Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2019; 25(44): 6495-6507
Published online Nov 28, 2019. doi: 10.3748/wjg.v25.i44.6495
Reduced microRNA 375 in colorectal cancer upregulates metadherin-mediated signaling
Seol-Hee Han, Ji-Su Mo, Won-Cheol Park, Soo-Cheon Chae
Seol-Hee Han, Ji-Su Mo, Soo-Cheon Chae, Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, South Korea
Ji-Su Mo, Won-Cheol Park, Soo-Cheon Chae, Digestive Disease Research Institute, Wonkwang University, Iksan, Chonbuk 54538, South Korea
Author contributions: Chae SC conceived and designed the experiments; Han SH and Mo JS performed the experiments; Han SH and Chae SC analyzed the data; Park WC and Chae SC contributed reagents/materials/analysis tools, and drafted the manuscript.
Supported by a grant from the National Research Foundation of Korea, No. 2017R1A2B4004801.
Institutional review board statement: The study was reviewed and approved by the Review Board of Wonkwang University, South Korea (WKIRB-201710-BR-012).
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: This study was prepared according to the ARRIVE guidelines.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Soo-Cheon Chae, PhD, Professor of Medicine, Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, South Korea. chaesc@wku.ac.kr
Telephone: +82-63-8506793 Fax: +82-63-8506760
Received: October 10, 2019
Peer-review started: October 10, 2019
First decision: November 10, 2019
Revised: November 20, 2019
Accepted: November 23, 2019
Article in press: November 23, 2019
Published online: November 28, 2019
Abstract
BACKGROUND

The human microRNA 375 (MIR375) is significantly downregulated in human colorectal cancer (CRC) and we have previously shown that MIR375 is a CRC-associated miRNA. The metadherin (MTDH) is a candidate target gene of MIR375.

AIM

To investigate the interaction and function between MIR375 and MTDH in human CRC.

METHODS

A luciferase reporter system was used to confirm the effect of MIR375 on MTDH expression. The expression levels of MIR375 and the target genes were evaluated by quantitative RT-PCR (qRT-PCR), western blotting, or immunohistochemistry.

RESULTS

MTDH expression was found to be upregulated in human CRC tissues compared to that in healthy controls. We show that MIR375 regulates the expression of many genes involved in the MTDH-mediated signal transduction pathways [BRAF-MAPK and phosphatidylinositol-4,5-biphosphate-3-kinase catalytic subunit alpha (PIK3CA)-AKT] in CRC cells. Upregulated MTDH expression levels were found to inhibit NF-κB inhibitor alpha, which further upregulated NFKB1 and RELA expression in CRC cells.

CONCLUSION

Our findings suggest that suppressing MIR375 expression in CRC regulates cell proliferation and angiogenesis by increasing MTDH expression. Thus, MIR375 may be of therapeutic value in treating human CRC.

Keywords: MicroRNA 375, Metadherin, Mitogen-activated protein kinase, Angiogenesis, Cell proliferation, Colorectal cancer

Core tip: The microRNA 375 (MIR375) is significantly downregulated in human colorectal cancer (CRC) tissues. In this study, we investigated that metadherin (MTDH) is a direct target gene of MIR375 and that MTDH expression levels were upregulated in CRC tissues. Upregulated MTDH expression levels were found to inhibit NF-κB inhibitor alpha expression, which further upregulated NFKB1 and RELA expression in CRC cells. MIR375 also regulate MTDH-mediated BRAF-MAPK and PIK3CA-AKT signal pathways in CRC cells. Consequently, MIR375 regulates cell proliferation, cell migration, and angiogenesis by suppressing MTDH expression in CRC progression.