• CircGCLM is identified as a critical determinant of DDP resistance in NSCLC. • A novel CircGCLM / miR-505-3p / ERBB4 regulatory axis is defined in conferring DDP resistance. • ERBB4 expression is profiled in NSCLC at single-cell resolution. The circular RNAs (circRNAs) have been implicated in chemoresistance, yet the specific roles of individual circRNAs in non-small cell lung cancer (NSCLC) remain largely unexplored. Here, we identified circGCLM as a novel driver of NSCLC tumorigenesis and cisplatin (DDP) resistance, and investigated its molecular mechanism of action. CircGCLM expression was examined in DDP-resistant and parental NSCLC cells. Loss-of-function studies were conducted to evaluate the effects on cell proliferation, apoptosis, and DDP sensitivity. The circGCLM/miR-505-3p/ERBB4 axis was validated using dual-luciferase reporter assays, RNA immunoprecipitation (RIP), and rescue experiments. ERBB4 expression dynamics was uncovered by single-cell transcriptomic analysis. CircGCLM was markedly upregulated in DDP-resistant NSCLC cells compared to their parental cells. Functional loss-of-function studies demonstrated that circGCLM knockdown suppressed proliferation, restored DDP sensitivity, and promoted apoptosis in these resistant cells. Mechanistically, circGCLM acted as a competitive endogenous RNA (ceRNA) for microRNA-505-3p (miR-505-3p), which led to the derepression and consequent upregulation of its target, erb-b2 receptor tyrosine kinase 4 (ERBB4). Thus, the oncogenic functions of circGCLM, including the promotion of DDP resistance and other malignant phenotypes, were mediated through the miR-505-3p/ERBB4 axis. In summary, our findings established that circGCLM contributed to DDP resistance in NSCLC, at least in part, by sponging miR-505-3p to derepress ERBB4, highlighting a potential therapeutic target for overcoming chemoresistance.
Ma et al. (Tue,) studied this question.
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