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:
Corresponding author: Soo-Cheon Chae, PhD, Professor of Medicine, Department of Pathology, School of Medicine, Wonkwang University, Iksan, Chonbuk 54538, South Korea.
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
Research background

Colorectal cancer (CRC) is the third most prevalent type of cancer worldwide. The cause of CRC is multifactorial including genetic variation and epigenetic and environmental factors. However, the precise molecular mechanism underlying the development and progression of CRC remains largely unknown. We previously found that microRNA 375 (MIR375) is significantly downregulated in CRC, and identified metadherin (MTDH) as a candidate target gene of MIR375.

Research motivation

MIR375 and their target MTDH will provide a new therapeutic information for human CRC.

Research objectives

To study the interaction and signaling between MIR375 and MTDH in human CRC pathogenesis.

Research methods

We constructed luciferase reporter plasmids to confirm the effect of MIR375 on MTDH gene expression. The expression levels of the MIR375 and MTDH were measured by qRT-PCR, Western blot, or immunohistochemistry. The effects of MIR375 on cell growth and angiogenesis were conducted by functional experiments in CRC cells. Assays were performed to explore functional correlation between MTDH and MIR375 in human CRC cells and tissues.

Research results

In the present study, we found that the expression levels of MTDH were significantly down-regulated in CRC cells by MIR375 mimic or siMTDH transfection. MTDH expression was up-regulated in human CRC tissues in comparing to match normal colon tissues. Upregulated MTDH expression levels were found to inhibit NF-κB inhibitor alpha (NFKBIA) expression, which further upregulated NFKB1 and RELA expression. We found that MIR375 regulate the expression levels of molecules in MTDH-mediated BRAF-MAPK and PIK3CA-AKT signal pathways in CRC cells.

Research conclusions

MIR375 regulates cell proliferation and angiogenesis by regulation of MTDH-mediated signaling pathways such as MTDH-BRAF-MAPK, MTDH-PIK3CA-AKT, and MTDH-NFKBIA-NFKB1/RELA in CRC progression.

Research perspectives

This study provides insight into the role of MIR375 in CRC pathogenesis by targeting MTDH. MIR375 might be a new therapeutic target for CRC.