Department of Gastroenterology, Shenzhen Hospital of Southern Medical University, Shenzhen, People's Republic of China.
Division of Science and Technology, Program of Food Science and Technology, 125809BNU-HKBU United International College, Tangjiawan, Zhuhai, Guangdong, People's Republic of China.
Technol Cancer Res Treat. 2020 Jan-Dec;19:1533033820945302. doi: 10.1177/1533033820945302.
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.
癌症干细胞是癌症细胞中的一个特殊亚群，具有自我更新能力和多向分化潜能，可能通过癌细胞去分化重新编程而来，这有助于解释临床治疗失败的原因。食管腺癌在脱氧胆酸刺激的炎症环境中生长，脱氧胆酸是胃食管反流内容物的重要组成部分，有助于食管鳞状上皮向食管腺癌癌前病变——巴雷特食管的转化。在本研究中，使用脱氧胆酸来研究其是否能诱导重编程因子 Krüppel 样因子、OCT4 和 Nanog 的表达；诱导食管腺癌向癌症干细胞的转化；以及白细胞介素-6/信号转导和转录激活因子 3 炎症信号通路的参与。OE33 细胞用脱氧胆酸（250μM）处理 0 小时、3 小时、6 小时和 12 小时，然后通过逆转录-定量聚合酶链反应评估 Krüppel 样因子、OCT4、Nanog、白细胞介素-6 和 Bcl-xL 的信使 RNA 表达。通过酶联免疫吸附试验检测白细胞介素-6 蛋白，通过 Western blot 检测信号转导和转录激活因子 3、磷酸化信号转导和转录激活因子 3、Krüppel 样因子和 OCT4。用信号转导和转录激活因子 3 小干扰 RNA 和人重组白细胞介素-6 处理 OE33 细胞，检测其对 Krüppel 样因子、OCT4、Nanog、CD44、低氧诱导因子 1-α 和 Bcl-xL 表达的影响。结果表明，脱氧胆酸促进了重编程因子 Krüppel 样因子和 OCT4 的表达，这是由白细胞介素-6/信号转导和转录激活因子 3 信号通路调节的。脱氧胆酸对食管腺癌干细胞的转化具有致癌作用，提高了肿瘤的抗凋亡能力，增加了食管腺癌的恶性程度。失活白细胞介素-6/信号转导和转录激活因子 3 的调节信号通路和中和脱氧胆酸可能是提高食管腺癌治疗临床疗效的新靶点。
