Published online Nov 28, 2019. doi: 10.3748/wjg.v25.i44.6495
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
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.
MIR375 and their target MTDH will provide a new therapeutic information for human CRC.
To study the interaction and signaling between MIR375 and MTDH in human CRC pathogenesis.
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.
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.
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.
This study provides insight into the role of MIR375 in CRC pathogenesis by targeting MTDH. MIR375 might be a new therapeutic target for CRC.