Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF-β activation in HCC.

Background & Aims: Transforming growth factor β (TGF-β) plays an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. (prostate transmembrane protein androgen induced 1) has been shown to promote TGF-β oncogenic effects in other tumour types. Thus, we aimed to explore the role of in hepatocellular carcinoma (HCC).

Methods: We analysed 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts with genomic and clinicopathological data. levels were assessed by qPCR (n = 228), gene expression data (n = 869) and at the single-cell level (n = 54). Genetically engineered mouse models overexpressing compared to were generated and molecular analyses were performed on the HCCs obtained.

Results: was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), a feature associated with TGF-β signalling activation (0.05) and absence of gene body hypomethylation (0.01). HCCs showing both TGF-β signalling and high levels (12% of cases) were linked to immune exhaustion, late TGF-β activation, aggressiveness and higher recurrence rates after resection, in contrast to HCCs with only TGF-β signalling (8%) or overexpression (9%). Single-cell RNA sequencing analysis identified expression in HCC and stromal cells. -expressing tumoural cells were predicted to interact with CD4 regulatory T cells and CD4 CXCL13 and CD8 exhausted T cells. , overexpression of + led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing alone ( 0.014). + tumours were enriched in TGF-β signalling, paralleling our human data.

Conclusions: In human HCC, upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of led to tumoural development , demonstrating the oncogenic role of in HCC for the first time.

Impact And Implications: can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we demonstrate that is highly expressed in ∼18% of patients with hepatocellular carcinoma (HCC), a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of as oncogenic driver in HCC and its role in immune exhaustion and poor clinical outcomes enhances our understanding of HCC pathogenesis and opens new avenues for targeted therapeutic interventions.