt3a and β-catenin in HCC tissues is associated with tumor differentiation, the TNM stage, tumor size, vascular invasion and liver cirrhosis in HCC patients (Wang et al. 2019b). The aberrant of Wnt/β-catenin signaling promotes the progression of liver cancer (He and Tang 2020; Wang et al. 2019c), which also determines the responses of hepatoma cells to lenvatinib treatment (Wang et al. 2023).
In HCC-derived exosomes, SALL4 regulates M2 polarization and miR-146a-5p expression, which promotes cancer progression (Yin et al. 2019). miR-146a-5p can be delivered into macrophages and promote them toward M2-polarized tumor-associated macrophages, which impair T-cell functions (Yin et al. 2019). In a DEN/CCL4-induced HCC mouse model, SALL4 directly modulates the expression of miR-146a-5p by binding to its promoter, and blocking the SALL4/miR-146a-5p interaction in HCC downregulates the expression of inhibitory receptors on T cells, reverses T-cell exhaustion, and delays HCC progression (Yin et al. 2019). These findings verify the role of the SALL4/miR-146a-5p axis in HCC.
The conversion of bioenergy metabolism often occurs in the process of tumorigenesis, with a common form of switching from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis (Liu and Shyh-Chang 2019). While in HCC cell line, SALL4 binds and upregulates the expression of OXPHOS genes and other mitochondrial genes to increase mitochondrial oxidative phosphorylation, which reveals the metabolic reprogramming function of SALL4 in tumorigenesis (Tan et al. 2019; Liu and Shyh-Chang 2019). It may be possible to find downstream targets of SALL4 by focusing on OXPHOS-related genes in GIT cancers.
An earlier study showed that SALL4 might promote cell proliferation by directly regulating the expression of cyclins D1 and D2 (Oikawa et al. 2013). Although SALL4 increases the expression of EMT genes such as TWIST1, the cell migration and invasion of liver cancer cells are not directly affected (Oikawa et al. 2013). Notably, other researchers have obtained somewhat different results. Activated SALL4 enhances spheroid formation, invasion capacities, and key characteristics of cancer stem cells while upregulating the EMT markers, hepatic stem cell markers KRT19, EpCAM, and CD44, in hepatocyte cell lines. In contrast, knockdown of SALL4 attenuates the invasion and spheroid formation capacities with decreased expression of EpCAM and CD44 in HCC cells (Zeng et al. 2014).
Recently, researchers have identified and validated a DNA-binding domain of SALL4 (an AT-rich motif) through an unbiased screen of a protein-binding microarray (PBM) and cleavage under targets and release using nuclease (CUT&RUN) experiments (Kong et al. 2021). In aggressive liver cancer cells, new target genes that are directly regulated by SALL4 (240 repressed and 190 activated by SALL4) have also been discovered by RNA sequencing analyses. The SALL4-repressed genes include a chromatin modifier gene (KDM3A) and a family of transcription factors (forkhead, BCL, KLF, and TBX5). KDMs are genes encoding a family of histone 3 lysine 9-specific demethylases that regulate the methylation statuses of H3K9 and the chromatin (Kong et al. 2021).
SALL4 induces epigenetic modification in HCC cells. SALL4 positively regulates histone deacetylase (HDAC) activity, and HDAC inhibitors suppress the proliferation of SALL4-positive HCC cells (Zeng et al. 2014).
Pancreatic cancer was responsible for approximately 496,000 new cases worldwide in 2020, ranking 14th among all cancers, with a poor prognosis and high mortality rate, accounting for nearly as many deaths (466,000) (Sung et al. 2021). Over 90% of cases of pancreatic cancer are pancreatic ductal adenocarcinomas (PDACs) (Wood and Hruban 2012), which have a low survival rate due to late diagnosis, highlighting the significance of early diagnosis and the use of biomarkers in the management of pancreatic cancer. The function and regulation of SALL4 in pancreatic cancer have received less attention. A recent study has identified the SALL4high PDAC subset that is associated with the poor prognosis, indicating SALL4 as a potential biomarker in pancreatic cancer (Vienot et al. 2023). New advances have suggested the role for SALL4 in promoting the proliferation and migration of PDAC cells and in regulating mitochondrial ROS levels through the FoxM1/PrxIII axis, which is activated by the phosphorylation of ERK1/2 (Huynh et al. 2018). In pancreatic cancer, TSPAN1 (tetraspanin 1) is upregulated by the activation of Wnt/β-catenin to promote cancer proliferation (Zhou et al. 2021). PVT1-induced gemcitabine resistance is also associated with the activation of Wnt/β-catenin signaling pathway in pancreatic cancer (Zhou et al. 2020). However, whether SALL4 acts via this pathway in pancreatic cancer is still unclear and worth investigating.
Future perspectives
Although some SALL4-related genes and pathways have been identified in GIT cancers, there are still unknown targets that need to be explored. Notably, there are genes and pathways that are aberrantly expressed or activated in GIT cancers have been identified as upstream regulatory genes or downstream signaling pathways of SALL4 in some cancers other than GIT (Table 3). It is necessary to explore the relationship between SALL4 and these potential targets in GIT cancers. Finding these genes and pathways and understanding the underlying mechanisms may aid in the diagnosis and treatment of gastrointestinal cancers.
A previous study has shown that the oncogenes HOXA11-AS and SALL4 are both upregulated in non-small cell lung cancer (NSCLC) tissues and cells, and HOXA11-AS regulates SALL4 expression by sponging miR-3619-5p (Xia et al. 2021). HOXA11-AS has been shown to be highly expressed and to act as an oncogene via different microRNA pathways in GC (Xie et al. 2021; You et al. 2021) and CRC (Chen et al. 2020). Therefore, exploring the relationship between HOXA11-AS and SALL4, as well as the role of the miR-3619-5p/SALL4 axis in GIT cancers, may provide new targets for therapy.
In glioma, SALL4 promotes cell proliferation by inhibiting PTEN expression, thereby activating the PI3K/AKT signaling pathway (Liu et al. 2017). PTEN, as a tumor suppressor gene, inhibits the PI3K/ AKT pathway in EC, GC, and CRC (Yang et al. 2021b; Liang et al. 2021; Hu et al. 2022). SALL4 has been reported to be an upstream regulatory gene of PTEN in gastric cancer (Wang et al. 2019a) and hepatocellular carcinoma (Yong et al. 2013), but it is unclear whether it has a similar effect on PTEN in esophageal, colorectal, and pancreatic cancer, which needs further investigation.
MAPK pathway plays a role in progression of many diseases including GIT cancers (Fang and Richardson 2005; Shen et al. 2023; Zhang et al. 2020; Yang and Huang 2015; Zheng et al. 2011; Chan et al. 2021; Wang et al. 2022a). A recent study has shown that MAPK pathway is involved in SALL4‐mediated prostate cancer progression (Zhou et al. 2023). These findings indicate that the potential relationship between SALL4 and MAPK pathway in GIT cancers is worth exploring.
TP53 acts a tumor suppressor gene that is frequently mutated in GTI cancers (Olivier et al. 2010; Zhong et al. 2023; Battista et al. 2021; Sahgal et al. 2021; Khemlina et al. 2017; Guichard et al. 2012; Liebl and Hofmann 2021). In mouse embryonic stem cells (mESCs), SALL4 has been shown to interact with p53 and play anti-apoptotic function in a p53-dependent manner (Wang et al. 2022b). It is necessary to investigate if SALL4 exerts its role as a p53-interacting partner.
Epigenetic changes participate in the pathogenesis and development of GIT cancers (Tamura et al. 2000; Fattahi et al. 2018; Lee et al. 2008; Yang et al. 2012). The CDH1 gene, also known as E-cadherin, is usually methylated in gastric cancer (Tamura et al. 2000; Fattahi et al. 2018), which is related to the recurrence of ESCC (Lee et al. 2008). The SALL4 protein can interact with various DNA methyltransferases (DNMTs) and modulate enzyme activities (Yang et al. 2012). Therefore, methylation genes may also be potential downstream targets of SALL4 in GIT cancers, which can be studied in more detail.
In addition, studies of the SALL4 isoforms usually focus on stem cells (Moein et al. 2022; Rao et al. 2023; Wu et al. 2014; Shen et al. 2016; Iseki et al. 2016; Xiong et al. 2016; Cohen et al. 2015). Differences in the functions and regulatory pathways of the SALL4 isoforms in tumorigenesis need further research.
Conclusion
As an oncogene, SALL4 has been found to be abnormally elevated in both tumor tissues and cells (Ardalan Khales et al. 2015; Cheng et al. 2015b). While the regulation of SALL4 and its targets has not been clearly demonstrated, our review summarizes the currently known functions, upstream regulatory mechanisms, and downstream targets of SALL4 in GIT cancers. This review shows that SALL4 participates not only in the growth, anti-apoptosis, metastasis, and invasion of these cancers but also in drug resistance (Cheng et al. 2015a), EMT (Zhang et al. 2018), OXPHOS (Tan et al. 2019), DNA methylation (Yang et al. 2012) and angiogenesis (Abouelnazar et al. 2023a), in some cases. The expression of SALL4 is regulated by upstream regulators such as THG-1 (Hwang et al. 2020), MEIS1 (Zargari et al. 2020), YAP (Bie et al. 2020), ILF2 (Li et al. 2021), KDM6A and EZH2 (Ren et al. 2023) and some members of the microRNA family (Jiang and Wang 2018; Chang et al. 2020; Cheng et al. 2015a; Yan et al. 2018; Peng et al. 2018). On the other hand, SALL4 acts as an oncogene via the Wnt/β-catenin pathway (He et al. 2016), TGF-β/SMAD pathway (Zhang et al. 2018), Notch pathway (Forghanifard et al. 2021), PI3K/AKT pathway (Tang et al. 2022), ERK, STAT3 and NF-κB pathway (Yuan et al. 2016) in various GIT cancers. Since many potential molecular mechanisms are still unknown, extensively exploring new regulators of SALL4 and its targets as promising biomarkers for the diagnosis and therapy of GIT cancers remains valuable and meaningful.
Availability of data and materials
Not applicable.
References
Abada E, Anaya IC, Abada O, Lebbos A, Beydoun R. Colorectal adenocarcinoma with enteroblastic differentiation: diagnostic challenges of a rare case encountered in clinical practice. J Pathol Transl Med. 2022;56(2):97–102.
Abdul-Latif M, Townsend K, Dearman C, Shiu KK, Khan K. Immunotherapy in gastrointestinal cancer: the current scenario and future perspectives. Cancer Treat Rev. 2020;88:102030.
Abouelnazar FA, Zhang X, Zhang J, Wang M, Yu D, Zang X, Zhang J, Li Y, Xu J, Yang Q, Zhou Y, Tang H, Wang Y, Gu J, Zhang X. SALL4 promotes angiogenesis in gastric cancer by regulating VEGF expression and targeting SALL4/VEGF pathway inhibits cancer progression. Cancer Cell Int. 2023a;23(1):149.
Abouelnazar FA, Zhang X, Wang M, Zhang J, Yu D, Zang X, Zhang J, Li Y, Xu J, Yang Q, Zhou Y, Tang H, Wang Y, Gu J, Zhang X. The new advance of SALL4 in cancer: function, regulation, and implication. J Clin Lab Anal. 2023b;37(9–10): e24927.
Ali Syeda Z, Langden SSS, Munkhzul C, Lee M, Song SJ. Regulatory mechanism of MicroRNA expression in cancer. Int J Mol Sci. 2020;21(5):1723.
Ardalan Khales S, Abbaszadegan MR, Abdollahi A, Raeisossadati R, Tousi MF, Forghanifard MM. SALL4 as a new biomarker for early colorectal cancers. J Cancer Res Clin Oncol. 2015;141(2):229–35.
Battista S, Ambrosio MR, Limarzi F, Gallo G, Saragoni L. Molecular alterations in gastric preneoplastic lesions and early gastric cancer. Int J Mol Sci. 2021;22(13):6652.
Bie Q, Li X, Liu S, Yang X, Qian Z, Zhao R, Zhang X, Zhang B. YAP promotes self-renewal of gastric cancer cells by inhibiting expression of L-PTGDS and PTGDR2. Int J Clin Oncol. 2020;25(12):2055–65.
Chai J, Lei Y, Xiang X, Ye J, Zhao H, Yi L. High expression of caspase-8 as a predictive factor of poor prognosis in patients with esophageal cancer. Cancer Med. 2023;12(6):7651–66.
Chan LK, Ho DW, Kam CS, Chiu EY, Lo IL, Yau DT, Cheung ET, Tang CN, Tang VW, Lee TK, Wong CC, Chok KS, Chan AC, Cheung TT, Wong CM, Ng IO. RSK2-inactivating mutations potentiate MAPK signaling and support cholesterol metabolism in hepatocellular carcinoma. J Hepatol. 2021;74(2):360–71.
Chang S, Sun G, Zhang D, Li Q, Qian H. MiR-3622a-3p acts as a tumor suppressor in colorectal cancer by reducing stemness features and EMT through targeting spalt-like transcription factor 4. Cell Death Dis. 2020;11(7):592.
Chen M, Li L, Zheng PS. SALL4 promotes the tumorigenicity of cervical cancer cells through activation of the Wnt/β-catenin pathway via CTNNB1. Cancer Sci. 2019;110(9):2794–805.
Chen D, Zhang M, Ruan J, Li X, Wang S, Cheng X, Zhao H, Zeng Y, Liu J, He K, Zhao P. The long non-coding RNA HOXA11-AS promotes epithelial mesenchymal transition by sponging miR-149-3p in colorectal cancer. J Cancer. 2020;11(20):6050–8.
Chen J, Duan Z, Liu Y, Fu R, Zhu C. Ginsenoside Rh4 suppresses metastasis of esophageal cancer and expression of c-Myc via targeting the Wnt/β-catenin signaling pathway. Nutrients. 2022;14(15):3042.
Cheng J, Deng R, Zhang P, Wu C, Wu K, Shi L, Liu X, Bai J, Deng M, Shuai X, Gao J, Wang G, Tao K. miR-219-5p plays a tumor suppressive role in colon cancer by targeting oncogene Sall4. Oncol Rep. 2015a;34(4):1923–32.
Cheng J, Deng R, Wu C, Zhang P, Wu K, Shi L, Liu X, Bai J, Deng M, Gao J, Shuai X, Wang G, Tao K. Inhibition of SALL4 suppresses carcinogenesis of colorectal cancer via regulating Gli1 expression. Int J Clin Exp Pathol. 2015b;8(9):10092–101.
Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell. 2010;37(3):299–310.
Cohen PE, Gely-Pernot A, Raverdeau M, Teletin M, Vernet N, Féret B, Klopfenstein M, Dennefeld C, Davidson I, Benoit G, Mark M, Ghyselinck NB. Retinoic acid receptors control spermatogonia cell-fate and induce expression of the SALL4A transcription factor. PLoS Genet. 2015;11(10): e1005501.
Cox JL, Mallanna SK, Luo X, Rizzino A. Sox2 uses multiple domains to associate with proteins present in Sox2-protein complexes. PLoS ONE. 2010;5(11): e15486.
De Rosa V, Iommelli F, Monti M, Fonti R, Votta G, Stoppelli MP, Del Vecchio S. Reversal of Warburg effect and reactivation of oxidative phosphorylation by differential inhibition of EGFR signaling pathways in non-small cell lung cancer. Clin Cancer Res. 2015;21(22):5110–20.
Dirican E, Akkiprik M. Functional and clinical significance of SALL4 in breast cancer. Tumour Biol. 2016;37(9):11701–9.
Du L, Xie F, Han H, Zhang L. Targeting SALL4 by entinostat inhibits the malignant phenotype of gastric cancer cells by reducing EMT signaling. Anticancer Res. 2023;43(10):4389–401.
Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005;6(5):322–7.
Fattahi S, Golpour M, Amjadi-Moheb F, Sharifi-Pasandi M, Khodadadi P, Pilehchian-Langroudi M, Ashrafi GH, Akhavan-Niaki H. DNA methyltransferases and gastric cancer: insight into targeted therapy. Epigenomics. 2018;10(11):1477–97.
Forghanifard MM, Moghbeli M, Raeisossadati R, Tavassoli A, Mallak AJ, Boroumand-Noughabi S, Abbaszadegan MR. Role of SALL4 in the progression and metastasis of colorectal cancer. J Biomed Sci. 2013;20(1):6.
Forghanifard MM, Ardalan Khales S, Javdani-Mallak A, Rad A, Farshchian M, Abbaszadegan MR. Stemness state regulators SALL4 and SOX2 are involved in progression and invasiveness of esophageal squamous cell carcinoma. Med Oncol. 2014;31(4):922.
Forghanifard MM, Taleb S, Abbaszadegan MR. Notch signaling target genes are directly correlated to esophageal squamous cell carcinoma tumorigenesis. Pathol Oncol Res. 2015;21(2):463–7.
Forghanifard MM, Kasebi P, Abbaszadegan MR. SOX2/SALL4 stemness axis modulates Notch signaling genes to maintain self-renewal capacity of esophageal squamous cell carcinoma. Mol Cell Biochem. 2021;476(2):921–9.
Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul J-L, Schirmacher P, Vilgrain V. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.
Ghodsi M, Jafarian AH, Montazer M, Sadeghian MH, Forghanifard MM. Diagnostic clinical relevance of developmental pluripotency-associated 2 (DPPA2) in colorectal cancer. Int J Surg. 2015;13:193–7.
Goossens S, Vandamme N, Van Vlierberghe P, Berx G. EMT transcription factors in cancer development re-evaluated: beyond EMT and MET. Biochim Biophys Acta Rev Cancer. 2017;1868(2):584–91.
Gryfe R, Swallow C, Bapat B, Redston M, Gallinger S, Couture J. Molecular biology of colorectal cancer. Curr Probl Cancer. 1997;21(5):233–300.
Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694–8.
Habano W, Sugai T, Jiao YF, Nakamura SI. Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy. Int J Cancer. 2007;121(7):1487–93.
Hao L, Zhao Y, Wang Z, Yin H, Zhang X, He T, Song S, Sun S, Wang B, Li Z, Su Q. Expression and clinical significance of SALL4 and β-catenin in colorectal cancer. J Mol Histol. 2016;47(2):117–28.
Hassouna MM, Naguib M, Radwan EM, Abdel-Samiee M, Estaphan S, Abdelsameea E. DNA methyltransferases as potential biomarkers for HCV related hepatocellular carcinoma. Asian Pac J Cancer Prev. 2020;21(11):3357–63.
He S, Tang S. WNT/beta-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020;132:110851.
He J, Zhou M, Chen X, Yue D, Yang L, Qin G, Zhang Z, Gao Q, Wang D, Zhang C, Huang L, Wang L, Zhang B, Yu J, Zhang Y. Inhibition of SALL4 reduces tumorigenicity involving epithelial-mesenchymal transition via Wnt/β-catenin pathway in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2016;35(1):98.
Hesari A, Rajab S, Rezaei M, Basam M, Golmohamadi S, Ghasemi F. Knockdown of Sal-like 4 expression by siRNA induces apoptosis in colorectal cancer. J Cell Biochem. 2019;120(7):11531–8.
Hu Y, He Y, Liu W, Yu S, Wei Y, Bai S, Su Y, Xiao B. SIAH2 regulates colorectal cancer tumorigenesis via PI3K/ATK signaling pathway. Tissue Cell. 2022;78:101878.
Hua F, Shang S, Yang YW, Zhang HZ, Xu TL, Yu JJ, Zhou DD, Cui B, Li K, Lv XX, Zhang XW, Liu SS, Yu JM, Wang F, Zhang C, Huang B, Hu ZW. TRIB3 interacts with β-catenin and TCF4 to increase stem cell features of colorectal cancer stem cells and tumorigenesis. Gastroenterology. 2019;156(3):708-721.e15.
Huang FL, Yu SJ. Esophageal cancer: risk factors, genetic association, and treatment. Asian J Surg. 2018;41(3):210–5.
Huynh DL, Zhang JJ, Chandimali N, Ghosh M, Gera M, Kim N, Park YH, Kwon T, Jeong DK. SALL4 suppresses reactive oxygen species in pancreatic ductal adenocarcinoma phenotype via FoxM1/Prx III axis. Biochem Biophys Res Commun. 2018;503(4):2248–54.
Hwang J, Haque MA, Suzuki H, Dijke PT, Kato M. THG-1 suppresses SALL4 degradation to induce stemness genes and tumorsphere formation through antagonizing NRBP1 in squamous cell carcinoma cells. Biochem Biophys Res Commun. 2020;523(2):307–14.
Inaguma S, Lasota J, Wang Z, Felisiak-Golabek A, Ikeda H, Miettinen M. Clinicopathologic profile, immunophenotype, and genotype of CD274 (PD-L1)-positive colorectal carcinomas. Mod Pathol. 2017;30(2):278–85.
Iseki H, Nakachi Y, Hishida T, Yamashita-Sugahara Y, Hirasaki M, Ueda A, Tanimoto Y, Iijima S, Sugiyama F, Yagami K-I, Takahashi S, Okuda A, Okazaki Y. Combined overexpression of JARID2, PRDM14, ESRRB, and SALL4A dramatically improves efficiency and kinetics of reprogramming to induced pluripotent stem cells. Stem Cells. 2016;34(2):322–33.
Ishiguro H, Kimura M, Takeyama H. Role of microRNAs in gastric cancer. World J Gastroenterol. 2014;20(19):5694–9.
Islam F, Gopalan V, Wahab R, Smith RA, Lam AK. Cancer stem cells in oesophageal squamous cell carcinoma: identification, prognostic and treatment perspectives. Crit Rev Oncol Hematol. 2015;96(1):9–19.
Jeong YS, Eun YG, Lee SH, Kang SH, Yim SY, Kim EH, Noh JK, Sohn BH, Woo SR, Kong M, Nam DH, Jang HJ, Lee HS, Song S, Oh SC, Lee J, Ajani JA, Lee JS. Clinically conserved genomic subtypes of gastric adenocarcinoma. Mol Cancer. 2023;22(1):147.
Jiang X, Wang Z. miR-16 targets SALL4 to repress the proliferation and migration of gastric cancer. Oncol Lett. 2018;16(3):3005–12.
Johdi NA, Sukor NF. Colorectal cancer immunotherapy: options and strategies. Front Immunol. 2020;11:1624.
Jones B. Liver cancer: SALL4–a cancer marker and target. Nat Rev Clin Oncol. 2013;10(8):426.
Jung J, Park S, Jang Y, Lee S-H, Jeong YS, Yim SY, Lee J-S. Clinical significance of glycolytic metabolic activity in hepatocellular carcinoma. Cancers. 2022;15(1):186.
Khemlina G, Ikeda S, Kurzrock R. The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer. 2017;16(1):149.
Kobayashi D, Kuribayashi K, Tanaka M, Watanabe N. Overexpression of SALL4 in lung cancer and its importance in cell proliferation. Oncol Rep. 2011;26(4):965–70.
Kong NR, Bassal MA, Tan HK, Kurland JV, Yong KJ, Young JJ, Yang Y, Li F, Lee JD, Liu Y, Wu C-S, Stein A, Luo HR, Silberstein LE, Bulyk ML, Tenen DG, Chai L. Zinc finger protein SALL4 functions through an AT-rich motif to regulate gene expression. Cell Rep. 2021;34(1):108574.
Leake I. Cancer: importance of oncofetal gene, SALL4, in a subset of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2013;10(8):441.
Lee EJ, Lee BB, Han J, Cho EY, Shim YM, Park J, Kim DH. CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma. Int J Cancer. 2008;123(9):2073–9.
Li A, Yang Y, Gao C, Lu J, Jeong HW, Liu BH, Tang P, Yao X, Neuberg D, Huang G, Tenen DG, Chai L. A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis. J Clin Invest. 2013;123(10):4195–207.
Li J, Zhang Y, Tao X, You Q, Tao Z, Zhang Y, He Z, Ou J. Knockdown of SALL4 inhibits the proliferation, migration, and invasion of human lung cancer cells in vivo and in vitro. Ann Transl Med. 2020;8(24):1678.
Li Y, Wang M, Yang M, Xiao Y, Jian Y, Shi D, Chen X, Ouyang Y, Kong L, Huang X, Bai J, Hu Y, Lin C, Song L. Nicotine-induced ILF2 facilitates nuclear mRNA export of pluripotency factors to promote stemness and chemoresistance in human esophageal cancer. Cancer Res. 2021;81(13):3525–38.
Liang X, Qin C, Yu G, Guo X, Cheng A, Zhang H, Wang Z. Circular RNA circRAB31 acts as a miR-885-5psponge to suppress gastric cancer progressionvia the PTEN/PI3K/AKT pathway. Mol Ther Oncolytics. 2021;23:501–14.
Liao Y, Yang Z, Huang J, Chen H, Xiang J, Li S, Chen C, He X, Lin F, Yang Z, Wang J. Nuclear receptor binding protein 1 correlates with better prognosis and induces caspase-dependent intrinsic apoptosis through the JNK signalling pathway in colorectal cancer. Cell Death Dis. 2018;9(4):436.
Liebl MC, Hofmann TG. The role of p53 signaling in colorectal cancer. Cancers. 2021;13(9):2125.
Liu T, Shyh-Chang N. Oncofetal SALL4-driven tumorigenesis is highly dependent on oxidative phosphorylation, revealing therapeutic opportunities. Gastroenterology. 2019;157(6):1475–7.
Liu C, Wu H, Li Y, Shen L, Yu R, Yin H, Sun T, Sun C, Zhou Y, Du Z. SALL4 suppresses PTEN expression to promote glioma cell proliferation via PI3K/AKT signaling pathway. J Neurooncol. 2017;135(2):263–72.
Liu Y, Li J, Wang S, Song H, Yu T. STAT4-mediated down-regulation of miR-3619-5p facilitates stomach adenocarcinoma by modulating TBC1D10B. Cancer Biol Ther. 2020;21(7):656–64.
Liu J, Sauer MA, Hussein SG, Yang J, Tenen DG, Chai L. SALL4 and microRNA: the role of Let-7. Genes. 2021;12(9):1301.
Lospinoso Severini L, Loricchio E, Navacci S, Basili I, Alfonsi R, Bernardi F, Moretti M, Conenna M, Cucinotta A, Coni S, Petroni M, De Smaele E, Giannini G, Maroder M, Canettieri G, Mastronuzzi A, Guardavaccaro D, Ayrault O, Infante P, Bufalieri F, Di Marcotullio L. SALL4 is a CRL3(REN/KCTD11) substrate that drives Sonic Hedgehog-dependent medulloblastoma. Cell Death Differ. 2024;31(2):170–87.
Luo Y, Xie C, Brocker CN, Fan J, Wu X, Feng L, Wang Q, Zhao J, Lu D, Tandon M, Cam M, Krausz KW, Liu W, Gonzalez FJ. Intestinal PPARα protects against colon carcinogenesis via regulation of methyltransferases DNMT1 and PRMT6. Gastroenterology. 2019;157(3):744-759.e4.
Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L. SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood. 2006;108(8):2726–35.
Ma S, Jia R, Li D, Shen B. Targeting cellular metabolism chemosensitizes the doxorubicin-resistant human breast adenocarcinoma cells. Biomed Res Int. 2015;2015:453986.
Ma YS, Liu JB, Lin L, Zhang H, Wu JJ, Shi Y, Jia CY, Zhang DD, Yu F, Wang HM, Yin YZ, Jiang XH, Wang PY, Tian LL, Cao PS, Wu XM, Lu HM, Gu LP, Zhang JJ, Cong GJ, Luo P, Zhong XM, Cai B, Shi MX, Zhang SQ, Li L, Zhang WJ, Liu Y, Li ZZ, Wu TM, Wu ZJ, Wang GR, Lv ZW, Ling CC, Chu KJ, Fu D. Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4. Cell Death Discov. 2021;7(1):224.
Milanovich S, Peterson J, Allred J, Stelloh C, Rajasekaran K, Fisher J, Duncan SA, Malarkannan S, Rao S. Sall4 overexpression blocks murine hematopoiesis in a dose-dependent manner. Exp Hematol. 2015;43(1):53-64.e8.
Minato H, Yoshikawa A, Tsuyama S, Katayanagi K, Hayashi K, Sakimura Y, Bando H, Hori T, Kito Y. Ureteral metastasis of colonic adenocarcinoma with enteroblastic differentiation: a rare case to be distinguished from clear cell adenocarcinoma of the urinary tract. Int J Surg Pathol. 2023;31(8):1553–8.
Moein S, Tenen DG, Amabile G, Chai L. SALL4: an intriguing therapeutic target in cancer treatment. Cells. 2022;11(16):2601.
Moeini A, Sia D, Zhang Z, Camprecios G, Stueck A, Dong H, Montal R, Torrens L, Martinez-Quetglas I, Fiel MI, Hao K, Villanueva A, Thung SN, Schwartz ME, Llovet JM. Mixed hepatocellular cholangiocarcinoma tumors: cholangiolocellular carcinoma is a distinct molecular entity. J Hepatol. 2017;66(5):952–61.
Murakami T, Yao T, Yatagai N, Yamashiro Y, Saito T, Sakamoto N, Nagahara A. Colorectal adenocarcinoma with enteroblastic differentiation: a clinicopathological study of five cases. Histopathology. 2019;76(2):325–32.
Nicolè L, Sanavia T, Veronese N, Cappellesso R, Luchini C, Dabrilli P, Fassina A. Oncofetal gene SALL4 and prognosis in cancer: a systematic review with meta-analysis. Oncotarget. 2017;8(14):22968–79.
Nishida N, Sakai K, Morita M, Aoki T, Takita M, Hagiwara S, Komeda Y, Takenaka M, Minami Y, Ida H, Ueshima K, Nishio K, Kudo M. Association between genetic and immunological background of hepatocellular carcinoma and expression of programmed cell death-1. Liver Cancer. 2020;9(4):426–39.
Oikawa T, Kamiya A, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y, Wauthier E, Tajiri H, Miller LD, Wang XW, Reid LM, Nakauchi H. Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. Hepatology. 2013;57(4):1469–83.
Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2(1): a001008.
Park DJ, Sung PS, Kim J-H, Lee GW, Jang JW, Jung ES, Bae SH, Choi JY, Yoon SK. EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer. 2020;8(1): e000301.
Peng HX, Liu XD, Luo ZY, Zhang XH, Luo XQ, Chen X, Jiang H, Xu L. Upregulation of the proto-oncogene Bmi-1 predicts a poor prognosis in pediatric acute lymphoblastic leukemia. BMC Cancer. 2017;17(1):76.
Peng Y, Shen X, Jiang H, Chen Z, Wu J, Zhu Y, Zhou Y, Li J. miR-188-5p suppresses gastric cancer cell proliferation and invasion via targeting ZFP91. Oncol Res. 2018;27(1):65–71.
Peng Z, Zhang Y, Shi D, Jia Y, Shi H, Liu H. miR-497-5p/SALL4 axis promotes stemness phenotype of choriocarcinoma and forms a feedback loop with DNMT-mediated epigenetic regulation. Cell Death Dis. 2021;12(11):1046.
Purkait S, Patra S, Mitra S, Behera MM, Panigrahi MK, Kumar P, Kar M, Hallur V, Chandra Samal S. Elevated expression of DNA methyltransferases and enhancer of zeste homolog 2 in Helicobacter pylori—gastritis and gastric carcinoma. Dig Dis. 2022;40(2):156–67.
Rao S, Zhen S, Roumiantsev S, McDonald LT, Yuan G-C, Orkin SH. Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. Mol Cell Biol. 2023;30(22):5364–80.
Ren F, Weng W, Zhang Q, Tan C, Xu M, Zhang M, Wang L, Sheng W, Ni S, Huang D. Clinicopathological features and prognosis of AFP-producing colorectal cancer: a single-center analysis of 20 cases. Cancer Manag Res. 2019;11:4557–67.
Ren L, Deng H, Jiang Y, Liu C. Dual-regulated mechanism of EZH2 and KDM6A on SALL4 modulates tumor progression via Wnt/β-catenin pathway in gastric cancer. Dig Dis Sci. 2023;68(4):1292–305.
Sahgal P, Huffman BM, Patil DT, Chatila WK, Yaeger R, Cleary JM, Sethi NS. Early TP53 alterations shape gastric and esophageal cancer development. Cancers. 2021;13(23):5915.
Sahin IH, Akce M, Alese O, Shaib W, Lesinski GB, El-Rayes B, Wu C. Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms. Br J Cancer. 2019;121(10):809–18.
Sajadi M, Fazilti M, Nazem H, Mahdevar M, Ghaedi K. The expression changes of transcription factors including ANKZF1, LEF1, CASZ1, and ATOH1 as a predictor of survival rate in colorectal cancer: a large-scale analysis. Cancer Cell Int. 2022;22(1):339.
Shao M, Zhang J, Zhang J, Shi H, Zhang Y, Ji R, Mao F, Qian H, Xu W, Zhang X. SALL4 promotes gastric cancer progression via hexokinase II mediated glycolysis. Cancer Cell Int. 2020;20:188.
Sharbatoghli M, Shamshiripour P, Fattahi F, Kalantari E, Habibi Shams Z, Panahi M, Totonchi M, Asadi-Lari Z, Madjd Z, Saeednejad Zanjani L. Co-expression of cancer stem cell markers, SALL4/ALDH1A1, is associated with tumor aggressiveness and poor survival in patients with serous ovarian carcinoma. J Ovarian Res. 2022;15(1):17.
Shen B, Zhang Y, Dai W, Ma Y, Jiang Y. Ex-vivo expansion of nonhuman primate CD34+ cells by stem cell factor Sall4B. Stem Cell Res Ther. 2016;7(1):152.
Shen Y, Zhang N, Chai J, Wang T, Ma C, Han L, Yang M. CircPDIA4 induces gastric cancer progression by promoting ERK1/2 activation and enhancing biogenesis of oncogenic circRNAs. Cancer Res. 2023;83(4):538–52.
Shi D-M, Shi X-L, Xing K-L, Zhou H-X, Lu L-L, Wu W-Z. miR-296-5p suppresses stem cell potency of hepatocellular carcinoma cells via regulating Brg1/Sall4 axis. Cell Signal. 2020;72:109650.
Shoji Y, Furuhashi S, Kelly DF, Bilchik AJ, Hoon DSB, Bustos MA. Current status of gastrointestinal tract cancer brain metastasis and the use of blood-based cancer biomarker biopsy. Clin Exp Metastasis. 2022;39(1):61–9.
Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020;70(3):145–64.
Smyth EC, Lagergren J, Fitzgerald RC, Lordick F, Shah MA, Lagergren P, Cunningham D. Oesophageal Cancer. Nat Rev Dis Primers. 2017;3:17048.
Song B, Li H, Guo S, Yang T, Li L, Cao L, Wang J. LINC00882 plays a tumor-promoter role in colorectal cancer by targeting miR-3619-5p to up-regulate CTNNB1. Arch Med Res. 2022;53(1):29–36.
Su JF, Zhao F, Gao ZW, Hou YJ, Li YY, Duan LJ, Lun SM, Yang HJ, Li JK, Dai NT, Shen FF, Zhou FY. piR-823 demonstrates tumor oncogenic activity in esophageal squamous cell carcinoma through DNA methylation induction via DNA methyltransferase 3B. Pathol Res Pract. 2020;216(4):152848.
Sugai T, Habano W, Takagi R, Yamano H, Eizuka M, Arakawa N, Takahashi Y, Yamamoto E, Kawasaki K, Yanai S, Ishida K, Suzuki H, Matsumoto T. Analysis of molecular alterations in laterally spreading tumors of the colorectum. J Gastroenterol. 2016;52(6):715–23.
Sun B, Xu L, Bi W, Ou WB. SALL4 oncogenic function in cancers: mechanisms and therapeutic relevance. Int J Mol Sci. 2022;23(4):2053.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
Tamura G, Yin J, Wang S, Fleisher AS, Zou T, Abraham JM, Kong D, Smolinski KN, Wilson KT, James SP, Silverberg SG, Nishizuka S, Terashima M, Motoyama T, Meltzer SJ. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst. 2000;92(7):569–73.
Tan JL, Li F, Yeo JZ, Yong KJ, Bassal MA, Ng GH, Lee MY, Leong CY, Tan HK, Wu CS, Liu BH, Chan TH, Tan ZH, Chan YS, Wang S, Lim ZH, Toh TB, Hooi L, Low KN, Ma S, Kong NR, Stein AJ, Wu Y, Thangavelu MT, Suzuki A, Periyasamy G, Asara JM, Dan YY, Bonney GK, Chow EK, Lu GD, Ng HH, Kanagasundaram Y, Ng SB, Tam WL, Tenen DG, Chai L. New high-throughput screening identifies compounds that reduce viability specifically in liver cancer cells that express high levels of SALL4 by inhibiting oxidative phosphorylation. Gastroenterology. 2019;157(6):1615-1629.e17.
Tanaka Y, Aishima S, Kohashi K, Okumura Y, Wang H, Hida T, Kotoh K, Shirabe K, Maehara Y, Takayanagi R, Oda Y. Spalt-like transcription factor 4 immunopositivity is associated with epithelial cell adhesion molecule expression in combined hepatocellular carcinoma and cholangiocarcinoma. Histopathology. 2015;68(5):693–701.
Tang Q, Chen J, Di Z, Yuan W, Zhou Z, Liu Z, Han S, Liu Y, Ying G, Shu X, Di M. TM4SF1 promotes EMT and cancer stemness via the Wnt/β-catenin/SOX2 pathway in colorectal cancer. J Exp Clin Cancer Res. 2020;39(1):232.
Tang Z, Zhao P, Zhang W, Zhang Q, Zhao M, Tan H. SALL4 activates PI3K/AKT signaling pathway through targeting PTEN, thus facilitating migration, invasion and proliferation of hepatocellular carcinoma cells. Aging. 2022;14(24):10081–92.
Tatetsu H, Kong NR, Chong G, Amabile G, Tenen DG, Chai L. SALL4, the missing link between stem cells, development and cancer. Gene. 2016;584(2):111–9.
Thrift AP, El-Serag HB. Burden of gastric cancer. Clin Gastroenterol Hepatol. 2020;18(3):534–42.
Ueno S, Lu J, He J, Li A, Zhang X, Ritz J, Silberstein LE, Chai L. Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target. Exp Hematol. 2014;42(4):307-316.e8.
Vienot A, Monnien F, Truntzer C, Mougey V, Bouard A, Pallandre JR, Molimard C, Loyon R, Asgarov K, Averous G, Ghiringhelli F, Bibeau F, Peixoto P, Borg C. SALL4-related gene signature defines a specific stromal subset of pancreatic ductal adenocarcinoma with poor prognostic features. Mol Oncol. 2023;17(7):1356–78.
Wang F, Gao C, Lu J, Tatetsu H, Williams DA, Müller LU, Cui W, Chai L. Leukemic survival factor SALL4 contributes to defective DNA damage repair. Oncogene. 2016;35(47):6087–95.
Wang H, Kohashi K, Yoshizumi T, Okumura Y, Tanaka Y, Shimokawa M, Iwasaki T, Aishima S, Maehara Y, Oda Y. Coexpression of SALL4 with HDAC1 and/or HDAC2 is associated with underexpression of PTEN and poor prognosis in patients with hepatocellular carcinoma. Hum Pathol. 2017;64:69–75.
Wang J, Garancher A, Ramaswamy V, Wechsler-Reya RJ. Medulloblastoma: from molecular subgroups to molecular targeted therapies. Annu Rev Neurosci. 2018;41:207–32.
Wang M, Qiu R, Gong Z, Zhao X, Wang T, Zhou L, Lu W, Shen B, Zhu W, Xu W. miR-188-5p emerges as an oncomiRNA to promote gastric cancer cell proliferation and migration via upregulation of SALL4. J Cell Biochem. 2019a;120(9):15027–37.
Wang J, Huang J, Ma Q, Liu G. Association between quantitative parameters of CEUS and Sall4/Wnt/β-catenin signaling in patients with hepatocellular carcinoma. Cancer Manag Res. 2019b;11:3339–47.
Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers. 2019c;11(7):926.
Wang W, He S, Zhang R, Peng J, Guo D, Zhang J, Xiang B, Li L. ALDH1A1 maintains the cancer stem-like cells properties of esophageal squamous cell carcinoma by activating the AKT signal pathway and interacting with β-catenin. Biomed Pharmacother. 2020;125:109940.
Wang B, Xie Y, Zheng L, Zheng X, Gao J, Liu X, Yuan Y, Li Z, Lu N, Xue L. Both the serum AFP test and AFP/GPC3/SALL4 immunohistochemistry are beneficial for predicting the prognosis of gastric adenocarcinoma. BMC Gastroenterol. 2021a;21(1):408.
Wang Q, Liang N, Yang T, Li Y, Li J, Huang Q, Wu C, Sun L, Zhou X, Cheng X, Zhao L, Wang G, Chen Z, He X, Liu C. DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer. J Hepatol. 2021b;75(5):1142–53.
Wang Q, Feng J, Tang L. Non-coding RNA related to MAPK signaling pathway in liver cancer. Int J Mol Sci. 2022a;23(19):11908.
Wang L, Tan X, Chen L, Xu S, Huang W, Chen N, Wu Y, Wang C, Zhou D, Li M. Sall4 guides p53-mediated enhancer interference upon DNA damage in mouse embryonic stem cells. Stem Cells. 2022b;40(11):1008–19.
Wang J, Yu H, Dong W, Zhang C, Hu M, Ma W, Jiang X, Li H, Yang P, Xiang D. N6-Methyladenosine-mediated up-regulation of FZD10 regulates liver cancer stem cells’ properties and lenvatinib resistance through WNT/beta-catenin and hippo signaling pathways. Gastroenterology. 2023;164(6):990–1005.
Wilson CH, Crombie C, van der Weyden L, Poulogiannis G, Rust AG, Pardo M, Gracia T, Yu L, Choudhary J, Poulin GB, McIntyre RE, Winton DJ, March HN, Arends MJ, Fraser AG, Adams DJ. Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation. EMBO J. 2012;31(11):2486–97.
Wood LD, Hruban RH. Pathology and molecular genetics of pancreatic neoplasms. Cancer J. 2012;18(6):492–501.
Wu M, Yang F, Ren Z, Jiang Y, Ma Y, Chen C-Y, Dai W. Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor. Cell Cycle. 2014;13(9):1456–62.
Wu HK, Liu C, Fan XX, Wang H, Zhou L. Spalt-like transcription factor 4 as a potential diagnostic and prognostic marker of colorectal cancer. Cancer Biomark. 2017;20(2):191–8.
Xia H, Niu Q, Ding Y, Zhang Z, Yuan J, Jin W. Long noncoding HOXA11-AS knockdown suppresses the progression of non-small cell lung cancer by regulating miR-3619-5p/SALL4 axis. J Mol Histol. 2021;52(4):729–40.
Xie G, Dong P, Chen H, Xu L, Liu Y, Ma Y, Zheng Y, Yang J, Zhou Y, Chen L, Shen L. Decreased expression of ATF3, orchestrated by β-catenin/TCF3, miR-17-5p and HOXA11-AS, promoted gastric cancer progression via increased β-catenin and CEMIP. Exp Mol Med. 2021;53(11):1706–22.
Xiong J, Zhang Z, Chen J, Huang H, Xu Y, Ding X, Zheng Y, Nishinakamura R, Xu G-L, Wang H, Chen S, Gao S, Zhu B. Cooperative action between SALL4A and TET proteins in stepwise oxidation of 5-methylcytosine. Mol Cell. 2016;64(5):913–25.
Yamashiro Y, Saito T, Hayashi T, Murakami T, Yanai Y, Tsuyama S, Suehara Y, Takamochi K, Yao T. Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation. Histopathology. 2020;77(3):492–502.
Yan TT, Ren LL, Shen CQ, Wang ZH, Yu YN, Liang Q, Tang JY, Chen YX, Sun DF, Zgodzinski W, Majewski M, Radwan P, Kryczek I, Zhong M, Chen J, Liu Q, Zou W, Chen HY, Hong J, Fang JY. miR-508 defines the stem-like/mesenchymal subtype in colorectal cancer. Cancer Res. 2018;78(7):1751–65.
Yang J. SALL4 as a transcriptional and epigenetic regulator in normal and leukemic hematopoiesis. Biomark Res. 2018;6:1.
Yang M, Huang CZ. Mitogen-activated protein kinase signaling pathway and invasion and metastasis of gastric cancer. World J Gastroenterol. 2015;21(41):11673–9.
Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y. Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA. 2007;104(25):10494–9.
Yang J, Corsello TR, Ma Y. Stem cell gene SALL4 suppresses transcription through recruitment of DNA methyltransferases. J Biol Chem. 2012;287(3):1996–2005.
Yang Y, Wang X, Liu Y, Hu Y, Li Z, Li Z, Bu Z, Wu X, Zhang L, Ji J. Up-regulation of SALL4 is associated with survival and progression via putative WNT pathway in gastric cancer. Front Cell Dev Biol. 2021a;9:600344.
Yang C, Chen C, Xiao Q, Wang X, Shou Y, Tian X, Wang S, Li H, Liang Y, Shu J, Chen K, Sun M. Relationship between PTEN and angiogenesis of esophageal squamous cell carcinoma and the underlying mechanism. Front Oncol. 2021b;11:739297.
Yang C, Zhang X, Gao C, Du K, Liu Y. NRBP1 negatively regulates SALL4 to reduce the invasion and migration, promote apoptosis and increase the sensitivity to chemotherapy drugs of breast cancer cells. Oncol Lett. 2022;23(4):139.
Yang X, Wu Y, Wang A, Ma X, Zhou K, Ji K, Ji X, Zhang J, Wu X, Li Z, Bu Z. Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases. J Pathol Clin Res. 2024;10(1): e343.
Ye G, Yang Q, Lei X, Zhu X, Li F, He J, Chen H, Ling R, Zhang H, Lin T, Liang Z, Liang Y, Huang H, Guo W, Deng H, Liu H, Hu Y, Yu J, Li G. Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis. Theranostics. 2020;10(17):7545–60.
Yin F, Han X, Yao S-K, Wang X-L, Yang H-C. Importance of SALL4 in the development and prognosis of hepatocellular carcinoma. World J Gastroenterol. 2016;22(9):2837.
Yin C, Han Q, Xu D, Zheng B, Zhao X, Zhang J. SALL4-mediated upregulation of exosomal miR-146a-5p drives T-cell exhaustion by M2 tumor-associated macrophages in HCC. Oncoimmunology. 2019;8(7):1601479.
Yong KJ, Gao C, Lim JS, Yan B, Yang H, Dimitrov T, Kawasaki A, Ong CW, Wong KF, Lee S, Ravikumar S, Srivastava S, Tian X, Poon RT, Fan ST, Luk JM, Dan YY, Salto-Tellez M, Chai L, Tenen DG. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma. N Engl J Med. 2013;368(24):2266–76.
You L, Wu Q, Xin Z, Zhong H, Zhou J, Jiao L, Song X, Ying B. The long non-coding RNA HOXA11-AS activates ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Cancer Cell Int. 2021;21(1):576.
Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther. 2021;6(1):307.
Yuan X, Zhang X, Zhang W, Liang W, Zhang P, Shi H, Zhang B, Shao M, Yan Y, Qian H, Xu W. SALL4 promotes gastric cancer progression through activating CD44 expression. Oncogenesis. 2016;5(11): e268.
Zargari S, Negahban Khameneh S, Rad A, Forghanifard MM. MEIS1 promotes expression of stem cell markers in esophageal squamous cell carcinoma. BMC Cancer. 2020;20(1):789.
Zeng SS, Yamashita T, Kondo M, Nio K, Hayashi T, Hara Y, Nomura Y, Yoshida M, Hayashi T, Oishi N, Ikeda H, Honda M, Kaneko S. The transcription factor SALL4 regulates stemness of EpCAM-positive hepatocellular carcinoma. J Hepatol. 2014;60(1):127–34.
Zhang X, Yuan X, Zhu W, Qian H, Xu W. SALL4: an emerging cancer biomarker and target. Cancer Lett. 2015;357(1):55–62.
Zhang X, Zhang P, Shao M, Zang X, Zhang J, Mao F, Qian H, Xu W. SALL4 activates TGF-β/SMAD signaling pathway to induce EMT and promote gastric cancer metastasis. Cancer Manag Res. 2018;10:4459–70.
Zhang Q, Wang X, Cao S, Sun Y, He X, Jiang B, Yu Y, Duan J, Qiu F, Kang N. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed Pharmacother. 2020;128:110245.
Zhang L, Yao L, Zhou W, Tian J, Ruan B, Lu Z, Deng Y, Li Q, Zeng Z, Yang D, Shang R, Xu M, Zhang M, Cheng D, Yang Y, Ding Q, Yu H. miR-497 defect contributes to gastric cancer tumorigenesis and progression via regulating CDC42/ITGB1/FAK/PXN/AKT signaling. Mol Ther Nucleic Acids. 2021;25:567–77.
Zhang W, Hu Y, Zhang W, Yi K, Xu X, Chen Z. The invasion and metastasis of colon adenocarcinoma (COAD) induced by SALL4. J Immunol Res. 2022;2022:9385820.
Zhao B, Wang Y, Tan X, Ke K, Zheng X, Wang F, Lan S, Liao N, Cai Z, Shi Y, Zheng Y, Lai Y, Wang L, Li Q, Liu J, Huang A, Liu X. Inflammatory micro-environment contributes to stemness properties and metastatic potential of HCC via the NF-kappaB/miR-497/SALL4 Axis. Mol Ther Oncolytics. 2019;15:79–90.
Zheng ST, Huo Q, Tuerxun A, Ma WJ, Lv GD, Huang CG, Liu Q, Wang X, Lin RY, Sheyhidin I, Lu XM. The expression and activation of ERK/MAPK pathway in human esophageal cancer cell line EC9706. Mol Biol Rep. 2011;38(2):865–72.
Zhong L, Li H, Chang W, Ao Y, Wen Z, Chen Y. TP53 mutations in esophageal squamous cell carcinoma. Front Biosci. 2023;28(9):219.
Zhou S, Venkatramani R, Gomulia E, Shillingford N, Wang L. The diagnostic and prognostic value of SALL4 in hepatoblastoma. Histopathology. 2016;69(5):822–30.
Zhou C, Yi C, Yi Y, Qin W, Yan Y, Dong X, Zhang X, Huang Y, Zhang R, Wei J, Ali DW, Michalak M, Chen XZ, Tang J. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/beta-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes. Mol Cancer. 2020;19(1):118.
Zhou C, Liang Y, Zhou L, Yan Y, Liu N, Zhang R, Huang Y, Wang M, Tang Y, Ali DW, Wang Y, Michalak M, Chen XZ, Tang J. TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the MIR454-FAM83A-TSPAN1 axis in pancreatic cancer. Autophagy. 2021;17(10):3175–95.
Zhou J, Peng S, Fan H, Li J, Li Z, Wang G, Zeng L, Guo Z, Lai Y, Huang H. SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway. Cancer Med. 2023;12(12):13471–85.
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This work was supported by the Opening Project of the State Key Laboratory of Esophageal Cancer Prevention and Treatment [K2022-007], the College Students’ Innovation and Entrepreneurship Training Programs of Henan Province [202210472030], and the Doctoral Research Fund Program of Xinxiang Medical University [YBSKYZZ202004].
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Y.T. contributed to the conception and design of the manuscript; T.W. wrote the first draft of the manuscript; Y.T., L.W. and X.C. revised and edited the manuscript; T.W., Y.J., M.W. and B.C. performed the literature search and made the tables; J.S., J.Z., H.Y and X.D. prepared the graphics. All authors read and approved the final manuscript.
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Wang, T., Jin, Y., Wang, M. et al. SALL4 in gastrointestinal tract cancers: upstream and downstream regulatory mechanisms. Mol Med 30, 46 (2024). https://0-doi-org.brum.beds.ac.uk/10.1186/s10020-024-00812-z
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DOI: https://0-doi-org.brum.beds.ac.uk/10.1186/s10020-024-00812-z