Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

Wang, Wenhui; Pan, Qiuwei; Fuhler, Gwenny M.; Smits, Ron

doi:10.1007/s00535-016-1299-5

Cited by 69 publications

(71 citation statements)

References 132 publications

(108 reference statements)

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“…ZEB1 has the most consistent inverse correlation with E‐cadherin across different types of carcinomas, thus showing involvement in cancer cell motility. In the further research, β‐catenin is the core molecule in activation of the Wnt signaling pathway, and its content and localization are regulated by the APC/Axin/GSK3β complex . The IF assay showed that miR143HG could assemble β‐catenin on the membranes of HCC cells and prevent its nuclear translocation and subsequent activation.…”

Section: Discussionmentioning

confidence: 99%

“…In the further research, β-catenin is the core molecule in activation of the Wnt signaling pathway, and its content and localization are regulated by the APC/Axin/ GSK3β complex. 34 The IF assay showed that miR143HG could assemble β-catenin on the membranes of HCC cells and prevent its nuclear translocation and subsequent activation. These results from several aspects indicate that miR143HG affects HCC invasion and migration through the Wnt pathway.…”

Section: Discussionmentioning

confidence: 99%

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Long non‐coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen‐activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma

Xiong

Chen

et al. 2019

Hepatology Research

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Aim The expression of microRNA143HG (miR143HG) was significantly downregulated in hepatocellular carcinoma (HCC) tissues by bioinformatics analysis. This study aimed to determine the role of miR143HG in HCC cell proliferation and metastasis. Methods Fifty patients with HCC were divided into two groups based on median miR143HG expression levels. The correlation between miR143HG expression and prognosis, and the correlations between miR143HG expression and the patients’ clinicopathological characteristics were evaluated based on the two groups. Gain‐of‐function and loss‐of‐function measurements of miR143HG were carried out to verify the biological function of miR143HG by Cell Counting Kit‐8, EdU, Transwell, and western blotting assays and flow cytometric analysis. The underlying mechanism was explored by quantitative real‐time polymerase chain reaction of miRNA (miR‐155‐5p and miR‐26b‐5p), luciferase reporter assay, western blotting of Wnt signaling pathway‐related proteins (β‐catenin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), ZEB1, and E‐cadherin), mitogen‐activated protein kinase (MAPK) signaling pathway‐related proteins (extracellular signal‐regulated kinase [ERK]1/2, p‐ERK1/2, c‐Jun N‐terminal kinase (JNK), p‐JNK, P38, and p‐P38), and immunofluorescence staining of β‐catenin. Results miR143HG expression was markedly downregulated in HCC tissues and cells. Its expression was associated with the presence or absence of portal vein tumor thrombus, hepatitis B virus infection, relapse and metastasis, and Barcelona Clinic Liver Cancer stage. Additionally, miR143HG expression predicted a good prognosis and acted as an independent prognostic factor in HCC for overall survival. Overexpression of miR143HG suppressed HCC cell proliferation and metastasis, and induced cell cycle arrest and apoptosis. Consistently, the depletion of miR143HG resulted in the opposite phenomenon of the aforementioned results. miR143HG inhibits miR‐155 expression; miR‐155 directly targets APC, which is a negative regulator of the Wnt/β‐catenin pathway, so miR143HG can act on the Wnt pathway. miR143HG was further found to reduce the expression of β‐catenin and block the nuclear accumulation of β‐catenin, ultimately inhibiting the activation of the Wnt pathway. It inhibits the expression of Wnt downstream target gene ZEB1, and then E‐cadherin expression is increased and cell motility is inhibited. Furthermore, miR143HG exerts its antiproliferative function by influencing the MAPK signaling pathway and then inducing G2/M arrest in cells. Conclusion This study showed that miR143HG plays critical roles in the development and progression of HCC by suppressing the MAPK and Wnt signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen‐activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma

Xiong

Chen

et al. 2019

Hepatology Research

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“…Core protein has been shown to decreases the expression of the Wnt antagonists; dickkopf and secreted frizzled-related protein by recruiting DMT1, and HDAC1 to their transcription start sites. 138,139 The NS5A protein activates PI3K/Akt signaling, leading to the inactivation of GSK3β and subsequently reducing the degradation of β-catenin. 140,141 The activation of c-Myc oncogene through Wnt/β-catenin pathways has been shown to promote HCC in HCV transgenic mice model.…”

Section: The Wnt/β-catenin/c-myc Pathwaymentioning

confidence: 99%

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Dash¹,

Aydın²,

Widmer³

et al. 2020

JHC

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Hepatitis C virus (HCV) infection is the major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). The mechanisms of HCC initiation, growth, and metastasis appear to be highly complex due to the decade-long interactions between the virus, immune system, and overlapping bystander effects of host metabolic liver disease. The lack of a readily accessible animal model system for HCV is a significant obstacle to understand the mechanisms of viral carcinogenesis. Traditionally, the primary prevention strategy of HCC has been to eliminate infection by antiviral therapy. The success of virus elimination by antiviral treatment is determined by the SVR when the HCV is no longer detectable in serum. Interferon-alpha (IFNα) and its analogs, pegylated IFN-α (PEG-IFN-α) alone with ribavirin (RBV), have been the primary antiviral treatment of HCV for many years with a low cure rate. The cloning and sequencing of HCV have allowed the development of cell culture models, which accelerated antiviral drug discovery. It resulted in the selection of highly effective direct-acting antiviral (DAA)-based combination therapy that now offers incredible success in curing HCV infection in more than 95% of all patients, including those with cirrhosis. However, several emerging recent publications claim that patients who have liver cirrhosis at the time of DAAs treatment face the risk of HCC occurrence and recurrence after viral cure. This remains a substantial challenge while addressing the long-term benefit of antiviral medicine. The host-related mechanisms that drive the risk of HCC in the absence of the virus are unknown. This review describes the multifaceted mechanisms that create a tumorigenic environment during chronic HCV infection. In addition to the potential oncogenic programming that drives HCC after viral clearance by DAAs, the current status of a biomarker development for early prediction of cirrhosis regression and HCC detection post viral treatment is discussed. Since DAAs treatment does not provide full protection against reinfection or viral transmission to other individuals, the recent studies for a vaccine development are also reviewed.

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“…Human HCC cell lines Hep3B, HepG2, HepaRG, Huh6, Huh7, PLC/PRF/5, SNU398, SNU182, and SNU449 were cultured as reported previously (7). Identity of all cell lines was confirmed by short tandem repeat genotyping.…”

Section: Cell Linesmentioning

confidence: 99%

Oncogenic STRAP Supports Hepatocellular Carcinoma Growth by Enhancing Wnt/β-Catenin Signaling

Wang

Liu

et al. 2019

Molecular Cancer Research

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Aberrant activation of Wnt/b-catenin signaling plays a key role in the onset and development of hepatocellular carcinomas (HCC), with about half of them acquiring mutations in either CTNNB1 or AXIN1. The serine/threonine kinase receptor-associated protein (STRAP), a scaffold protein, was recently shown to facilitate the aberrant activation of Wnt/ b-catenin signaling in colorectal cancers. However, the function of STRAP in HCC remains completely unknown. Here, increased levels of STRAP were observed in human and mouse HCCs. RNA sequencing of STRAP knockout clones generated by gene editing of Huh6 and Huh7 HCC cells revealed a significant reduction in expression of various metabolic and cell-cycle-related transcripts, in line with their general slower growth observed during culture. Importantly, Wnt/b-catenin signaling was impaired in all STRAP knockout/down cell lines tested, regardless of the underlying CTNNB1 or AXIN1 mutation. In accordance with b-catenin's role in (cancer) stem cell maintenance, the expressions of various stem cell markers, such as AXIN2 and LGR5, were reduced and concomitantly differentiationassociated genes were increased. Together, these results show that the increased STRAP protein levels observed in HCC provide growth advantage among others by enhancing Wnt/b-catenin signaling. These observations also identify STRAP as a new player in regulating b-catenin signaling in hepatocellular cancers.Implications: Elevated STRAP levels in hepatocellular cancers provide a growth advantage by enhancing Wnt/b-catenin signaling.

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Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

Cited by 69 publications

References 132 publications

Long non‐coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen‐activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma

Long non‐coding RNA miR143HG predicts good prognosis and inhibits tumor multiplication and metastasis by suppressing mitogen‐activated protein kinase and Wnt signaling pathways in hepatocellular carcinoma

<p>Hepatocellular Carcinoma Mechanisms Associated with Chronic HCV Infection and the Impact of Direct-Acting Antiviral Treatment</p>

Oncogenic STRAP Supports Hepatocellular Carcinoma Growth by Enhancing Wnt/β-Catenin Signaling

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