TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Huang, Jiawei; Qiu, Mengyuan; Wan, Li; Gui, Wang; Huang, Tongzhou; Chen, Zhuo; Jiang, Songmin; Li, Xiaokun; Xie, Lixiao; Cai, Lin

doi:10.1159/000487737

Cited by 31 publications

(26 citation statements)

References 30 publications

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“…Studies performed on human HCC patients with metastasis showed a significant increase of CNPY2 protein levels and activity, arguing for a functional link between GSNOR-dependent S-nitrosylation and HCC existing also in humans [12]. Chronic oxidative stress produced by mitochondria promotes hepatocarcinogenesis and tumor progression [32]. Thus, we could speculate that CNPY2 might promote the development of HCC and maintain cancer cell growth under metabolic Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry…”

Section: Discussionmentioning

confidence: 98%

Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage

Wang

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Canopy homolog 2 (CNPY2) is a signature gene highly associated with tumor progression, including hepatocellular carcinoma (HCC). The presence of tumor hemorrhage (TH) implies a fast-growing and worse tumor microenvironment. We examined a possible association between CNPY2 levels and TH and evaluated their prognostic values in patients with HCC. Methods: CNPY2 mRNA and protein levels were respectively determined in two independent cohorts of HCC specimens using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry of tissue microarrays. Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. CNPY2 knockout HCC cell lines were established by the CRISPR/Cas9 gene editing system, and the functional role of CNPY2 in HCC cell proliferation and growth was examined in vitro and in vivo. Results: qRT-PCR showed that CNPY2 expression was significantly higher in HCC tumor tissue than in adjacent non-tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that CNPY2 expression was significantly correlated with TH and clinicopathological features indicating worse HCC progression. The prognostic value of CNPY2 expression and TH was validated by Cox proportional hazards analyses. Furthermore, CNPY2 knockout resulted in the significant suppression of MHCC97H cell proliferation, tumor growth, and hemorrhage. Bioinformatics analysis revealed that CNPY2 was closely associated with the expression levels of 6 positive impact genes in HCC, namely, ROMO1, BOLA2, HSF1, ATG4B, ATF4, and DENR, which are implicated in the regulation of the tumor microenvironment. Conclusion: CNPY2 is an oncogene that plays a critical role in the progression of HCC with TH. CNPY2 could be exploited as a novel prognostic marker and potential target for therapeutic intervention in HCC.

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Section: Discussionmentioning

confidence: 98%

Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage

Wang

Zhang

et al. 2018

Cell Physiol Biochem

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“…However, both repressors appeared to contribute to AFP overexpression . To add complexity, other studies have identified additional effects of cytokine signalling, such as TGF‐β, on AFP expression, which is only further complicated by the well‐known fact that TGF‐β also has distinct roles in tumour inhibition vs tumour progression depending on the stage of disease . Despite progress to date, additional research is clearly needed to better characterize the regulation of AFP in HCC.…”

Section: Pathophysiologymentioning

confidence: 99%

Biology and significance of alpha‐fetoprotein in hepatocellular carcinoma

Galle

Foerster

Kudo

et al. 2019

Liver International

392

284

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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker.In fact, numerous biomarkers have been studied in HCC, but alpha-fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro-proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are | 2215 GALLE Et AL.

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“…In contrast, Smad4 was also found to play important oncogenic roles in a vast diversity of cancer types, including breast cancer (Taylor et al, 2013;Xue et al, 2014), ovarian cancer (Chan et al, 2017), glioblastoma (Eichhorn et al, 2012), and HCC (Huang et al, 2018;Moon et al, 2017). And metastasis is the most common outcome in TGF-b-hyperactivated cancer cells, generally owing to the promotion of epithelial-mesenchymal transition (Bertran et al, 2013;Taylor et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…And metastasis is the most common outcome in TGF-b-hyperactivated cancer cells, generally owing to the promotion of epithelial-mesenchymal transition (Bertran et al, 2013;Taylor et al, 2013). Particularly, in HCC models, TGF-b/Smad4 promotes invasion/metastasis by promoting ERK pathway-mediated FGFR4 expression (Huang et al, 2018) or through lncRNA activated by TGF-b (lncRNA-ATB) by competitively binding the miR-200 family and up-regulating ZEB1/2 (Yuan et al, 2014). In line with these studies, we found that the activation of TGF-b/Smad4 is closely correlated with the poor prognosis of HCC patients.…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

et al. 2019

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Hepatocellular carcinoma (HCC) has emerged as one of the most prevalent life-threatening cancers, and the high mortality rate is largely due to the metastasis. The sustained activation of Smad4 and transforming growth factor-b (TGF-b) is closely associated with advanced HCC metastasis. However, the regulatory mechanism underlying the aberrant activation of Smad4 and TGF-b pathway remains elusive. In this study, using a functional screen of USPs siRNA library, we identified ubiquitin-specific proteases USP10 as a deubiquitinating enzyme (DUB) that sustains the protein level of Smad4 and activates TGF-b signaling. Further analysis showed that USP10 directly interacts with Smad4 and stabilizes it through the cleavage of its proteolytic ubiquitination, thus promoting HCC metastasis. The suppression of USP10 by either shRNAs or catalytic inhibitor Spautin-1 significantly inhibited the migration of HCC cells, whereas the reconstitution of Smad4 was able to efficiently rescue this defect. Overall, our study not only uncovers the regulatory effect of USP10 on the protein abundance of Smad4, but also indicates that USP10 could be regarded as a potential intervention target for the metastatic HCC in Smad4-positive patients.

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TGF-β1 Promotes Hepatocellular Carcinoma Invasion and Metastasis via ERK Pathway-Mediated FGFR4 Expression

Cited by 31 publications

References 30 publications

Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage

Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage

Biology and significance of alpha‐fetoprotein in hepatocellular carcinoma

Deubiquitinating enzyme USP10 promotes hepatocellular carcinoma metastasis through deubiquitinating and stabilizing Smad4 protein

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