LINC00626 promotes oxaliplatin resistance in hepatocellular carcinoma in association with STAT3 Tyr705 phosphorylation and CCL20 expression

Oxaliplatin-containing regimens are used in selected patients with hepatocellular carcinoma (HCC), although acquired resistance can curtail their effectiveness. This study examined whether LINC00626 contributes to the oxaliplatin response and investigated the associated signaling mechanism. LINC00626 was evaluated in public HCC datasets, clinical specimens, parental cells, and an oxaliplatin-resistant Hep3B derivative. Its function was tested by bidirectional genetic manipulation, transcriptome profiling, subcellular fractionation, immunofluorescence, CCL20 promoter-reporter experiments, STAT3 inhibition or mutation, CCL20 rescue studies, and subcutaneous xenografts. LINC00626 was elevated in HCC specimens and Hep3B/OXA cells, increased after oxaliplatin exposure, and correlated with unfavorable clinicopathological characteristics. Silencing LINC00626 restrained malignant behavior, increased oxaliplatin responsiveness, and reduced xenograft growth; overexpression produced reciprocal effects. LINC00626 primarily enhanced STAT3 Tyr705 phosphorylation and nuclear enrichment rather than STAT3 transcription, with a parallel increase in CCL20 expression and CCL20 promoter-reporter activity. STAT3 depletion, Stattic, and the Y705F mutant weakened these effects. CCL20 knockdown reduced CD133/CD44 abundance and tumorsphere formation and counteracted the oxaliplatin-tolerant phenotype driven by LINC00626. These findings associate LINC00626-dependent oxaliplatin tolerance with STAT3 Tyr705 phosphorylation and CCL20 expression in HCC cells.