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DNA甲基化介导的ANGPTL4下调通过激活ERK通路促进结直肠癌转移。

DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway.

作者信息

Zhang Kunning, Zhai Zhiwei, Yu Sanshui, Tao Yu

机构信息

Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.

Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China.

出版信息

J Cancer. 2021 Jul 13;12(18):5473-5485. doi: 10.7150/jca.52338. eCollection 2021.

DOI:10.7150/jca.52338
PMID:34405010
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8364648/
Abstract

Colorectal cancer (CRC) imposes significant health burden and is increasing in incidence. NGPTL4 has been implicated in the development of CRC. The present study aimed to investigate the molecular mechanisms by which ANGPTL4 expression might regulate epithelial-mesenchymal transition (EMT) and the tumor microenvironment in CRC. CRC and para-carcinoma tissues were collected from 67 CRC patients. ANGPTL4 expression levels and DNA methylation of ANGPTL4 promoter region were determined. Next, the migration and invasion capacities of CRC cells were assessed. Immunofluorescence and Western blot were used to identify the signaling pathways by which ANGPTL4 mediated tumor metastasis. A tumorigenesis mice model with transplanted fibroblast cells and ANGPTL4 overexpressed CRC cells was established to investigate the effects of ANGPTL4 on the metastasis of cancer cells . ANGPTL4 was significantly decreased in CRC tissues and DNA hypermethylation was involved in the regulation of ANGPTL4. Mechanistically, ANGPTL4 induced activation of cancer-associated fibroblasts in the tumor microenvironment and promoted EMT in CRC cells through the ERK signaling pathway. , the overexpression of ANGPTL4 was found to inhibit the metastasis of tumor cells in lung tissues. DNA hypermethylation induced ANGPTL4 downregulation promoted the activation of cancer-associated fibroblasts and epithelial mesenchymal transformation of CRC cells via the ERK signaling pathway, thereby promoting invasion and metastasis in CRC.

摘要

结直肠癌（CRC）带来了巨大的健康负担，且发病率呈上升趋势。血管生成素样蛋白4（ANGPTL4）与CRC的发生发展有关。本研究旨在探讨ANGPTL4表达可能调控CRC上皮-间质转化（EMT）及肿瘤微环境的分子机制。收集了67例CRC患者的CRC组织和癌旁组织。测定ANGPTL4的表达水平及ANGPTL4启动子区域的DNA甲基化情况。接下来，评估CRC细胞的迁移和侵袭能力。采用免疫荧光和蛋白质印迹法鉴定ANGPTL4介导肿瘤转移的信号通路。建立了移植成纤维细胞和过表达ANGPTL4的CRC细胞的肿瘤发生小鼠模型，以研究ANGPTL4对癌细胞转移的影响。ANGPTL4在CRC组织中显著降低，DNA高甲基化参与了ANGPTL4的调控。机制上，ANGPTL4诱导肿瘤微环境中癌相关成纤维细胞的激活，并通过ERK信号通路促进CRC细胞的EMT。此外，发现ANGPTL4的过表达可抑制肺组织中肿瘤细胞的转移。DNA高甲基化诱导的ANGPTL4下调通过ERK信号通路促进癌相关成纤维细胞的激活和CRC细胞的上皮间质转化，从而促进CRC的侵袭和转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80ca/8364648/d121d8bd2342/jcav12p5473g007.jpg
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