Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

Wu, Jia-Ru; Hu, Chi-Tan; You, Ren-In; Pan, Siou-Mei; Cheng, Chuan-Chu; Lee, Ming-Che; Wu, Chung Chih; Chang, Yao-Jen; Lin, Shu-Chuan; Chen, Chang–Shan; Lin, Teng-Yi; Wu, Wen-Sheng

doi:10.18632/oncotarget.5322

Cited by 24 publications

(49 citation statements)

References 47 publications

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“…1D , upper panel). Moreover, TPA can induce activation of MMP9-950 and ZEB1-1079 by 35.0- and 7.0-fold, respectively, in HCC340, a patient derived HCC cell line 24 (Fig. 1D , lower panel).…”

Section: Resultsmentioning

confidence: 99%

Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

You

Cheng

et al. 2017

Sci Rep

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The Snail transcription factor plays as a master regulator of epithelial mesenchymal transition (EMT), one of the steps of tumor metastasis. Snail enhances expressions of a lot of mesenchymal genes including the matrix degradation enzyme matrix metalloproteinases 9 (MMP9) and the EMT transcription factor zinc finger E-box binding homeobox 1 (ZEB1), however, the underlying mechanisms are not clarified. Herein, we investigated how Snail upregulated transcription of ZEB1 and MMP9 induced by the tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA) in hepatoma cell HepG2. According to deletion mapping and site directed mutagenesis analysis, the TPA-responsive elements on both MMP9 and ZEB1 promoters locate on a putative EGR1 and SP1 overlapping region coupled with an upstream proposed Snail binding motif TCACA. Consistently, chromatin immunoprecipitation (ChIP) assay showed TPA triggered binding of Snail, EGR1 and SP1 on MMP9 and ZEB1 promoters. Double ChIP further indicated TPA induced association of Snail with EGR1 and SP1 on both promoters. Also, electrophoresis mobility shift assay revealed TPA enhanced binding of Snail with a MMP9 promoter fragment. According to shRNA techniques, Snail was essential for gene expression of both ZEB1 and MMP9. In conclusion, Snail transactivates genes involved in tumor progression via direct binding to a specific promoter region.

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Section: Resultsmentioning

confidence: 99%

Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

You

Cheng

et al. 2017

Sci Rep

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“…Another molecule, hydrogen peroxide-inducible clone-5 (Hic-5) is a TGF-β1-inducible focal adhesion protein that facilitates cell proliferation and ECM expansion in various organs[67]. Previous studies have shown that Hic-5 contributes to vascular restoration and restructuring[67,68]; however, a recent study revealed that Hic-5 expression also plays a critical role in attenuating fibrosis by enhancing TGF-β-induced Smad2 phosphorylation via the downregulation of Smad7 in both human and mouse aHSCs[69]. Taken together, these data indicate that Hic-5 is a novel therapeutic target and a potential marker of activated HSCs.…”

Section: Novel Therapeutic Targets In Liver Fibrosismentioning

confidence: 99%

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Zhang¹,

Yuan²,

He³

et al. 2016

WJG

445

327

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Liver fibrosis is a reversible wound-healing process aimed at maintaining organ integrity, and presents as the critical pre-stage of liver cirrhosis, which will eventually progress to hepatocellular carcinoma in the absence of liver transplantation. Fibrosis generally results from chronic hepatic injury caused by various factors, mainly viral infection, schistosomiasis, and alcoholism; however, the exact pathological mechanisms are still unknown. Although numerous drugs have been shown to have antifibrotic activity in vitro and in animal models, none of these drugs have been shown to be efficacious in the clinic. Importantly, hepatic stellate cells (HSCs) play a key role in the initiation, progression, and regression of liver fibrosis by secreting fibrogenic factors that encourage portal fibrocytes, fibroblasts, and bone marrow-derived myofibroblasts to produce collagen and thereby propagate fibrosis. These cells are subject to intricate cross-talk with adjacent cells, resulting in scarring and subsequent liver damage. Thus, an understanding of the molecular mechanisms of liver fibrosis and their relationships with HSCs is essential for the discovery of new therapeutic targets. This comprehensive review outlines the role of HSCs in liver fibrosis and details novel strategies to suppress HSC activity, thereby providing new insights into potential treatments for liver fibrosis.

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“…Different reports suggest for Hic-5 implications in malignant diseases, as Hic-5 has been intensively studied for its role in modulating the TGFβ signaling pathway and ECM remodeling during prostate cancerogenesis [ 10 , 11 , 17 , 30 , 36 - 40 , 54 - 57 ]. Similarly, Hic-5-mediated regulatory functions were shown to induce metastasis in breast cancer [ 14 , 32 , 55 ], melanoma [ 33 ] and hepatocellular carcinoma [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner

et al. 2017

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The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. We have previously identified the hydrogen peroxide-inducible clone-5 (Hic-5) gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. Hic-5 is a focal adhesion scaffold protein and has been primarily studied for its role as a key mediator of TGF-β–induced epithelial-to-mesenchymal transition (EMT) in epithelial cells of both normal and malignant origin; however, its role in EOC has been never investigated.Here we demonstrate that Hic-5 is overexpressed in advanced EOC, and that Hic-5 is upregulated upon TGFβ1 treatment in the EOC cell line with epithelial morphology (A2780s), associated with EMT induction. However, ectopic expression of Hic-5 in A2780s cells induces EMT independently of TGFβ1, accompanied with enhancement of cellular proliferation rate and migratory/invasive capacity and increased resistance to chemotherapeutic drugs. Moreover, Hic-5 knockdown in the EOC cells with mesenchymal morphology (SKOV3) was accompanied by induction of mesenchymal-to-epithelial transition (MET), followed by a reduction of their proliferative, migratory/invasive capacity, and increased drugs sensitivity in vitro, as well as enhanced tumor cell colonization and metastatic growth in vivo. The modulation of Hic-5 expression in EOC cells resulted in altered regulation of numerous EMT-related canonical pathways and was indicative for a possible role of Hic-5 in controlling EMT through a RhoA/ROCK mediated mechanism.To our knowledge, this is the first report examining the role of Hic-5 in EOC, and its role in maintaining the mesenchymal phenotype of EOC cells independently of exogenous TGFβ1 treatment.

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Hydrogen peroxide inducible clone-5 mediates reactive oxygen species signaling for hepatocellular carcinoma progression

Cited by 24 publications

References 47 publications

Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1

Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets

Hic-5 regulates epithelial to mesenchymal transition in ovarian cancer cells in a TGFβ1-independent manner

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