Single-cell transcriptomic analysis reveals that the circRNA circGCLM promotes tumorigenesis and confers cisplatin resistance in NSCLC through the miR-505-3p/ERBB4 axis

Yirou Ma; Baiqing Huang; Haiyang Wang; Mengchao Xue; Yiyang Liu; Yibo Jin; Chunping Wang; Shaorui Gu; Yongxin Zhou

doi:10.1016/j.tranon.2026.102759

Single-cell transcriptomic analysis reveals that the circRNA circGCLM promotes tumorigenesis and confers cisplatin resistance in NSCLC through the miR-505-3p/ERBB4 axis

Transl Oncol. 2026 May:67:102759. doi: 10.1016/j.tranon.2026.102759. Epub 2026 Apr 7.

Authors

Yirou Ma¹, Baiqing Huang¹, Haiyang Wang¹, Mengchao Xue¹, Yiyang Liu¹, Yibo Jin¹, Chunping Wang¹, Shaorui Gu², Yongxin Zhou³

Affiliations

¹ Department of Thoracic and Cardiovascular Surgery, Tongji Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China.
² Department of Thoracic and Cardiovascular Surgery, Tongji Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China. Electronic address: 870005908@qq.com.
³ Department of Thoracic and Cardiovascular Surgery, Tongji Hospital of Tongji University, School of Medicine, Tongji University, Shanghai, China. Electronic address: zhou6302@tongji.edu.cn.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CircGCLM; DDP resistance; ERBB4; NSCLC; miR-505-3p.