Dataset Information

MGP Promotes Colon Cancer Proliferation by Activating the NF-?B Pathway through Upregulation of the Calcium Signaling Pathway.

ABSTRACT: Matrix Gla protein (MGP), an extracellular matrix protein, is mainly associated with the inhibition of calcification in skeleton, coronary artery, and kidney, and more recently it has also been implicated in cancer. However, the biological function of MGP inside cancer cells and its role in colon cancer (CC) remain largely unknown. MGP expression and its association with clinicopathologic characteristics in CC were analyzed by immunohistochemistry and verified by Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The effects of MGP on CC cell proliferation were evaluated via knockdown and overexpression experiments in vitro. Mechanisms of MGP in CC were explored by western blots, quantitative real-time PCR, Fluo-3 AM staining, Rhod-2 AM staining, immunofluorescence, and other techniques. Our study confirmed that MGP was upregulated in different stages of CC and associated with a worse prognosis. MGP could enrich intracellular free Ca2+ concentration and promote nuclear factor ?B (NF-?B)/p65 phosphorylation, activating the expression of c-MYC, ICAM-1, and VEGFA. Furthermore, the reduction of intracellular free Ca2+ concentration and the subsequent growth inhibition effect on CC cells induced by small interfering RNA targeting MGP (siMGP) could be rescued by a higher calcium concentration environment. Therefore, MGP promotes the growth and proliferation of CC cells by enriching intracellular calcium concentration and activating the NF-?B pathway, and it could serve as a potential prognostic biomarker in CC patients.

SUBMITTER: Li X

PROVIDER: S-EPMC7210384 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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MGP Promotes Colon Cancer Proliferation by Activating the NF-κB Pathway through Upregulation of the Calcium Signaling Pathway.

Li Xueqing X Wei Rui R Wang Mizhu M Ma Li L Zhang Zheng Z Chen Lei L Guo Qingdong Q Guo Shuilong S Zhu Shengtao S Zhang Shutian S Min Li L

Molecular therapy oncolytics 20200419

Matrix Gla protein (MGP), an extracellular matrix protein, is mainly associated with the inhibition of calcification in skeleton, coronary artery, and kidney, and more recently it has also been implicated in cancer. However, the biological function of MGP inside cancer cells and its role in colon cancer (CC) remain largely unknown. MGP expression and its association with clinicopathologic characteristics in CC were analyzed by immunohistochemistry and verified by Gene Expression Omnibus (GEO) an ...[more]

PMID: 32405535

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Project description:Matrix Gla protein (MGP) was originally reported as a physiological suppressor of ectopia calcification and has also been reported to be associated with cancer. However, the relation between the biological functions of MGP and the immune response in colorectal cancer (CRC) remains unclear. Here, we investigated the regulatory role of MGP in the immune microenvironment of CRC. MGP expression in CRC samples was assessed by single-cell RNA sequencing and the Gene Expression Omnibus (GEO) database, and confirmed by quantitative real-time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry analysis of human CRC samples. The effect of MGP on proliferation and invasion of CRC cells was evaluated by in vitro assays involving MGP knockdown and overexpression. Luciferase reporter assay and chromatin immunoprecipitation (ChIP)-qPCR assay were performed to identify transcriptional regulatory sites of the nuclear factor kappa-B (NF-κB) and programmed cell death ligand 1 (PD-L1). In vivo experiments were performed in mouse model of CRC liver metastasis established via spleen injection. The results revealed that MGP was significantly upregulated in cancer cell clusters from the primary CRC or liver metastases, compared with that in the corresponding paracancerous tissues via single-cell RNA sequencing. MGP enriched intracellular free Ca2+ levels and promoted NF-κB phosphorylation, thereby activated PD-L1 expression to promote CD8+ T cell exhaustion in CRC. The luciferase reporter assay and ChIP-qPCR assay indicated that the transcriptional regulation of NF-κB upregulated PD-L1 expression. In vivo, MGP inhibition significantly decreased the rate of CRC liver metastasis, which was further reduced after combined therapy with αPD1 (anti-PD1). In conclusions, this study revealed that MGP can facilitate CD8+ T cell exhaustion by activating the NF-κB pathway, leading to liver metastasis of CRC. The combination of MGP knockdown and αPD1 can synergistically resist liver metastasis of CRC.

Dataset Information

MGP Promotes Colon Cancer Proliferation by Activating the NF-?B Pathway through Upregulation of the Calcium Signaling Pathway.

Publications

MGP Promotes Colon Cancer Proliferation by Activating the NF-κB Pathway through Upregulation of the Calcium Signaling Pathway.

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