The relationship between EZH2 expression and microRNA-31 in colorectal cancer and the role in evolution of the serrated pathway.

Abstract

Polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that correlates with the regulation of invasion and metastasis and is overexpressed in human cancers such as colorectal cancer. MicroRNA-31 (miR-31) plays an oncogenic role and is associated with BRAF mutation and poor prognosis in colorectal cancer. EZH2 is functionally considered to suppress miR-31 expression in human cancers; however, no study has reported its relationship with colon cancer. We therefore evaluated EZH2 expression using immunohistochemistry and assessed miR-31 and epigenetic alterations using 301 colorectal carcinomas and 207 premalignant lesions. Functional analysis was performed to identify the association between EZH2 and miR-31 using cancer cell lines. In the current study, negative, weak, moderate, and strong EZH2 expressions were observed in 15%, 19%, 25%, and 41% of colorectal cancers, respectively. EZH2 was inversely associated with miR-31 (P < 0.0001), independent of clinicopathological and molecular features. In a multivariate stage-stratified analysis, high EZH2 expression was related to favorable prognosis (P = 0.0022). Regarding premalignant lesions, negative EZH2 expression was frequently detected in sessile serrated adenomas/polyps (SSA/Ps) (76%; P < 0.0001) compared with hyperplastic polyps, traditional serrated adenomas, and non-serrated adenomas (25-36%). Functional analysis demonstrated that the knockdown of EZH2 increased miR-31 expression. In conclusion, an inverse association was identified between EZH2 and miR-31 in colorectal cancers. Our data also showed that upregulation of EZH2 expression may be rare in SSA/Ps. These results suggest that EZH2 suppresses miR-31 in colorectal cancer and may correlate with differentiation and evolution of serrated pathway.

• Authors: Hiroyoshi Kurihara, Reo Maruyama, Kazuya Ishiguro, Shinichi Kanno, Itaru Yamamoto, Keisuke Ishigami, Kei Mitsuhashi, Hisayoshi Igarashi, Miki Ito, Tokuma Tanuma, Yasutaka Sukawa, Kenji Okita, Tadashi Hasegawa, Kohzoh Imai, Hiroyuki Yamamoto, Yasuhisa Shinomura, Katsuhiko Nosho
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 11 Pg. 12704-17 (Mar 15 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26871294 (Publication Type: Journal Article)

Chemical References

• MIRN31 microRNA, human
• MicroRNAs
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Adenomatous Polyps (genetics, metabolism, pathology)
• Adult
• Aged
• Colonic Polyps (genetics, metabolism, pathology)
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Enhancer of Zeste Homolog 2 Protein (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Humans
• Kaplan-Meier Estimate
• Male
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Precancerous Conditions (genetics, metabolism, pathology)