Role of the transcription factor SOX8 in hepatocellular carcinoma development and lymph node metastasis

Lymph node metastasis (LNM) is one of the forms of hepatocellular carcinoma (HCC) dissemination, a phenomenon that is strongly correlated with an adverse prognosis. The transcription factor SOX8 has been implicated in tumor progression in other malignancies, but its prognostic significance and mechanistic role in HCC LNM remain unexplored. This study aims to explore the prognostic significance and mechanistic role of the transcription factor SOX8 in HCC LNM.

We retrospectively enrolled 387 HCC patients who underwent radical hepatectomy with lymph-node dissection between 2013 and 2021, among whom 57 were LNM-positive and the remaining 330 were negative. Recurrence-free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier curves and compared by log-rank test; independent prognostic factors were identified with Cox proportional-hazards regression. SOX8 mRNA levels in matched primary tumors and metastatic lymph nodes were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional impacts of SOX8 knockdown and overexpression were assessed in HCC cell lines via proliferation, migration, and invasion assays. Changes in epithelial-mesenchymal transition (EMT) markers (E-cadherin, N-cadherin, Vimentin) were examined by Western blot.

LNM, microvascular invasion (MVI), and the China Liver Cancer (CNLC) stage emerged as independent predictors of both shorter RFS and OS in the matched cohort; metastatic lymph nodes exhibited a 3.8-fold increase in SOX8 mRNA compared to primary tumors (P<0.001). In vitro, SOX8 knockdown significantly inhibited HCC cell proliferation, migration, and invasion, whereas SOX8 overexpression produced the opposite effects. At the molecular level, SOX8 modulation altered EMT marker expression-specifically, SOX8 overexpression reduced E-cadherin while upregulating N-cadherin and Vimentin-demonstrating that SOX8 drives EMT to promote HCC cell invasiveness and metastatic potential.

In summation, this study established a correlation between LNM and diminished RFS and OS among HCC patients. Moreover, it demonstrated the significant role of SOX8 in HCC progression and LNM, which appears to modulate the malignant phenotype of HCC cells, encompassing enhanced proliferation, stem cell-like properties, and invasive migration through the induction of EMT. These collective findings implicate SOX8 as a promising candidate for targeted therapeutic intervention in HCC.