Deoxycholic Acid Upregulates the Reprogramming Factors KFL4 and OCT4 Through the IL-6/STAT3 Pathway in Esophageal Adenocarcinoma Cells.

Abstract

Cancer stem cells, a special subgroup of cancer cells, have self-renewal capabilities and multidirectional potential, which may be reprogrammed from the dedifferentiation of cancer cells, contributing to the failure of clinical treatments. Esophageal adenocarcinoma grows in an inflammatory environment stimulated by deoxycholic acid, an important component of gastroesophageal reflux content, contributing to the transformation of esophageal squamous epithelium to the precancerous lesions of esophageal adenocarcinoma, that is, Barrett esophagus. In the present study, deoxycholic acid was used to investigate whether it could induce the expression of reprogramming factors Krüppel-like factor, OCT4, and Nanog; the transformation to cancer stem cells in esophageal adenocarcinoma; and the involvement of the interleukin-6/signal transduction and activation of transcription 3 inflammatory signaling pathway. OE33 cells were treated with deoxycholic acid (250 μM) for 0 hour, 3 hours, 6 hours, and 12 hours before evaluating the messenger RNA expression of Krüppel-like factor, OCT4, Nanog, interleukin-6, and Bcl-xL by reverse transcription-quantitative polymerase chain reaction. Interleukin-6 protein was detected by enzyme linked immunosorbent assay, while signal transduction and activation of transcription 3, phosphorylated signal transduction and activation of transcription 3, Krüppel-like factor, and OCT4 were detected by Western blot. Signal transduction and activation of transcription 3 small interfering RNA and human recombinant interleukin-6 were used to treat OE33 cells and to detect their effects on Krüppel-like factor, OCT4, Nanog, CD44, hypoxia-inducible factor 1-α, and Bcl-xL expression. Results showed that deoxycholic acid promotes the expression of reprogramming factors Krüppel-like factor and OCT4, which are regulated by the interleukin-6/signal transduction and activation of transcription 3 signaling pathway. Deoxycholic acid has a malignancy-inducing effect on the transformation of esophageal adenocarcinoma stem cells, improving the antiapoptotic ability of tumors, and increasing the malignancy of esophageal adenocarcinoma. Deactivating the regulatory signaling pathway of interleukin-6/signal transduction and activation of transcription 3 and neutralizing deoxycholic acid may be novel targets for improving the clinical efficacy of esophageal adenocarcinoma therapy.