Overexpression of EMT-inducing transcription factors as a potential poor prognostic factor for hepatocellular carcinoma in Asian populations: A meta-analysis

Wan, Tao; Zhang, Tianwei; Si, Xiaoying; Zhou, Yanming

doi:10.18632/oncotarget.18352

Cited by 20 publications

(20 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EMT is an important biological process involved in the progression and immune evasion of cancers. In HCC, EMT contributes to a poor prognosis ( 34 , 35 ). Emerging research has found higher expression of PD-L1 in mesenchymal cells in non-small cell lung carcinoma ( 36 ).…”

Section: Resultsmentioning

confidence: 99%

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

Prithviraj²,

et al. 2018

View full text Add to dashboard Cite

The global burden of hepatocellular carcinoma (HCC), one of the frequent causes of cancer-related deaths worldwide, is rapidly increasing partly due to the limited treatment options available for this disease and recurrence due to therapy resistance. Immune checkpoint inhibitors that are proved to be beneficial in the treatment of advanced melanoma and other cancer types are currently in clinical trials in HCC. These ongoing trials are testing the efficacy and safety of a few select checkpoints in HCC. Similar to observations in other cancers, these immune checkpoint blockade treatments as monotherapy may benefit only a fraction of HCC patients. Studies that assess the prevalence and distribution of other immune checkpoints/modulatory molecules in HCC have been limited. Moreover, robust predictors to identify which HCC patients will respond to immunotherapy are currently lacking. The objective of this study is to perform a comprehensive evaluation on different immune modulators as predictive biomarkers to monitor HCC patients at high risk for poor prognosis. We screened publically available HCC patient databases for the expression of previously well described immune checkpoint regulators and evaluated the usefulness of these immune modulators to predict high risk, patient overall survival and recurrence. We also identified the immune modulators that synergized with known immune evasion molecules programmed death receptor ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and correlated with worse patient outcomes. We evaluated the association between the expression of epithelial-to-mesenchymal transition (EMT) markers and PD-L1 in HCC patient tumors. We also examined the relationship of tumor mutational burden with HCC patient survival. Notably, expression of immune modulators B7-H4, PD-L2, TIM-3, and VISTA were independently associated with worse prognosis, while B7-H4, CD73, and VISTA predicted low recurrence-free survival. Moreover, the prognosis of patients expressing high PD-L1 with high B7-H4, TIM-3, VISTA, CD73, and PD-L2 expression was significantly worse. Interestingly, PD-L1 expression in HCC patients in the high-risk group was closely associated with EMT marker expression and prognosticates poor survival. In HCC patients, high tumor mutational burden (TMB) predicted worse patient outcomes than those with low TMB.

show abstract

Section: Resultsmentioning

confidence: 99%

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

Prithviraj²,

et al. 2018

View full text Add to dashboard Cite

show abstract

“…EMT plays a crucial role in metastasis dissemination and is correlated with poor prognosis in cancer patients [24–26]. However, the precise molecular events that initiate this complex process in bladder cancer are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated fibroblasts induce epithelial–mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling

et al. 2019

View full text Add to dashboard Cite

BackgroundCancer-associated fibroblasts (CAFs), activated by tumour cells, are the predominant type of stromal cells in cancer tissue and play an important role in interacting with neoplastic cells to promote cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. However, the mechanism by which CAFs induce EMT program in bladder cancer cells remains unclear.MethodsTo investigate the role of CAFs in bladder cancer progression, healthy primary bladder fibroblasts (HFs) were induced into CAFs (iCAFs) by bladder cancer-derived exosomes. Effect of conditioned medium from iCAFs (CM iCAF) on EMT markers expression of non-invasive RT4 bladder cancer cell line was determined by qPCR and Western blot. IL6 expression in iCAFs was evaluated by ELISA and Western blot. RT4 cell proliferation, migration and invasion were assessed in CM iCAF +/− anti-IL6 neutralizing antibody using cyQUANT assay, scratch test and transwell chamber respectively. We investigated IL6 expression relevance for bladder cancer progression by querying gene expression datasets of human bladder cancer specimens from TCGA and GEO genomic data platforms.ResultsCancer exosome-treated HFs showed CAFs characteristics with high expression levels of αSMA and FAP. We showed that the CM iCAF induces the upregulation of mesenchymal markers, such as N-cadherin and vimentin, while repressing epithelial markers E-cadherin and p-ß-catenin expression in non-invasive RT4 cells. Moreover, EMT transcription factors SNAIL1, TWIST1 and ZEB1 were upregulated in CM iCAF-cultured RT4 cells compared to control. We also showed that the IL-6 cytokine was highly expressed by CAFs, and its receptor IL-6R was found on RT4 bladder cancer cells. The culture of RT4 bladder cancer cells with CM iCAF resulted in markedly promoted cell growth, migration and invasion. Importantly, inhibition of CAFs-secreted IL-6 by neutralizing antibody significantly reversed the IL-6-induced EMT phenotype, suggesting that this cytokine is necessary for CAF-induced EMT in the progression of human bladder cancer. Finally, we observed that IL6 expression is up-regulated in aggressive bladder cancer and correlate with CAF marker ACTA2.ConclusionsWe conclude that CAFs promote aggressive phenotypes of non-invasive bladder cancer cells through an EMT induced by the secretion of IL-6.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5353-6) contains supplementary material, which is available to authorized users.

show abstract

“…The main features of the EMT include the downregulation of epithelial markers, such as E-cadherin, beta-catenin, tight junction protein-1, laminin, and cytokeratin, and the upregulation of mesenchymal markers such as N-cadherin, vimentin, and α -smooth muscle actin ( α -SMA). A number of transcription factors are involved in the EMT of HCC, including Snail, Twist, and zinc finger E-box binding protein 1 (ZEB1), and their presence is associated with a poor prognosis [29–31]. These EMT transcription factors activate multiple cellular signaling pathways and molecules, such as Akt, MAPK, STAT3, transforming growth factor beta (TGF- β ), β -catenin, Wnt, Ras, Notch, nuclear factor κ B (NF- κ B), tumor necrosis factor alpha (TNF- α ), and hypoxia-inducible factor-1 alpha (HIF-1 α ) [31].…”

Section: Emt and Hccmentioning

confidence: 99%

The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

Scheau

Bădărău

Costache

et al. 2019

Analytical Cellular Pathology

259

219

View full text Add to dashboard Cite

The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of many malignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellular regeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal development and also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCC invasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. While gelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes have been proven to be involved in this process, favoring not only invasion and metastasis (MMP-1, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP-14, MMP-16, MMP-26, and MMP-28) but also angiogenesis (MMP-8 and MMP-10). There is also data suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have some degree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent of implication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential in preventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which is addressed herein.

show abstract

Overexpression of EMT-inducing transcription factors as a potential poor prognostic factor for hepatocellular carcinoma in Asian populations: A meta-analysis

Cited by 20 publications

References 43 publications

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

Monitoring Immune Checkpoint Regulators as Predictive Biomarkers in Hepatocellular Carcinoma

Cancer-associated fibroblasts induce epithelial–mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling

The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

Contact Info

Product

Resources

About