Graduate Institute of Clinical Medical Sciences

Our research primarily focuses on the molecular mechanisms underlying hepatocellular carcinoma (HCC) and the interactions between tumor cells and the tumor microenvironment.

Regarding early-stage HCC, since 2000 we have followed a small cohort of patients with hepatitis B virus–related HCC. Using the Affymetrix U133A microarray platform, we analyzed gene signatures in early HBV-related tumor specimens. In this study, we identified GPC3 and SPP1 as independent risk factors (Annals of Surgical Oncology. 2012 Jul;19(3):455–463). Subsequently, using the OncoScan platform, we demonstrated that chromosomal copy number alterations were associated with patient prognosis and therapeutic response (World Journal of Gastroenterology. 2017 Nov 28;23(44):7818–7829; Biomedical Journal. 2021 Dec;44(6 Suppl 1):S73–S83). In addition, genomic DNA extracted from HCC tissues was subjected to bisulfite conversion followed by pyrosequencing analysis to determine the methylation status of VTRNA2-1. We found that promoter methylation of VTRNA2-1 was strongly correlated with tumor recurrence, tumor size, and disease-free survival in HCC patients (International Journal of Surgery. 2020 Jul;79:282–289).

Regarding the oncogenic mechanism of SOX4, we observed that HCC patients with tumor overexpression of SOX4 were more likely to exhibit vascular invasion, distant metastasis, and poor prognosis (Oncogene. 2020 Jun;39(24):4695–4710). Building on this work, we discovered that SOX4 forms a complex with NRF2 and directly activates the transcription of phosphoserine phosphatase (PSPH). Activation of PSPH enhances serine biosynthesis and the production of downstream metabolites, which are critical for oxidative phosphorylation (OXPHOS) and redox balance. Inhibition of SOX4 or NRF2 reduced PSPH expression, leading to increased oxidative damage (as indicated by elevated 4-hydroxynonenal [4-HNE]) and enhanced sensitivity of HCC cells to sorafenib treatment. Moreover, PSPH-driven metabolites, particularly serine, promote M2 macrophage polarization, thereby contributing to an immunosuppressive tumor microenvironment (Cancer Gene Therapy. 2025 Nov;32(11):1218–1232). In continuation of this research, we identified STAT6 as a transcriptional target regulated by SOX4, and confirmed the protein–protein interaction between SOX4 and STAT6 through co-immunoprecipitation and immunofluorescence assays. Chromatin immunoprecipitation (ChIP) assays further demonstrated that SOX4 and STAT6 co-bind to the promoter region of the key folate metabolism enzyme MTHFD2, thereby regulating NADH/NADPH production and nucleotide biosynthesis. Knockdown of SOX4 or STAT6, or mutation of their respective binding sites within the MTHFD2 promoter, resulted in decreased MTHFD2 expression, reduced NADPH levels, and impaired nucleotide synthesis. Transcriptomic and proteomic analyses from the TCGA-LIHC database as well as from our patient cohort revealed a strong positive correlation among SOX4, STAT6, and MTHFD2 expressions. Overexpression of MTHFD2 was associated with poorer overall survival. Clinically, both in our cohort and in public datasets (e.g., GSE109211), elevated expression of the SOX4/STAT6/MTHFD2 axis correlated with resistance to immunotherapy and tyrosine kinase inhibitors (TKIs). Metabolomic analyses further showed significantly increased NADPH and nucleotide synthesis in tumors with high SOX4/STAT6/MTHFD2 expression. In patient-derived xenograft (PDx) models resistant to TKIs, targeting STAT6 or MTHFD2 effectively suppressed tumor growth. This work was published in Cell Death & Disease (2026 Jan 3;17(1):154).

Overall, our research has progressed from the identification of molecular biomarkers to a systematic dissection of metabolism-driven mechanisms underlying tumor progression and therapeutic resistance, thereby establishing therapeutically actionable targets with translational potential. Moving forward, by further deepening our investigation into tumor metabolism and its interaction with the tumor microenvironment, we aim to develop more effective and personalized treatment strategies for therapy-resistant hepatocellular carcinoma.