Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma

Wang, Weiwei; Zhong, Wei; Yuan, Jiahui; Yan, Congcong; Hu, Shaoping; Tong, Yinping; Mao, Yonghui; Hu, Tianhui; Zhang, Bing; Song, Gang

doi:10.18632/oncotarget.5514

Cited by 82 publications

(67 citation statements)

References 39 publications

(43 reference statements)

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“…In the Wnt signaling pathway, the binding of Wnt ligand to its receptors leads to nuclear translocation of b-catenin. 21 In our study, HGA markedly accumulated b-catenin in the nuclei of MSCs compared with that incubated in only the OIM. In contrast, Noggin treatment obviously blocked HGA-induced accumulation of bcatenin; however, Dkk-1 only moderately decreased HGAinduced accumulation of b-catenin (Fig.…”

Section: Noggin and Dkk-1 Inhibit The Effect Of Hga On Osteogenesis Isupporting

confidence: 45%

Aqueous Fraction of Huogu Formula Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells Through the BMP and Wnt Signaling Pathways

Kong

Zhang

et al. 2016

Rejuvenation Research

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Our recent studies have shown that Huogu (HG) formula was effective both in clinic experience and in experimental osteonecrosis of the femoral head (ONFH). Given that defective of bone marrow stromal cells (MSCs) contribute to the development of osteonecrosis and MSCs show enormous potential in the treatment of ONFH, especially to aging people. How HG impacts the differentiation of MSCs and what is the underlying cellular and molecular mechanism remains largely unknown. Here, we found that an aqueous fraction of HG (HGA) significantly increased the alkaline phosphatase (ALP) activity, mineralized nodules, and migration of MSCs in a dose-dependent manner. Meanwhile, HGA could enhance the mRNA and protein expression of Runt-related transcription factor 2 (Runx2), Alp, Bmp2, osteocalcin (Ocn), and Osterix (Osx). Further investigation of the molecular mechanisms revealed that HGA treatment obviously increased expression, secretion, and activation of bone morphogenetic protein (BMP) 2 and b-catenin, two key regulators of the BMP or Wnt signaling pathway. Furthermore, osteogenic differentiation of MSCs could be blocked by using pharmacological inhibitors for these signaling pathways such as Noggin and Dkk-1. Besides, HGA could inhibit adipogenic differentiation of MSCs. Our study reveals that HGA promotes the osteogenesis of MSCs via the BMP and Wnt signaling pathways. Our findings provide mechanistic insights into the role of HG in treating ONFH.

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Section: Noggin and Dkk-1 Inhibit The Effect Of Hga On Osteogenesis Isupporting

confidence: 45%

Aqueous Fraction of Huogu Formula Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells Through the BMP and Wnt Signaling Pathways

Kong

Zhang

et al. 2016

Rejuvenation Research

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“…This interaction between sFRPs and Wnt proteins prevents the Wnt protein binding to frizzled receptors and in turn shuts down Wnt/β-catenin signaling [40]. Masses of studies have shown that Wnt/β-catenin signaling pathway is quite critical for CCA carcinogenesis and its progression [41,42]. We identified sFRP1as a direct target of miR-191, and further found that miR-191 regulates the Wnt/β-catenin signaling pathway via targeting sFRP1.…”

Section: Discussionmentioning

confidence: 80%

miR-191 Inhibition Induces Apoptosis Through Reactivating Secreted Frizzled-Related Protein-1 in Cholangiocarcinoma

Kang

Leng

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cholangiocarcinoma (CCA) is one of the most common malignant tumors of the biliary tract originating from biliary epithelial cells. Although many therapeutic strategies have been developed to treat CCA, the survival rate for CCA patients is still quite low. Thus it is urgent to elucidate the pathogenesis of CCA and to explore novel therapeutic targets. miR-191 has been shown to be associated with many human solid cancers, but the function of miR-191 in CCA is still poorly understood. Methods: We first investigated the expression level of miR-191 in human CCA tissues and cell lines with quantitative real-time PCR (qRT-PCR). The effects of miR-191 on CCA cells were determined by Cell Counting Kit-8 assay, colony formation assay and acridine orange/ethidium bromide staining. Finally, we utilized qRT-PCR, western blot and luciferase reporter assays to verify the miR-191 target gene. Results: We showed that miR-191 was up-regulated in CCA cell lines and patients. Knockdown of miR-191 by transfection of its inhibitor sequence blocked RBE cells viability and induced apoptosis of RBE cells. Both qRT-PCR and western blot analysis showed that the secreted frizzled-related protein-1 (sFRP1) level was negatively correlated with that of miR-191. Luciferase assay validated that sFRP1 was a direct target of miR-191. Moreover, knockdown of miR-191 led to suppression of Wnt/β-catenin signaling activation. Co-transfection of sFRP1 small interfering RNA (siRNA) and miR-191 inhibitor re-activated the Wnt/β-catenin signaling pathway as detected by an increased level of β-catenin and phosphorylation of GSK-3β, and restored the expression of survivin and c-myc in RBE cells. Co-transfection of sFRP1 siRNA with miR-191 inhibitor restored the colony formation ability and viability of RBE cells. Conclusion: Taken together, our results demonstrate a novel insight into miR-191 biological function in CCA. Our findings suggest that miR-191 is a potential therapeutic target of CCA treatment.

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“…Among them are transcription factors belonging to morphogenetic signaling pathways that are active during biliary development, and become reactivated during liver repair and carcinogenesis, including Hedgehog 77 , Wnt 68,78 , and notably, Notch 79–83 signaling. YAP/TAZ are less characterized transcriptional co-activators critically involved in organ development that are drawing much attention in cancer research and thus, will be discussed in detail.…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 99%

“…Consistently, in CCA cells, both PI3K/Akt and Wnt/β-catenin signaling were turned off upon SALL4 silencing 109 . Importantly, both pathways promote CCA metastatization 68,78,112 .…”

Section: Novel Signaling Mechanisms and Trascription Factors Promotinmentioning

confidence: 99%

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

et al. 2018

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The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.

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Involvement of Wnt/β-catenin signaling in the mesenchymal stem cells promote metastatic growth and chemoresistance of cholangiocarcinoma

Cited by 82 publications

References 39 publications

Aqueous Fraction of Huogu Formula Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells Through the BMP and Wnt Signaling Pathways

Aqueous Fraction of Huogu Formula Promotes Osteogenic Differentiation of Bone Marrow Stromal Cells Through the BMP and Wnt Signaling Pathways

miR-191 Inhibition Induces Apoptosis Through Reactivating Secreted Frizzled-Related Protein-1 in Cholangiocarcinoma

Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview

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