CircCDK6 Regulates Stemness Maintenance and Cisplatin Resistance in Lung Adenocarcinoma via the Wnt/β-Catenin...

This study investigates the role of circCDK6 in maintaining cancer stem cell (CSC) properties and mediating cisplatin resistance in lung adenocarcinoma (LUAD), with a focus on the involvement of the Wnt/β-catenin signaling pathway.

The expression levels of circCDK6 in various LUAD cell lines were measured using quantitative real-time PCR. Gain- and loss-of-function experiments were conducted by plasmid-mediated overexpression and siRNA-mediated knockdown of circCDK6. Cisplatin sensitivity was assessed using the Cell Counting Kit-8 assay and colony formation assay. The involvement of the Wnt/β-catenin pathway was examined by inhibiting the pathway with IWR-1. A subcutaneous xenograft model in BALB/c nude mice was used to evaluate the in vivo effects of circCDK6 knockdown on cisplatin responsiveness, and tumor tissues were analyzed through hematoxylin and eosin staining and immunohistochemistry for Ki-67 expression.

CircCDK6 expression was significantly elevated in H1299 and H1975 cells compared to A549 and PC-9 cells. Overexpression of circCDK6 increased stemness markers, such as CD133, Oct4, and Sox2, and enhanced cisplatin resistance, as demonstrated by higher IC₅₀ values and increased colony formation. In contrast, circCDK6 silencing significantly reduced cisplatin resistance. Western blot analysis revealed that circCDK6 activated the Wnt/β-catenin pathway by upregulating Axin2, β-catenin, and c-Myc. In vivo, circCDK6 knockdown reduced tumor volume, improved the anti-tumor effect of cisplatin, and decreased Ki-67 expression.

CircCDK6 may promote CSC properties and contribute to cisplatin resistance in LUAD, potentially through activation of the Wnt/β-catenin pathway. These findings suggest that circCDK6 may represent a potential therapeutic target for overcoming chemoresistance in LUAD, although further studies are needed to validate its role and clinical relevance.