GSK-3β suppresses HCC cell dissociation <i>in vitro</i> by upregulating epithelial junction proteins and inhibiting Wnt/β-catenin signaling pathway

Zhang, Jinghua; Jiao, Liyan; Li, Tiejun; Zhu, York Yuanyuan; Zhou, Jianwei; Tian, Jing

doi:10.7150/jca.18744

Cited by 12 publications

(16 citation statements)

References 24 publications

(22 reference statements)

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“…N-cad and Vimentin are considered as pivotal mesenchymal markers, commonly used to reflect EMT [ 28 ]. In the cytoplasm, β -catenin continues binding and dissociating the cytoskeleton proteins, which promotes tumor cell migration by regulating cytoskeleton and modulating the coordinated cell–cell adhesion [ 29 , 30 ]. As our data suggested, ARG1 could promote the EMT process in HCC cells through upregulating the expression of N-cad, Vimentin, and β -catenin both at protein and mRNA levels, which was further supported by the downregulation of N-cad, Vimentin, and β -catenin and upregulation of E-cadherin in ARG1 knockdown cells.…”

Section: Discussionmentioning

confidence: 99%

The Oncogenic Role of ARG1 in Progression and Metastasis of Hepatocellular Carcinoma

You

Chen

et al. 2018

BioMed Research International

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ARG1, which encodes Arginase1, is expressed in the liver cytoplasm and plays a major role in the hepatic urea cycle. The past research works shed light on the fact that ARG1 participates in anti-inflammation, tumor immunity, and immunosuppression-related diseases. Nevertheless, the concrete role and clinical significance of ARG1 in the progression of hepatocellular carcinoma (HCC) remain unclear. Herein, we aimed at examining the expression and clinicopathological significance of ARG1 in HCC, together with determining the effect of ARG1 on the progression and metastasis of HCC. In the current study, evaluation of the expression of ARG1 and clinicopathological significance of ARG1 was carried out in the human HCC tissues microarray, and the ARG1 overexpression vector and shRNA-ARG1 plasmids were constructed for the assessment of the concrete effect of ARG1 on cellular behaviors of Huh7 cells. As our data revealed, ARG1 was significantly downregulated in HCC, and the higher expression of ARG1 was positively correlated with more aggressive tumor growth, size, ALT, and GGT level. Significantly, we found that the high expression of ARG1 was correlated with poor DFS of HCC patients. Besides, in vitro study revealed that overexpression of ARG1 could enhance arginase activity, cell viability, migration, and invasion of Huh7 cells, and loss-of-function of ARG1 by shRNA interference could inhibit these cellular behaviors. Additionally, overexpression of ARG1 led to a significant increase in the expression of Vimentin, N-cadherin, and β-catenin both at protein and mRNA levels, which promotes the EMT process. On the other hand, these proteins' expression was significantly downregulated in ARG1 silenced Huh7 cells. Besides, the level of E-cadherin protein was upregulated in ARG1 knocked down cells. In conclusion, ARG1 might play a pivotal role as an oncogene in the progression of HCC through promoting the EMT process.

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Section: Discussionmentioning

confidence: 99%

The Oncogenic Role of ARG1 in Progression and Metastasis of Hepatocellular Carcinoma

You

Chen

et al. 2018

BioMed Research International

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“…Accumulating evidence indicated that GSK3β mediated β-catenin phosphorylation is the key step to generate the β-TrCP-binding site for the subsequent degradation [ 35 , 52 , 53 ]. A recent study in HCC also showed that GSK-3β suppresses HCC cell dissociation in vitro by inhibiting Wnt/β-catenin signaling pathway [ 19 ]. Furthermore we found that the expression of ALX4 was positively correlated with the expression of the key members of the “β-catenin degradation complex”.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that ALX4 could suppress lung cancer progression by inducing cell apoptosis [ 18 ]. Recent studies showed its tumor-promoting or tumor-suppressive roles in HCC and ovarian cancers, indicating its diverse functions among different types of cancer [ 19 , 20 ]. Previous mice model study demonstrated that ALX4 is required for normal mammary gland morphogenesis during mouse puberty and lost expression in stromal and epithelial cells in breast tumors [ 13 , 14 ], suggesting it may be involved in the precancerous lesions of breast cancer.…”

Section: Introductionmentioning

confidence: 99%

ALX4, an epigenetically down regulated tumor suppressor, inhibits breast cancer progression by interfering Wnt/β-catenin pathway

Yang

Han

Liu

et al. 2017

J Exp Clin Cancer Res

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BackgroundALX4 is a paired-like homedomain transcription factor mainly expressed in the mesenchymal compartment of variety of developing tissues, but its functions, regulation mechanisms and clinical values in breast cancer remains unclear.MethodsThe expression of ALX4 in breast cancer cell lines and patients’ tissues were detected by RT-PCR, qPCR and western blot. Furthermore TCGA database was applied to confirm these results. MSP and BSP methods were used to assess the methylation of ALX4 promoter region. In vitro proliferation, metastasis and in vivo nude mice model were used to evaluate the anti-tumor effect of ALX4 on breast cancer cell lines. Luciferase reporter assay, western blot and TCGA database were used to investigate the tumor suppression mechanisms of ALX4. TMA of 142 breast patients was generated to evaluate the clinical significance of ALX4.ResultsExpression analysis revealed that ALX4 expression is down regulated in breast cancer cell lines and tissues. MSP study showed that the promoter region of ALX4 was hyper-methylated 100% (3/3) in breast cancer cell lines and 69.44% (75/108) in primary breast tumors tissues while 0% (0/8) in normal breast tissues. 5-aza-dc de-methylation treatment restored ALX4 expression in breast cancer cell lines. Functional studies showed that ectopic expression of ALX4 in breast cancer cells inhibited cell proliferation, metastasis in vitro and in vivo. Mechanism study found that ALX4 exerted its anti-tumor function by suppressing the Wnt/β-catenin pathway through promoting the phosphorylation degradation of β-catenin in a GSK3β dependent manner. Clinically multivariate analysis showed that ALX4 expression was an independent favorable prognostic factor in breast cancer patients.ConclusionsWe reveal for the first time that ALX4 acts as a novel functional tumor suppressor inactivated by DNA methylation and is an independent prognostic factor in breast cancer.Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0643-9) contains supplementary material, which is available to authorized users.

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“…Mutations and the overexpression of β‐catenin are detected in HCC tumour tissues and associated with the progression of HCC . The inhibition of Wnt/β‐catenin signalling by GSK‐3β restricts the proliferation, migration and invasion of HCC cells, suggesting an important role of GSK‐3β/Wnt/β‐catenin signalling in the progression of HCC . Wnt/β‐catenin signalling has been suggested as a promising target for the treatment of HCC.…”

Section: Introductionmentioning

confidence: 99%

“…22,23 The inhibition of Wnt/β-catenin signalling by GSK-3β restricts the proliferation, migration and invasion of HCC cells, suggesting an important role of GSK-3β/Wnt/β-catenin signalling in the progression of HCC. 24 Wnt/β-catenin signalling has been suggested as a promising target for the treatment of HCC. Despite the fact that the main components of the canonical Wnt/β-catenin signalling pathway have been characterized, the precise regulatory network of Wnt/β-catenin signalling transduction remains partially understood.…”

mentioning

confidence: 99%

ATDC promotes the growth and invasion of hepatocellular carcinoma cells by modulating GSK‐3β/Wnt/β‐catenin signalling

Xue

et al. 2019

Clin Exp Pharma Physio

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Accumulating evidence has suggested that the ataxia telangiectasia group D complementing (ATDC) gene is an emerging cancer‐related gene in multiple human cancer types. However, little is known about the role of ATDC in hepatocellular carcinoma (HCC). In this study, we aimed to investigate the expression level, biological function and underlying mechanism of ATDC in HCC. The expression of ATDC in HCC cells was detected by quantitative real‐time polymerase chain reaction and western blot analysis. Cell growth was determined by cell counting kit‐8 assay and colony formation assay. Cell invasion was assessed by Transwell invasion assay. The activation status of Wnt/β‐catenin signalling was evaluated by the luciferase reporter assay. Functional experiments showed that the silencing of ATDC expression significantly suppressed the growth and invasion of HCC cells, whereas the overexpression of ATDC promoted the growth and invasion of HCC cells in vitro. Moreover, we showed that ATDC overexpression promoted the phosphorylation of glycogen synthase kinase (GSK)‐3β and resulted in the activation of Wnt/β‐catenin signalling. Notably, the inhibition of GSK‐3β activity significantly abrogated the tumour suppressive effect of ATDC silencing, while the silencing of β‐catenin partially reversed the oncogenic effect of ATDC overexpression. Taken together, these findings reveal an oncogenic role of ATDC in HCC and show that the suppression of ATDC impedes the growth and invasion of HCC cells associated with the inactivation of Wnt/β‐catenin signalling. Our study suggests that ATDC may serve as a potential therapeutic target for HCC.

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GSK-3β suppresses HCC cell dissociation in vitro by upregulating epithelial junction proteins and inhibiting Wnt/β-catenin signaling pathway

Cited by 12 publications

References 24 publications

The Oncogenic Role of ARG1 in Progression and Metastasis of Hepatocellular Carcinoma

The Oncogenic Role of ARG1 in Progression and Metastasis of Hepatocellular Carcinoma

ALX4, an epigenetically down regulated tumor suppressor, inhibits breast cancer progression by interfering Wnt/β-catenin pathway

ATDC promotes the growth and invasion of hepatocellular carcinoma cells by modulating GSK‐3β/Wnt/β‐catenin signalling

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