The miR‐148/152 Family Suppresses Apoptosis and Necroptosis for Cancer Evasion Through Direct RIPK1 Repression

Evasion of programmed cell death, including apoptosis and necroptosis, is a critical hallmark of cancer that contributes to tumorigenesis and chemoresistance. While microRNAs (miRNAs) are known to modulate cell death pathways, the role of specific miRNA families in coordinated death resistance remains incompletely understood. Through functional screening, we identified the miR-148/152 family as potent suppressors of tumor necrosis factor (TNF)-induced cell death, prompting an investigation into their regulatory mechanism in both apoptosis and necroptosis and their oncogenic role. Ectopic expression of miR-148a or miR-152 inhibits TNF-induced apoptosis and necroptosis in multiple human cancer cell lines, accompanied by reduced activation of caspase-8, caspase-3, RIPK1, and RIPK3. Mechanistically, the miR-148/152 family directly target the 3'UTR of RIPK1, which is a critical regulator in TNF-mediated cell death, thus downregulating its expression. Functionally, miR-152 enhances cancer cell proliferation and colony formation. Clinically, high expression of miR-152 correlates with poor prognosis in gastric cancer patients. Importantly, this miRNA confers resistance to cisplatin-induced, RIPK1-mediated cell death, promoting gastric cancer cell survival and proliferation. Our study defines the miR-148/152 family as critical oncogenic drivers that promote cancer cell survival and chemoresistance by directly suppressing RIPK1 expression. These findings highlight this miRNA family as a promising therapeutic target to overcome cell death evasion in cancer.