Dataset Information

MAGP2, a Component of Extracellular Matrix, Is Upregulated in Colorectal Cancer and Negatively Modulated by miR-200b-3p.

ABSTRACT:

Background

Colorectal cancer is one of the leading causes of cancer-related death worldwide, but its mechanism has not been clarified clearly. Microfibrial-associated glycoprotein 2 is mainly located in extracellular matrix, and its role in colorectal cancer is obscure.

Methods

Immunohistochemical staining and quantitative real-time polymerase chain reaction were used to compare the expression level of microfibrial-associated glycoprotein 2 in colorectal cancer tissues and adjacent tissues. Western blot was used to detect the expression of microfibrial-associated glycoprotein 2 in colorectal cancer cell lines and normal colonic epithelium cell line. Kaplan-Meier analysis and ?² test were applied to evaluate the potential of microfibrial-associated glycoprotein 2 to function as cancer biomarker. Lentiviral transduction was used to induce microfibrial-associated glycoprotein 2 overexpression in HCT116 cells and NCM460 cells, followed by detecting cell proliferation, migration, and invasion. Quantitative real-time polymerase chain reaction was used to investigate the changes in downstream genes after microfibrial-associated glycoprotein 2 overexpression. Luciferase assay was conducted to validate whether miR-200b-3p can directly target microfibrial-associated glycoprotein 2.

Results

We validated that microfibrial-associated glycoprotein 2 was upregulated in colorectal cancer samples and cells. We also demonstrated its upregulation was associated with several clinicopathologic features such as Dukes stage (P = .048), differentiation status (P = .034), and local lymphatic metastasis (P = .036) of patients with colorectal cancer, and its high expression indicated shorter overall survival of the patients. Microfibrial-associated glycoprotein 2 overexpression remarkably promoted cell proliferation and metastasis via regulating the downstream genes of Notch, including hes family bHLH transcription factor 1 (HES1), Slug, Snail, matrix metalloproteinase 2, matrix metalloproteinase 9, and Kruppel-like factor 4. We also identified miR-200b-3p as a posttranscriptional regulator of microfibrial-associated glycoprotein 2, which partly explain the high expression mechanism of microfibrial-associated glycoprotein 2 in cancer tissues. Conclusion: Microfibrial-associated glycoprotein 2, negatively modulated by miR-200b-3p, is an oncogene of colorectal cancer associated with patients' prognosis. It may function as a potential biomarker and therapeutic target for colorectal cancer.

SUBMITTER: Feifei W

PROVIDER: S-EPMC6702771 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

MAGP2, a Component of Extracellular Matrix, Is Upregulated in Colorectal Cancer and Negatively Modulated by miR-200b-3p.

Feifei Wei W Hui Guo G Ruiqiang Zhao Z Qunxiang Jiang J Yu'an Xie X

Technology in cancer research & treatment 20190101

<h4>Background</h4>Colorectal cancer is one of the leading causes of cancer-related death worldwide, but its mechanism has not been clarified clearly. Microfibrial-associated glycoprotein 2 is mainly located in extracellular matrix, and its role in colorectal cancer is obscure.<h4>Methods</h4>Immunohistochemical staining and quantitative real-time polymerase chain reaction were used to compare the expression level of microfibrial-associated glycoprotein 2 in colorectal cancer tissues and adjacen ...[more]

PMID: 31426719

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Project description:BackgroundMetastasis is a major threat to colorectal cancer (CRC) patients. We have reported that peroxiredoxin-2 (PRDX2) is associated with CRC invasion and metastasis. However, the mechanisms regulating PRDX2 expression remain unclear. We investigate whether microRNAs (miRNAs) regulate PRDX2 expression in CRC progression.MethodsQuantitative real-time polymerase chain reaction (qPCR) was used to measure microRNA-200b-3p (miR-200b-3p) expression. Immunohistochemistry (IHC) was performed to detect c-Myc and PRDX2 protein levels in CRC tissue samples (n = 97). Western blot was used to quantify PRDX2, c-Myc, AKT2/GSK3β pathway-associated proteins and epithelial-mesenchymal transition (EMT)-related proteins in CRC cells. Luciferase reporter assays were used to analyze the interaction between miR-200b-3p and 3'untranslated region (3'UTR) of PRDX2 mRNA and AKT2 mRNA as well as c-Myc and the miR-200b-3p promoter. Chromatin immunoprecipitation (ChIP) assay was used to evaluate binding of c-Myc to the miR-200b-3p promoter. Invasive assay and metastatic model were used to assess invasive and metastatic capacities of CRC cells in vitro and in vivo. Moreover, drug-induced apoptosis was measured by flow cytometry.ResultsWe found that miR-200b-3p was significantly downregulated, whereas c-Myc and PRDX2 were upregulated in metastatic CRC cells and CRC tissues compared to their counterparts. An inverse correlation existed between c-Myc and miR-200b-3p, and between miR-200b-3p and PRDX2. We also found that PRDX2 was a target of miR-200b-3p. Importantly, overexpression of nontargetable PRDX2 eliminated the suppressive effects of miR-200b-3p on proliferation, invasion, EMT, chemotherapeutic resistance and metastasis of CRC cells. Moreover, c-Myc bound to the promoter of miR-200b-3p and repressed its transcription. In turn, miR-200b-3p disrupted the stability of c-Myc protein by inducing c-Myc protein threonine 58 (T58) phosphorylation and serine 62 (S62) dephosphorylation via AKT2/GSK3β pathway.ConclusionsOur findings reveal that the c-Myc/miR-200b/PRDX2 loop regulates CRC progression and its disruption enhances tumor metastasis and chemotherapeutic resistance in CRC.

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Dataset Information

MAGP2, a Component of Extracellular Matrix, Is Upregulated in Colorectal Cancer and Negatively Modulated by miR-200b-3p.

Background

Methods

Results

Publications

MAGP2, a Component of Extracellular Matrix, Is Upregulated in Colorectal Cancer and Negatively Modulated by miR-200b-3p.

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