Fas signaling induces stemness properties in colorectal cancer by regulation of Bmi1

• DOI: 10.1002/mc.22680
• Publication Date: 2017-05-25T17:22:52Z
• Authors: Jiaxuan Chen; Yadong Wang; Linghao Zhuo; Zhizhong Liu; Tao Liu; Wenjing Li; Yidong Cai; Haoxuan Zheng
• Keywords: Polycomb Repressive Complex 1; 0301 basic medicine; Epithelial-Mesenchymal Transition; Fas Ligand Protein; Cell Survival; Zinc Finger E-box-Binding Homeobox 1; Apoptosis; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; 03 medical and health sciences; Cell Line, Tumor; Neoplastic Stem Cells; Humans; Colorectal Neoplasms; Promoter Regions, Genetic; 3' Untranslated Regions; beta Catenin; Cell Proliferation; Signal Transduction

Fas signaling promotes colorectal cancer (CRC) metastasis by inducing epithelial‐mesenchymal transition (EMT). The acquisition of EMT properties in turn induces stemness but the mechanism by which Fas signaling contributes to it still remains unclear. Hence, the aim of this study was to investigate how Fas signaling regulates CRC stemness. For this purpose, soft agar assay, sphere formation assay, cell survival analysis, immunoblot, qRT‐PCR, chromatin immunoprecipitation, and luciferase reporter assay were performed. Expression of FasL, Bmi1, and the miR‐200c in CRC specimens was examined through immunohistochemistry, qRT‐PCR, and immunoblot. In our study, Fas signaling induced stem cell properties in CRC specimens, relying on ERK1/2 MAPK pathway, with Bmi1 being mainly responsible for FasL‐induced stemness. FasL treatment promoted Bmi1 expression by inhibiting miR‐200c, which targets Bmi1 3′UTR region. Furthermore, FasL‐induced Zeb1 binded with miR‐200c promoter and inhibited its expression. Moreover, FasL‐induced β‐catenin nuclear expression promoted Zeb1 expression by binding with Zeb1 promoter. GSK‐3β, which regulates β‐catenin, was inhibited by FasL‐induced ERK1/2 MAPK signaling. Finally, FasL and Bmi1 expression in clinical samples increased during CRC progression, and a positive correlation between them was observed. Patients with high FasL and Bmi1 expression had a worse prognosis than patients with low expression. In conclusion, our results showed that Fas signaling can promote stemness in CRC through the modulation of Bmi1 expression via the ERK1/2 MAPK/GSK‐3β/β‐catenin/Zeb1/miR‐200c axis, suggesting that Fas signaling‐based cancer therapies should be administered cautiously, as the activation of this pathway not only leads to apoptosis but also induces stemness in CRC.