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miR-944 Suppresses EGF-Induced EMT in Colorectal Cancer Cells by Directly Targeting GATA6

Authors Tang J, Gao W, Liu G, Sheng W, Zhou J, Dong Q, Dong M

Received 30 November 2020

Accepted for publication 14 March 2021

Published 31 March 2021 Volume 2021:14 Pages 2311—2325


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Arseniy Yuzhalin

JingTong Tang,1 Wei Gao,1 Gang Liu,1 WeiWei Sheng,1 JianPing Zhou,1 Qi Dong,2 Ming Dong1

1Department of Gastrointestinal Surgery & Hernia and Abdominal Wall Surgery, The First Hospital, China Medical University, Shenyang, 110001, Liaoning, People’s Republic of China; 2Department of General Surgery, The People’s Hospital of China Medical University, Shenyang, People’s Republic of China

Correspondence: JianPing Zhou Fax +86 24-83282886
Email [email protected]

Background: miR-944 belongs to the MicroRNAs family, as shown in our previous study, and is essential in the colorectal cancer (CRC) progression. It is negatively associated with invasion depth and lymph node status. Epithelial-mesenchymal transition (EMT) is essential in tumor invasion and metastasis. However, the relationship between miR-944 and EMT in CRC is unknown and should be further investigated.
Methods: Epithelial–mesenchymal transition (EMT) progression in CRC cell lines was detected with Cell morphology and Western blotting. CRC cell migration and invasion were examined using Transwell assays. Transcriptome and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. The potential pathway of miR-944 and GATA6 were predicted using KEGG analysis. Colocalization was validated using immunofluorescence and Immunohistochemistry. Nuclear and Cytoplasmic Protein Extraction assays were conducted to determine the effects of miR-944 on Wnt/β-catenin signaling.
Results: We found that miR‑944 influences EGF-induced EMT malignant phenotype in vitro. KEGG analyses showed that miR-944 and GATA6 are associated with EMT related pathways, wnt signaling pathways. On the other hand, Western Blot analyses showed that miR-944 can regulate EMT and wnt-β-catenin pathway-related protein, including β-catenin, ZEB1, snail1 via GATA6 regulation. miR-944 also abrogates E-ca after EGF induction. Immunohistochemistry (IHC) and Immunofluorescence (IF) co-expression showed that GATA6 expression is positively associated with β-catenin and ZEB1. GATA6 silencing can reverse EMT malignant phenotype and alterations of related protein induced by miR-944. Quantitative polymerase chain reaction analysis results showed that miR-944 is negatively associated with the UICC stage (P= 0.02), lymph nodes (p=0.04), and liver metastasis (p=0.03). Moreover, patients with high miR-944 expression have better survival (p=0.045). We finally combined miR-944 and GATA6 and found that miR-944/GATA6 ratio could be a novel prognostic biomarker in the TCGA dataset and it is an independent risk prognosis factor (p=0.045).
Conclusion: Our results suggest that miR-944 suppresses the aggressive biological processes by directly repressing GATA6 expression and could be a potential candidate for therapeutic applications in CRC.

Keywords: miR-944, colorectal cancer, GATA6, epithelial-mesenchymal transition

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