A let-7/Fas double-negative feedback loop regulates human colon carcinoma cells sensitivity to Fas-related apoptosis

• Published in: Biochemical and biophysical research communications Vol. 408; no. 3; pp. 494 - 499
• Main Authors: Geng, Li, Zhu, Bin, Dai, Bing-Hua, Sui, Cheng-Jun, Xu, Feng, Kan, Tong, Shen, Wei-Feng, Yang, Jia-Mei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.05.2011
• Subjects: 3' Untranslated Regions; Animals; Apoptosis; Carcinoma - genetics; Carcinoma - immunology; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Fas; Fas ligand; fas Receptor - biosynthesis; fas Receptor - genetics; FasL; Feedback, Physiological; Female; Humans; IFN-γ; Interferon-gamma - immunology; Interferon-gamma - pharmacology; interferon-γ; Let-7; mAb CH11; Mice; Mice, Nude; microRNA; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; monoclonal antibody CH11; NC; negative control; pre-miRNA; precursor microRNA; pri-miRNA; primary transcript of microRNA; TNF-α; tumor necrosis factor-α; IFN-γ; TNF-α; FasL; mAb CH11; NC; Interferon-γ; pre-miRNA; Fas; microRNA; Let-7; pri-miRNA; Apoptosis
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2011.04.074

► Let-7/Fas form a double-negative feedback loop which regulates Fas-mediated apoptosis. ► Fas activation suppresses Dicer processing and let-7 microRNA biogenesis. ► Let-7 inhibitor sensitizes colon carcinoma cells to Fas-related apoptosis. Interferon-γ (IFN-γ) is considered essential for the regulation of anti-tumor reactions as it sensitizes Fas-related apoptosis in HT29 cells, but the mechanism is unclear. In the current study, our data demonstrated that IFN-γ stimulation and Fas activation suppressed Dicer processing and let-7 microRNA biogenesis, while let-7 microRNA strongly inhibited Fas expression by directly targeting Fas mRNA. Accordingly, our results indicate that Fas and let-7 microRNAs form a double-negative feedback loop in IFN-γ and Fas induced apoptosis in colon carcinoma cell line HT29, which may be an important synergistic mechanism in anti-tumor immune response. We also found that a let-7 microRNA inhibitor increased Fas expression and sensitized cells to Fas-related apoptosis, which may have future implications in colon carcinoma therapy.