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

Abstract

Background & AimsTransforming growth factor β (TGF-β) has an oncogenic role in advanced cancer by promoting cell proliferation, metastasis and immunosuppression. PMEPA1 (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 PMEPA1 in hepatocellular carcinoma (HCC). MethodsWe analysed n=1097 tumours from HCC patients, including a discovery (n=228) and validation cohort (n=361) with genomic and clinicopathological data. PMEPA1 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 MYC+PMEPA1 compared to MYC were generated and HCCs obtained were molecularly analysed. ResultsPMEPA1 was overexpressed in 18% of HCC samples [FC>2; n=201/1097], a feature associated with TGF-β signalling activation (p<0.05) and absence of gene body hypomethylation (p<0.01). HCCs showing both TGF-β signalling and high PMEPA1 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 PMEPA1 overexpression (9%). Single-cell RNA-sequencing analysis identified PMEPA1 expression in HCC and stromal cells. PMEPA1-expressing tumoural cells were predicted to interact with CD4+ Tregs and CD4+ CXCL13+ and CD8+ exhausted T cells. In vivo, overexpression of MYC+PMEPA1 led to HCC development in ∼60% of mice and a decreased survival compared to mice overexpressing MYC alone (p=0.014). MYC+PMEPA1 tumours were enriched in TGF-β signalling, paralleling our human data. ConclusionsIn human HCC, PMEPA1 upregulation is linked to TGF-β activation, immune exhaustion, and an aggressive phenotype. Overexpression of PMEPA1+MYC led to tumoural development in vivo, demonstrating the oncogenic role of PMEPA1 in HCC for the first time. Impact and implicationsPMEPA1 can enhance the tumour-promoting effects of TGF-β in cancer. In this study, we describe that PMEPA1 is highly expressed in ∼18% of HCC patients, a feature associated with poor prognosis, TGF-β activation and exhaustion of immune cells. Similarly, in mouse models, PMEPA1 overexpression promotes HCC development, which demonstrates its oncogenic role. The identification of PMEPA1 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.