β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation

Ge, Wensong; Wang, Yaojun; Wu, Jianxin; Fan, Jian‐Gao; Chen, Yingwei; Zhu, Liang

doi:10.3892/mmr.2014.2099

Cited by 86 publications

(64 citation statements)

References 36 publications

(39 reference statements)

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“…β-catenin is critically responsible for epithelial cell-cell adhesion (37), and plays a key role in several developmental and pathologic processes including early embryonic development (38), fibrosis (39)(40)(41)(42), cystic disease (43), renal failure (44) and cancer. For example, the expression level of β-catenin has been shown to correlate with progression in colorectal (18), cervical (19), prostate (20), renal cell carcinoma (45,46), hepatocellular carcinoma (47,48), cholangiocarcinoma (26) and several other types of tumors.…”

Section: +mentioning

confidence: 99%

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Feng

Zhang

et al. 2015

Oncology Reports

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Abstract. Prostaglandin E2 (PGE2) is involved in cholangiocarcinoma cell proliferation, migration and invasion through E prostanoid receptors, including EP1, EP2 and EP4. However, the functions and the mechanisms of those splice variants of EP3 receptors in promoting liver cancer cell growth and invasion remain to be elucidated. In our previous studies, four isoforms of EP3 receptors, EP3-4, EP3-5, EP3-6 and EP3-7 receptors, were detected in CCLP1 and HuCCT1 cells. However, the functions of these receptors in these cells have yet to be determined. It was reported that β-catenin is closely correlated with malignancy, including cholangiocarcinoma. The present study was designed to examine the effects of 4-7 isoforms of EP3 in promoting cholangiocarcinoma progression and the mechanisms by which PGE2 increases β-catenin protein via EP3 receptors. The results showed that PGE2 promotes cholangiocarcinoma progression via the upregulation of β-catenin protein, and the EP3-4 receptor pathway is mainly responsible for this regulation. These findings reveal that PGE2 upregulated the cholangiocarcinoma cell β-catenin protein through the EP3-4R/Src/EGFR/PI3K/AKT/GSK-3β pathway. The present study identified the functions of EP3 and the mechanisms by which PGE2 regulates β-catenin expression and promoted cholangiocarcinoma cell growth and invasion.

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Section: +mentioning

confidence: 99%

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Feng

Zhang

et al. 2015

Oncology Reports

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“…Consistently, miR-197 has been shown to promote pulmonary metastasis for non-small cell lung cancer [37,46]. miR-197 also participates in the development of a number of types of cancer [26][27][28][29][30][31][32][33][34], including HCC [29,30], indicating the role of miR-197 in cancer.miR-197 also participates in liver fibrosis [35,36], in which Wnt/β-catenin signaling also plays a central role [47].…”

Section: Discussionmentioning

confidence: 96%

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling

Wang

Lin

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/β-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/β-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/β-catenin pathway in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. Results: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/β-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/β-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. Conclusion: miR-197 promotes HCC invasion and metastasis by activating Wnt/β-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.

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“…The role of Wnt signaling in liver fibrosis is still controversially discussed [8,9,15,16,17,18,19]. Several studies supported the importance and functional existence of canonical Wnt signaling in HSC activation [8,15,33] and experimental liver fibrosis by antagonizing/blocking Wnt components and β-catenin [15,34].…”

Section: Discussionmentioning

confidence: 99%

“…The mitogenic activity of Wnt/β-catenin signaling has been shown in several studies [1,16]. However, the transcriptional targets by which β-catenin induces proliferation in liver injury and cancer remain elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Some studies reported that canonical Wnt/β-catenin signaling works in a combinatorial manner with transforming growth factor-β signaling, stimulates hepatic stellate cells (HSC) [8,15,16] and enhances liver fibrosis. In this regard, blockage of canonical Wnt signaling inhibited HSC activation, accompanied by decreased collagen 1 and α-smooth muscle actin (αSMA) expression [16], and ameliorated matrix accumulation in mice which underwent bile duct ligation (BDL) [15]. In contrast, others state the importance of Wnt/β-catenin in maintaining the quiescent stage of HSC [9,17] or suggest a significant role of noncanonical Wnt pathways in the development of liver fibrosis, respectively [18,19].…”

Section: Introductionmentioning

confidence: 99%

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Differential Effects of Axin2 Deficiency on the Fibrogenic and Regenerative Response in Livers of Bile Duct-Ligated Mice

Abshagen

Senne²,

Genz³

et al. 2015

Eur Surg Res

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Background: Wnt signaling is involved in the pathogenesis of liver fibrosis. Axin2 is a negative regulator of the canonical Wnt pathway by promoting β-catenin degradation. β-Catenin-activating and loss-of-function mutations of Axin2 are thought to be functionally relevant for liver diseases and cancer. Thus, we hypothesized that Axin2 deficiency promotes fibrogenesis. Methods: As the functions and mechanisms of how Axin2/β-catenin signaling participates in the progression of liver fibrosis are unclear, we investigated the progression of liver fibrosis in Axin2-deficient mice using Axin2-LacZ reporter mice (Axin2^+/-, Axin2^-/-, and Axin2^+/+) which underwent bile duct ligation (BDL). Results: Here, we show that the expression of Axin2 is downregulated during fibrogenesis in wild-type mice, which is consistent with a decreased expression of the reporter gene LacZ in Axin2^+/- and Axin2^-/- mice. Surprisingly, no alteration in active β-catenin/Wnt signaling occurs in Axin2-deficient mice upon BDL. Despite a less pronounced liver injury, Axin2 deficiency had only minor and no significant effects on the fibrogenic response upon BDL, i.e. slightly reduced hepatic stellate cell activity and collagen mRNA expression. However, livers of Axin2^-/- mice shared a stronger cell proliferation both already at baseline as well as immediately after BDL. Conclusion: Our results strongly suggest, contrary to expectation, that a deficiency in Axin2 is not equivalent to an increase in active β-catenin and target genes, indicating no functional relevance of Axin2-dependent regulation of the canonical Wnt/β-catenin pathway in the progression of cholestatic liver injury. This also suggests that the negligible effects of Axin2 deficiency during fibrogenesis may be related to an alternative pathway.

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β-catenin is overexpressed in hepatic fibrosis and blockage of Wnt/β-catenin signaling inhibits hepatic stellate cell activation

Cited by 86 publications

References 36 publications

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling

Differential Effects of Axin2 Deficiency on the Fibrogenic and Regenerative Response in Livers of Bile Duct-Ligated Mice

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