ArticleJournal of experimental & clinical cancer research : CR2025
HHLA2 activates c-Met and identifies patients for targeted therapy in hepatocellular carcinoma.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Hepatocyte BPGM Induces RET Lactylation and Macrophage Reprogramming to Promote Tumorigenesis in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Preclinical exploration and current clinical applications of immunotherapeutic strategies for hepatocellular carcinoma.Frontiers in immunology · 2026Review
- Distinct Roles of HHLA2 and PD-L1 in the Immune Cell and Prognosis of Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
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16 authors.
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Abstract
backgroundHepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options in advanced stages. While c-Met is a promising therapeutic target in HCC, identifying patients who will benefit from c-Met inhibitors remains a significant challenge. This study aimed to investigate the role of HHLA2, a B7 family member, in HCC and its potential as a liquid biopsy marker for c-Met inhibitor therapy.
methodsHHLA2 expression was analyzed in clinical HCC samples and public databases. In vitro studies using HCC cell lines assessed HHLA2's impact on proliferation, migration, invasion, and angiogenesis. In vivo studies using mouse models (orthotopic xenografts and hydrodynamic tail vein injection) evaluated HHLA2's role in tumor growth and metastasis. Mass spectrometry, co-immunoprecipitation, split-luciferase, and ELISA assays were used to investigate HHLA2-c-Met interactions. Patient-derived organoids (PDOs) were used to assess drug response. Statistical analyses included Student's t-tests, ANOVA, and Cox regression.
resultsHHLA2 was found to be upregulated in HCC and associated with advanced disease, aggressive clinicopathological features, and poor prognosis. HHLA2 interacted with and constitutively activated c-Met, leading to increased expression of MMP9 and VEGFA, enhancing HCC cell proliferation, invasion, and angiogenesis. HHLA2 also suppressed hepatic natural killer cell infiltration in vivo. Inhibition of c-Met with PHA665752 effectively reversed HHLA2-mediated tumor-promoting effects in vitro and in vivo. HHLA2 expression in HCC tissues correlated with c-Met phosphorylation, and HHLA2 could be detected in the serum of patients with high tumor HHLA2 levels. PDOs with high HHLA2 expression exhibited increased sensitivity to c-Met inhibition.
conclusionsHHLA2 acts as an oncogene in HCC by activating c-Met, promoting tumor progression and metastasis. HHLA2 expression correlates with c-Met activation and predicts poor prognosis in HCC patients. Importantly, HHLA2 can serve as a stratification marker for c-Met inhibitor therapy, potentially enabling a personalized approach to improve therapeutic outcomes in this challenging disease.
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