J Cancer 2021; 12(18):5473-5485. doi:10.7150/jca.52338 This issue

Research Paper

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

Kunning Zhang1,#, Zhiwei Zhai2,#,✉, Sanshui Yu2, Yu Tao2

1. Department of Pathology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
2. Department of General Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, P.R. China
# Kunning Zhang and Zhiwei Zhai have equal contribution.

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Citation:
Zhang K, Zhai Z, Yu S, Tao Y. DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway. J Cancer 2021; 12(18):5473-5485. doi:10.7150/jca.52338. Available from https://www.jcancer.org/v12p5473.htm

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Abstract

Graphic abstract

Background: 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.

Methods: 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 in vivo.

Results: 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. In vivo, the overexpression of ANGPTL4 was found to inhibit the metastasis of tumor cells in lung tissues.

Conclusion: 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.

Keywords: Colorectal cancer, DNA methylation, Angiopoietin-like 4, Carcinoma-associated fibroblasts, Epithelial-mesenchymal transition