The Upregulation of OCT4 in Acidic Extracellular pH is Associated with Gemcitabine Resistance in Cholangiocarcinoma Cell Lines

Abstract

Background: Cholangiocarcinoma (CCA), although is an uncommon liver cancer originating from bile duct epithelial cells, is one of the top 10 most fatal cancers. Chemoresistance is an unmet need always found in CCA patients. Tumor microenvironment conditions such as hypoxia, nutrient starvation and acidic extracellular pH play critical roles in chemoresistance and cancer progression. However, the effect of acidic extracellular pH on cellular response and chemoresistance in CCA has not been studied. Methods: Human CCA cell lines (KKU-M213, KKU-M055 and KKU-100) were cultured under acidic (pH 6.5) or non-acidic (pH 7.4) condition and were used for gene expression, doubling time and cytotoxicity assay. Results: The acidic extracellular pH (pH 6.5) significantly increased doubling times of CCA cell lines compared with non-acidic condition (pH 7.4). Interestingly, extracellular acid condition induced gemcitabine resistance in CCA cell lines. We showed that Octamer-binding transcription factor 4 (Oct4) was upregulated in these cell lines under extracellular acid condition. Conclusion: Our findings demonstrate that CCA cells can adapt to survive in acidic environment after which chemoresistance has been developed. Oct4 may be a key transcriptional regulator which mediates chemoresistance in response to acidic extracellular pH.