The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma?
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ABSTRACT:
SUBMITTER: Gonzalez-Sanchez E
PROVIDER: S-EPMC8268320 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AGO1 is a major component of RNA-induced silencing complexes and plays a crucial role in solid tumors. The aim of our study was to investigate AGO1 functions in hepatocellular carcinoma (HCC). Using small interfering RNA, AGO1 functions were investigated in HCCLM3 cell lines. Cell proliferation, immigration, and invasion significantly decreased after AGO1 depletion using MTT, wound-healing, and transwell assay. The associated proteins in the epithelial-mesenchymal transition (EMT) and the activation of its signal pathways were measured using western blot. After AGO1 depleted, increased E-cadherin and decreased N-cadherin, Vimentin, Snail, and Zeb1 were founded. In its upstream pathway, the phosphorylation of ERK1/2(Thr202/Tyr204), Smad2(S425/250/255), and Smad4 were significantly inhibited. Meanwhile, inhibitor of ERK1/2(LY3214996) significantly inhibited the growth and migration of the AGO1 cells. The nuclear importing of Smad4 was blocked and furthermore, the transcription of Snail was also influenced for the decrease of combination between Smad4 and the promotor region of Snail. After Snail was overexpressed, the invasion of HCCLM3 cells was significantly rescued. Immunohistochemistry in tissue microarrays consisting of 200 HCC patients was used to analyze the associations between AGO1 expression and prognosis. Intratumoral AGO1 expression was an independent risk factor for overall survival (P = 0.008) and recurrence-free survival (P < 0.001). In conclusion, AGO1 may promote HCC metastasis through TGF-β pathway, and AGO1 may be a reliable prognostic factor in HCC.
| S-EPMC5832432 | biostudies-literature
Project description:CHI3L1 (YKL40) is a secreted glycoprotein and elevated serum CHI3L1 level has been proved to be associated with poor prognosis in many human cancers. However, the mechanism of how CHI3L1 causes poor prognosis in cancers is still unknown. Here, considering that CHI3L1 is a liver specific/enriched protein, we use hepatocellular carcinoma as a model to study the function of CHI3L1. We showed that, both in vivo and in vitro, overexpression of CHI3L1 could promote liver cancer cells growth, migration and invasion. We then used RNA-seq to analyze the expression profiles of CHI3L1 overexpressed in two HCC cell lines and found that CHI3L1 overexpression affected genes that were involved in cell-cell adhesion, extracellular exosome and adherens junction. Western blot analysis further revealed that CHI3L1 could activate TGF-β signal pathways. Our data added new understanding of the mechanism of CHI3L1's action. 1) CHI3L1 promoted cancer cell proliferation by regulating cell cycles; 2) CHI3L1 promoted cancer cell invasion and metastasis; 3) CHI3L1 regulate liver cancer potentially by regulating the TGF-β signaling pathways; 4) CHI3L1 has direct kinase activities or activate kinase to phosphorylate SMAD2, SMAD3.
| S-EPMC6177412 | biostudies-literature
Project description:Transforming growth factor beta (TGF-β) signaling pathway plays important roles in hepatocellular carcinoma (HCC) progression. Long intergenic non-protein coding RNAs (lincRNAs) are important components of TGF-β signaling pathway and perform their functions through different mechanisms. Here, we found that LINC02551 was activated by TGF-β transcriptionally and identified a 174-amino-acid peptide, Jun binding micropeptide (JunBP), encoded by LINC02551 in HCC tissues and HCC cell lines. Functional study showed that JunBP promotes HCC metastasis through binding to c-Jun and subsequent promotion of its phosphorylated activation. Activated c-Jun has higher binding affinity to SMAD3, which in turn leads to more SMAD3 recruited to the promoter region of LINC02551. We find a positive feedback among them, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in HCC.
| S-EPMC9816058 | biostudies-literature
Project description:The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.
| S-EPMC8022551 | biostudies-literature
Project description:Transforming growth factor β (TGF-β) is a potent inducer of epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC), and plays a critical role in its tumorigenesis and progression. Accumulating evidence indicates that protein-coding mRNAs, as well as non-coding RNAs (ncRNAs), may play key roles in the tumorigenesis and progression of HCC. In this study, we first report on the differential expression of lncRNAs, mRNAs, miRNAs, and circRNAs in Huh7 cells treated with TGF-β or DMSO for 7 days. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for significantly differentially expressed RNAs (DE RNAs). Then the competing endogenous RNA (ceRNA) network based on these DE RNAs was predicted and constructed. Among them, we identified that lncRNA SLC7A11-AS1 and hsa_circ_0006123 are involved in the EMT process induced by TGF-β and may promotes the metastasis of HCC. This knowledge may pave the way to develop novel clinical diagnostics and therapeutic approaches. Our study might open a new avenue for future investigations of the molecular mechanisms driving the EMT process induced by TGF-β in HCC.
| S-EPMC7732333 | biostudies-literature
Project description:Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.
| S-EPMC5528517 | biostudies-other
Project description:Modifications in adhesion molecules profile may change the way tumor cells interact with the surrounding microenvironment. The Cadherin family is a large group of transmembrane proteins that dictate the specificity of the cellular interactions. The Cadherin switch that takes place during epithelial-mesenchymal transition (EMT) contributes to loosening the rigid organization of epithelial tissues and to enhancing motility and invasiveness of tumor cells. Recently, we found Cadherin-6 (CDH6, also known as K-CAD) highly expressed in thyroid tumor cells that display mesenchymal features and aggressive phenotype, following the overexpression of the transcriptional regulator Id1. In this work, we explored the possibility that CDH6 is part of the EMT program in thyroid tumors. We demonstrate that CDH6 is a new transforming growth factor-β (TGF-β) target and that its expression is modulated similarly to other EMT mesenchymal markers, both in vitro and in thyroid tumor patients. We show for the first time that CDH6 is expressed in human thyroid carcinomas and that its expression is enhanced at the invasive front of the tumor. Finally, we show that CDH6 is under the control of the transcription factor RUNX2, which we previously described as a crucial mediator of the Id1 pro-invasive function in thyroid tumor cells. Overall, these observations provide novel information on the mechanism of the EMT program in tumor progression and indicate CDH6 as a potential regulator of invasiveness in thyroid tumors.
| S-EPMC3772092 | biostudies-literature
Project description:EndMT has an important effect on metastasis and progression of tumor. This work will elucidate the effect of miR-494 on EndMT and development of HCC. Therefore, the differential miRNA expression among non-tumorous, para-tumorous and tumorous tissues was analyzed. Moreover, luciferase activities of SIRT3 3'UTR treated with miR-494 were determined. Then human hepatoma cell lines were dealt with mimics or inhibitors of miR-494, migration and proliferation ability were assessed. The expression of SIRT3 and markers of mesenchymal cell were analyzed. The influences of miR-494 on development of HCC through inducing EndMT by targeting SIRT3 and TGF-β/SMAD signaling pathways in hepatoma cell lines were investigated. Xenograft mice were used to explore the potential roles of miR-494 on EndMT and development of HCC in vivo. Our results showed that, compared with non-tumorous tissues, 17 miRNAs were upregulated and 3 miRNAs were down-regulated in tumor tissues. In tumor tissues, the miR-494 expression level was much more than the expression of para-tumorous and non-tumorous tissues. MiR-494 suppressed SIRT3 expression, additionally enhanced expression of mesenchymal cell markers, while exerted effects on cell proliferation and migration of hepatoma cell lines. Moreover, the antagomir of miR-494 could protect against development process in xenogarft murine model. In conclusions, our work demonstrated that miR-494 targeted to SIRT3, and was a crucial mediator of EndMT and development of HCC through regulating SIRT3/TGF-β/SMAD signaling pathway. It suggested that aim at SIRT3/TGF-β/SMAD signaling pathway through suppressing the miR-494 expression level, was a feasible therapy strategy for HCC.
| S-EPMC6510769 | biostudies-literature
Project description:BackgroundHyper-activation of TGF-β signaling is critically involved in progression of hepatocellular carcinoma (HCC). However, the events that contribute to the dysregulation of TGF-β pathway in HCC, especially at the post-translational level, are not well understood.MethodsAssociations of deubiquitinase POH1 with TGF-β signaling activity and the outcomes of HCC patients were examined by data mining of online HCC datasets, immunohistochemistry analyses using human HCC specimens, spearman correlation and survival analyses. The effects of POH1 on the ubiquitination and stability of the TGF-β receptors (TGFBR1 and TGFBR2) and the activation of downstream effectors were tested by western blotting. Primary mouse liver tissues from polyinosinic:polycytidylic acid (poly I:C)- treated Mx-Cre+, poh1f/f mice and control mice were used to detect the TGF-β receptors. The metastatic-related capabilities of HCC cells were studied in vitro and in mice.FindingsHere we show that POH1 is a critical regulator of TGF-β signaling and promotes tumor metastasis. Integrative analyses of HCC subgroups classified with unsupervised transcriptome clustering of the TGF-β response, metastatic potential and outcomes, reveal that POH1 expression positively correlates with activities of TGF-β signaling in tumors and with malignant disease progression. Functionally, POH1 intensifies TGF-β signaling delivery and, as a consequence, promotes HCC cell metastatic properties both in vitro and in vivo. The expression of the TGF-β receptors was severely downregulated in POH1-deficient mouse hepatocytes. Mechanistically, POH1 deubiquitinates the TGF-β receptors and CAV1, therefore negatively regulates lysosome pathway-mediated turnover of TGF-β receptors.ConclusionOur study highlights the pathological significance of aberrantly expressed POH1 in TGF-β signaling hyperactivation and aggressive progression in HCC.
| S-EPMC6441868 | biostudies-literature
Project description:Both transforming growth factor-β (TGF-β) and parathyroid hormone-related protein (PTHrP) regulate important cellular processes, such as apoptosis in the development of hepatocellular carcinoma. However, the mechanisms of regulation of PTHrP by TGF-β are largely unknown. We hypothesized that TGF-β regulates the expression of PTHrP protein through a post-translational mechanism. Using hepatocellular carcinoma cell lines as the in vitro model, we investigated the effects of TGF-β on protein expression and post-translational processing of PTHrP. We found that TGF-β treatment led to protein degradation of PTHrP through the ubiquitin-proteasome-dependent pathway. We also provided evidence to show that Smurf2 was the E3 ligase responsible for the ubiquitination of PTHrP. Furthermore, using immunohistochemistry on human hepatocellular carcinoma specimens and a tissue array, we found that the expression of PTHrP was predominantly in the cancer cells, whereas the expression of TGF-β was present in non-neoplastic liver tissue adjacent to hepatocellular carcinoma. Our findings reveal a novel mechanism whereby TGF-β may regulate PTHrP in hepatocellular carcinogenesis and lack of TGF-β in hepatocellular carcinoma may promote cancer progression. Promotion of PTHrP degradation provides a novel target of therapeutic intervention to sensitize hepatocellular carcinoma cells to cytostatic and/or pro-apoptotic signals.
| S-EPMC4439935 | biostudies-literature