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Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.

ABSTRACT: Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-β family, TGF-β1 modulates most of its biological outcomes. Despite the abundant expression of TGF-β1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-β1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-β1 levels in the tumor microenvironment create an immunosuppressive stage via various mechanisms. TGF-β1 has a prime role as a diagnostic and prognostic biomarker in HCC. Moreover, TGF-β1 is widely studied as a therapeutic target either as monotherapy or combined with immune checkpoint inhibitors. This review provides clinical relevance and up-to-date information regarding the potential of TGF-β1 in diagnosis, prognosis, and therapy against HCC.

SUBMITTER: Devan AR

PROVIDER: S-EPMC9521521 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.

Devan Aswathy R AR Pavithran Keechilat K Nair Bhagyalakshmi B Murali Maneesha M Nath Lekshmi R LR

World journal of gastroenterology 20220901 36

Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that performs a dual role as a tumor suppressor and tumor promoter during cancer progression. Among different ligands of the TGF-β family, TGF-β1 modulates most of its biological outcomes. Despite the abundant expression of TGF-β1 in the liver, steatosis to hepatocellular carcinoma (HCC) progression triggers elevated TGF-β1 levels, contributing to poor prognosis and survival. Additionally, elevated TGF-β1 levels in the tumor m ...[more]

PMID: 36185626

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Project description:ObjectivesDystrobrevin beta (DTNB) is a constituent of the dystrophin-associated protein complex (DPC). Our previous RNA sequencing (RNA-seq) study revealed that knockdown of the oncogenic long noncoding RNA (lncRNA) HOXD cluster antisense RNA 1 (HOXD-AS1) in hepatocellular carcinoma (HCC) cells could reduce the expression levels of DTNB. However, the association between DTNB and HCC remains uncertain.MethodsThe upregulation of DTNB in HCC cell lines and the regulatory effect of HOXD-AS1 on its expression were verified using quantitative real-time PCR (qRT-PCR). The potential clinical significance, biological functions and underlying mechanisms of DTNB in HCC were investigated through bioinformatics analysis. The high expression of DTNB was validated in HCC tissues, and its biological function in HCC was investigated by performing loss-of-function assays in vitro.ResultsDTNB was highly expressed in HCC cells and was positively regulated by the lncRNA HOXD-AS1 in several HCC cell lines. The upregulation of DTNB was significantly associated with T stage, histologic grade, tumour status, adjacent hepatic tissue inflammation, alpha-fetoprotein (AFP) level, and unfavorable prognosis, serving as an independent risk indicator associated with overall survival with substantial diagnostic and prognostic implications for HCC. DTNB was also closely linked to immune cell infiltration, immunotherapy, and sensitivity to anti-HCC drugs. Genes co-expressed with DTNB in HCC were identified, and functional enrichment analysis indicated that DTNB may function in HCC by regulating the cell cycle. A potential ceRNA (competing endogenous RNA) regulatory axis of HOXD-AS1/miR-139-3p/DTNB in HCC was predicted and validated. The high expression of DTNB was validated in our HCC cohort and loss-of-function assays revealed that DTNB knockdown can suppress the proliferation, migration, and invasion of HCC cells and trigger cell cycle arrest at the G0/G1 phase.ConclusionsDTNB, a downstream target of the lncRNA HOXD-AS1, has potential utility as a prognostic biomarker and a target for the treatment of HCC.

Project description:BackgroundPancreatic carcinoma (PC) is one of the most aggressive cancers affecting human health. It is essential to identify candidate biomarkers for the diagnosis and prognosis of PC. The present study aimed to investigate the diagnosis and prognosis biomarkers of PC.MethodsDifferentially expressed genes (DEGs) were identified from the mRNA expression profiles of GSE62452, GSE28735 and GSE16515. Functional analysis and the protein-protein interaction network analysis was performed to explore the biological function of the identified DEGs. Diagnosis markers for PC were identified using ROC curve analysis. Prognosis markers were identified via survival analysis of TCGA data. The protein expression pattern of the identified genes was verified in clinical tissue samples. A retrospective clinical study was performed to evaluate the correlation between the expression of candidate proteins and survival time of patients. Moreover, comprehensive analysis of the combination of multiple genes/proteins for the prognosis prediction of PC was performed using both TCGA data and clinical data. In vitro studies were undertaken to elaborate the potential roles of these biomarkers in clonability and invasion of PC cells.FindingsIn total, 389 DEGs were identified. These genes were mainly associated with pancreatic secretion, protein digestion and absorption, cytochrome P450 drug metabolism, and energy metabolism pathway. The top 10 genes were filtered out following Fisher's exact test. ROC curve analysis demonstrated that TMPRSS4, SERPINB5, SLC6A14, SCEL, and TNS4 could be used as biomarkers for the diagnosis of PC. Survival analysis of TCGA data and clinical data suggested that TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can be potential biomarkers for the prognosis of PC. Comprehensive analysis show that a combination of identified genes/proteins can predict the prognosis of PC. Mechanistically, the identified genes attributes to clonability and invasiveness of PC cells.InterpretationWe synthesized several sets of public data and preliminarily clarified pathways and functions of PC. Candidate molecular markers were identified for diagnosis and prognosis prediction of PC including a novel gene, TMC7. Moreover, we found that the combination of TMC7, TMPRSS4, SCEL, SLC2A1, CENPF, SERPINB5 and SLC6A14 can serve as a promising indicator of the prognosis of PC patients. The candidate proteins may attribute to clonability and invasiveness of PC cells. This research provides a novel insight into molecular mechanisms as well as diagnostic and prognostic markers of PC. FUND: National Natural Science Foundation of China [No. 81602646 &81802339], Natural Science Foundation of Guangdong Province [No. 2016A030310254] and China Postdoctoral Science Foundation [No. 2016M600648].

Dataset Information

Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.

Publications

Deciphering the role of transforming growth factor-beta 1 as a diagnostic-prognostic-therapeutic candidate against hepatocellular carcinoma.

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