Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF‑β activation in HCC
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE274750 | GEO | 2025/12/01
REPOSITORIES: GEO
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Project description:Oncogenic role of PMEPA1 and its association with immune exhaustion and TGF‑β activation in HCC
| PRJNA1147754 | ENA
Project description:Background & aimsTransforming growth factor β (TGF-β) plays 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 1,097 tumours from patients with HCC, including discovery (n = 228) and validation (n = 361) cohorts 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 molecular analyses were performed on the HCCs obtained.ResultsPMEPA1 was overexpressed in 18% of HCC samples (fold-change >2; n = 201/1,097), 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+ regulatory T cells 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 demonstrate that PMEPA1 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, 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.
| S-EPMC11550205 | biostudies-literature
Project description:Ferroptosis has been suggested to have a potential role in cancer therapy as an iron-dependent programmed cell death distinguished from other forms. Hepatocellular carcinoma (HCC) remains a great threat with high lethality and limited therapies. Induction of ferroptosis has emerged as a novel and promising therapeutic strategy for HCC. Here, we identify PIAS3 as a driver of ferroptosis in HCC through TMT-based quantitative proteomics and ferroptosis-related functional assays. Mechanistically, TXNIP is confirmed as a downstream of PIAS3 in promoting ferroptotic cell death based on RNA-seq analysis. The knockdown of TXNIP degrades ferroptotic susceptibility caused by PIAS3-overexpression, whereas the transfection-forced re-expression of TXNIP restores sensitivity to ferroptosis in PIAS3-downregulated cells. In the meantime, PIAS3 interacts with SMAD2/3 to activate TGF-β signaling, which leads to increased TXNIP expression. Our study uncovers the critical role of PIAS3 in ferroptosis and a novel actionable axis-PIAS3/TGF-β/TXNIP that could govern ferroptotic sensitivity, paving the path for targeting ferroptosis as an efficient approach in HCC therapies.
2023-06-15 | PXD043038 |
Project description:The role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-β signaling is still unknown. In this study, we observed that the lncRNA-Activated by TGF-β (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB promotes the invasion-metastasis cascade, which suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose HCC patients to metastases and may serve as a potential target for anti-metastatic therapies.
2014-02-08 | GSE54797 | GEO
Project description:Transforming growth factor-β (TGF-β) signaling and cellular senescence are key hallmarks of hepatocellular carcinoma (HCC) pathogenesis. While provoking senescence-associated growth arrest in epithelial HCC cells, elevated TGF-β activity paradoxically correlates with aggressiveness and poor prognosis in advanced tumors. Whether the transition between these dichotomous functions involves bypassing the senescence barrier during disease progression remains unknown. Exploiting the epithelial HCC cell line Huh7, we demonstrate that chronic TGF-β exposure prompts escape from Smad3-mediated senescence, leading to the development of TGF-β resistance. The resistant state is characterized by restoration of proliferative capacity and acquisition of molecular and functional traits of mesenchymal cells, coinciding with hybrid EMT, increased invasiveness, and metastasis. Mechanistically, resistant cells exhibit defective signaling of Smad molecules, as ectopic activation of the TGF-β/Smad3 axis reinstates TGF-β sensitivity. Gene expression landscape profiling reveals both shared and distinct gene signatures associated with senescent and TGF-β resistant states. Importantly, genetic ablation and molecular studies identify GRM8 (Glutamate Metabotropic Receptor 8) as a critical modulator of the resistance phenomenon, potentially by impairing subcellular spatiotemporal dynamics of Smad activity. Our findings unveil a novel phenomenon wherein epithelial HCC cells may exploit senescence evasion as a mechanism to oppose TGF-β anti-tumor responses and progress towards more aggressive HCC phenotypes.
2025-03-17 | GSE261099 | GEO
Project description:Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Transforming growth factor beta (TGF-β) is highly expressed in the liver tumor microenvironment and is known to inhibit immune cell activity. Here, we used human iPSCs to produce natural killer (NK) cells engineered to mediate improved anti-HCC activity. Specifically, we produced iPSC-NK cells with either knock out TGF-β receptor 2 (TGFBR2-KO) or expression of a dominant negative (DN) form of the TGF-β receptor 2 (TGFBR2-DN) combined with CARs that target either GPC3 or AFP. The TGFBR2-KO and TGFBR2-DN iPSC-NK cells are resistant to TGF-β inhibition and improved anti-HCC activity. However, expression of anti-HCC CARs on iPSC-NK cells did not lead to effective anti-HCC activity unless there was also inhibition of TGF-b activity. Our findings demonstrate that TGF-β signaling blockade is required for effective NK cell function against HCC and potentially other malignancies which express high levels of TGF-β.
2024-04-08 | GSE263459 | GEO
Project description:Cancer-Associated Fibroblasts (CAFs) were isolated from specimens taken from primary human hepatocellular carcinoma (HCC) nodules (4 patients in total), characterized for expression of typical stromal markers (including vimentin and alpha smooth muscle actin), and then incubated in complete medium (Iscove's Modified Dulbecco Medium, IMDM + 20% fetal bovine serum + antibiotic/antimycotic) without any treatment, or in the presence of Transforming Growth Factor Beta 1 (TGF beta 1) at a concentration of 5 ng/ml. The medium and the treatment were renewed every 2 days until the 14th day. At that time point, cells were washed 4 times with serum-free IMDM medium and then incubated with serum free IMDM medium for 48 hours to allow for enrichment with secreted CAFs proteins. The CAFs conditioned medium was then collected, concentrated using a centricon device (10 kDa cutoff), assayed for protein concentration, and finally subjected to Liquid Chromatography with tandem mass spectrometry (LC-MS/MS).
2021-11-11 | PXD029586 | Pride
Project description:TGF-β and Hippo signaling are two critical pathways engaged in cancer progression by regulating both oncogenes and tumor suppressors, yet how the two pathways coordinately exert their functions in the development of hepatocellular carcinoma (HCC) remains elusive. In this study, we firstly conducted an integrated analysis of public liver cancer databases and our experimental TGF-β target genes, identifying CYR61 as a pivotal gene relating to HCC development. Evidence revealed that CYR61 is a direct target gene of TGF-β in liver cancer cells. In addition, TGF-β-stimulated Smad2/3 and the Hippo pathway downstream effectors YAP and TEAD4 can form a protein complex on the promoter of CYR61, thereby activating the promoter activity and stimulating CYR61 gene transcription in a collaborative manner. Functionally, depletion of CYR61 enhanced TGF-β- or YAP activation-mediated growth and migration of liver cancer cells. Consistently, ectopic expression of CYR61 was capable of impeding TGF-β- or YAP-induced malignant transformation of HCC cells in vitro, and attenuating HCC xenograft growth in nude mice. Finally, Downregulation of CYR61 expression in HCC tissues than that in normal liver tissues is well associated with a bad clinical outcome in patients. Together, these results add new evidence for the interplay between TGF-β and Hippo signaling and unveil an important tumor suppressor function of CYR61 in liver cancer.
2023-08-19 | GSE240760 | GEO
Project description:CTNNB1 is the most frequently mutated gene in hepatocellular carcinoma (HCC). However, its clinical relevance remains controversial. We determined an evolutionarily conserved β-catenin signature by comparative analysis of gene expression data from human HCC and a mouse model (GSE43628). We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment. We used these gene expression data to develop a new prognostification model for prognosis of HCC after surgery. We generated gene expression data from the tumors of 88 HCC patients who underwent surgical resection as the primary treatment.
2015-05-21 | E-GEOD-43619 | biostudies-arrayexpress
Project description:Loss of TGF-beta growth-inhibitory responses is a hallmark of human cancer. However, the molecular mechanisms underlying the TGF-beta resistance of cancer cells remain to be fully elucidated. Splicing factor proline- and glutamine-rich protein (SFPQ) is a prion-like RNA-binding protein that is frequently upregulated in human cancers, such as Hepatocellular carcinoma (HCC). In this study, we identified SFPQ as a potent suppressor of TGF-beta signaling. The ability of SFPQ to suppress TGF-beta responses depended on its prion-like domain (PrLD) that drives phase separation (LLPS). Mechanistically, SFPQ physically restrained Smad4 in its condensates, which excluded Smad4 from the Smad complex and chromatin occupancy, and thus functionally dampened Smad-dependent transcriptional responses. Accordingly, SFPQ deficiency or loss of LLPS rendered cells hypersensitive to TGF-beta responses. Together, our data reveal a unique function of SFPQ through LLPS that suppresses Smad transcriptional activation and TGF-beta tumor-suppressive activity.
2023-11-16 | GSE236125 | GEO