MicroRNA-148a and -152 counteract RIPK1-mediated apoptosis and necroptosis to promote cancer cell proliferation and cisplatin resistance

Abstract Evasion of cell death is a hallmark of cancer cells. Receptor-interacting protein kinase 1 (RIPK1) is a common mediator in cancer cell death signaling pathways of apoptosis and necroptosis. MicroRNAs (miRNAs) are non-coding small RNAs that are involved in various biological processes such as cell proliferation and death by regulating target genes. Here, we identified miR-148a and miR-152 as suppressors of TNF-induced apoptosis based on the screening of apoptosis-regulating miRNAs. Elevated expression of miR-148a or miR-152 blocks cellular activation of caspase-8 and caspase-3 in multiple cancer cells. Moreover, overexpression of miR-148a or miR-152 inhibits TNF-induced necroptosis as well as cellular activation of RIPK1, RIPK3 and MLKL. We found that both miR-148a and miR-152 downregulate the expression of RIPK1, an essential regulator of both TNF-induced apoptosis and necroptosis. MiR-148a and miR-152 directly target the 3’UTR of RIPK1 to inhibit RIPK1 expression. Importantly, miR-148a or miR-152 overexpression promotes colony formation in multiple types of cancer cells. Of note, Kaplan-Meier Plotter analysis reveals that gastric carcinoma patients with high miR-152 expression are associated with lower overall survival. Overexpression of miR-148a or miR-152 significantly counteracts the chemotherapy drug cisplatin-induced RIPK1-mediated cell death and promotes gastric cancer cell survival and proliferation. These findings demonstrate the miR-148a and miR-152 as a class of oncogenic miRNAs capable of evading apoptosis and necroptosis via the suppression of RIPK1. Our study also suggests the miR-148a and miR-152 as a potential anti-cancer target for overcoming cell death resistance to chemotherapy drugs such as cisplatin.