Exploring the potential mechanisms of sorafenib resistance in hepatocellular carcinoma cell lines based on RNA sequencing.

Background: Exploring the mechanisms underlying sorafenib resistance that arises in hepatocellular carcinoma (HCC) may provide new treatment perspectives.

Methods: Drug-resistant and drug-sensitive HCC cell lines were constructed from existing HepG2 and Huh7 cell lines, and gene expression profiles were determined. Genes differentially expressed between the resistant and sensitive lines were identified and organized into modules based on weighted gene co-expression network analysis. Pathways and biological processes involving the module genes were explored and validated using gene set enrichment analysis. By analyzing the expression differences of Long non-coding ribonucleic acid (RNAs), microRNAs (miR), circular RNAs, and messenger RNAs between drug-resistant and sensitive cell lines, a gene regulatory network was constructed to reveal the mechanism of sorafenib resistance. In addition, we also analyzed the correlation between the candidate sorafenib resistance gene and the survival of patients with liver cancer.

Results: Our analyses suggested that sorafenib resistance could arise when the circular RNA circ_SPECC1 regulated the microRNA hsa-let-7c-5p, which in turn regulated the cell cycle proteins cyclin-dependent kinase 1 and polo-like kinase 1, as well as interleukin 13 receptor, alpha 1 in the Janus kinase-signal transducer (JAK-STAT) and activator of transcription signaling pathway. Patient survival was associated with miR-18a-z and mitogen-activated protein kinase kinase 4 levels.

Conclusions: Sorafenib resistance in HCC may involve the circ_SPECC1, hsa-let-7c-5p, cell cycle, and JAK-STAT signaling pathways. These insights may guide future efforts to mitigate or prevent such resistance.