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The role of hypoxia response element in TGFβ-induced carbonic anhydrase IX expression in Hep3B human hepatoma cells

Yildirim Hatice (University of Balikesir, Faculty of Science and Literature, Department of Molecular Biology and Genetics, Balikesir, Turkey)
Karaman Merve (University of Balikesir, Faculty of Science and Literature, Department of Molecular Biology and Genetics, Balikesir, Turkey)
Köçkar Feray (University of Balikesir, Faculty of Science and Literature, Department of Molecular Biology and Genetics, Balikesir, Turkey)

Carbonic anhydrase IX (CAIX) is a hypoxia-regulated gene. It is over expressed in a variety of cancers, including hepatocellular cancer. Transforming growth factor β (TGFβ) is considered to have an impact on cancer biology due to its important roles in cell proliferation and differentiation. The effect of the TGFβ on CAIX expression under hypoxia and the mechanism underlying the role of the hypoxia response element (HRE) on this expression are unknown. In this study, we demonstrate that TGFβ upregulates CAIX expression under hypoxic conditions in the Hep3B hepatoma cell line, indicating that the mitogen-activated protein kinase (MAPK)- and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-signaling pathways might be responsible for this response. Site-directed mutagenesis of the HRE region in CAIX promoter reduced the TGFβ-induced CAIX promoter activity, pointing to the significance of HRE for this response. Up regulation of TGFβ-stimulated CAIX expression was consistent with the up regulation of promoter activity of five different truncated constructs of the CAIX promoter under hypoxia. Our findings show that the HRE region is critical for TGFβ-induced CAIX expression, which is mainly controlled by MAPK and PI3K pathways.

Keywords: carbonic anhydrase IX (CAIX), hypoxia response element (HRE), transforming growth factor β (TGFβ), mitogen-activated protein kinase (MAPK) signaling, phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling