Abstract
Circular RNAs (circRNAs) are novel RNA molecules that play important roles in chemoresistance in different cancers, including breast and gastric cancers. However, whether circRNAs are involved in the response to chemotherapy in small cell lung cancer (SCLC) remains largely unknown. In this study, we observed that cESRP1 (circular RNA epithelial splicing regulatory protein-1) expression was significantly downregulated in the chemoresistant cells compared with the parental chemosensitive cells. cESRP1 enhanced drug sensitivity by repressing miR-93-5p in SCLC. Cytoplasmic cESRP1 could directly bind to miR-93-5p and inhibit the posttranscriptional repression mediated by miR-93-5p, thereby upregulating the expression of the miR-93-5p downstream targets Smad7/p21(CDKN1A) and forming a negative feedback loop to regulate transforming growth factor-β (TGF-β) mediated epithelial-mesenchymal transition. Furthermore, cESRP1 overexpression and TGF-β pathway inhibition both altered tumour responsiveness to chemotherapy in an acquired chemoresistant patient-derived xenograft model. Importantly, cESRP1 expression was downregulated in SCLC patient tissues and was associated with survival. Our findings reveal, for the first time, that cESRP1 plays crucial a role in SCLC chemosensitivity by sponging miR-93-5p to inhibit the TGF-β pathway, suggesting that cESRP1 may serve as a valuable prognostic biomarker and a potential therapeutic target in SCLC patients.
Highlights
Lung cancer remains one of the most common causes of cancer-related mortality worldwide, with small cell lung cancer (SCLC) accounting for ~15% of all lung cancer cases [1, 2]
Of the ten circRNAs, we observed six circRNAs with consistent and significant deregulated expression in chemorensistant cells (Fig. 1c). Among these circRNAs, because cESRP1 originates from the ESRP1 gene, which is closely linked to tumour-associated epithelial-to-mesenchymal transition (EMT) [45, 46], we selected cESRP1 to further investigate the role of cESRP1 in SCLC chemoresistance
The results showed that a lower level of cESRP1 expression significantly correlated with extensive disease-SCLC (ED-SCLC) and a worse status (Table 1)
Summary
Lung cancer remains one of the most common causes of cancer-related mortality worldwide, with small cell lung cancer (SCLC) accounting for ~15% of all lung cancer cases [1, 2]. The functional roles of circRNAs have been well characterised to date, such as in mesenchymal stem cell identity maintenance [5], differentiation [6], development [7], and oncogenesis [8, 9]. CircRNAs can influence various cellular processes including proliferation, cell cycle progression, and cell apoptosis [10, 11]. They can act as oncogenes or tumour suppressors through diverse mechanisms to regulate tumour progression [9, 12] and tumour resistance to chemotherapy [13, 14]. The circRNAs involved in SCLC chemoresistance remain largely unknown
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