Oncogenic Role and Drug Resistance Effect of CCDC6 in iCCA: Potential Strategies for Targeted Intervention

Intrahepatic cholangiocellular carcinoma (iCCA) is a digestive neoplasm with a very poor prognosis. This study examined the role of CCDC6 in the progression of iCCA and gemcitabine resistance through bioinformatics analysis and functional assays. Database analysis showed that CCDC6 was significantly overexpressed in iCCA, with its expression positively correlating with TNM stage and lymph node metastasis. Although its value as an independent prognostic biomarker was not statistically significant in survival analysis, its expression profile suggested potential as a therapeutic target. Functional experiments demonstrated that CCDC6 knockdown inhibited iCCA cell proliferation, migration and invasion in vitro in a dose-dependent manner, while overexpression enhanced these malignant phenotypes. Western blot analysis demonstrated that CCDC6 regulated epithelial-mesenchymal transition (EMT) by modulating Vimentin and Snail expression, promoting metastasis. In vivo xenograft and metastasis models confirmed that CCDC6 depletion significantly reduced tumour burden and lung metastases. Moreover, CCDC6 and the EMT marker Vimentin were upregulated in gemcitabine-resistant iCCA cells. γH2AX foci staining indicated that CCDC6 enhanced DNA damage repair (DDR), reducing chemotherapy-induced genomic instability, while CCDC6 inhibition exacerbated DNA damage, reversing resistance. These findings suggest CCDC6 drives chemoresistance through EMT activation and enhanced DDR, making it a promising therapeutic target in iCCA.