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© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Simple Summary

Colorectal cancer (CRC) is the third leading cause for cancer related death, in which metastasis exerts a pivotal role. Therefore, we aim to find out the possible mechanism underlying CRC metastasis. We found that the level of miR-125b was elevated in normal, primary CRC, and distant metastasis tissues stepwise, and high level miR-125b was positively correlated with lymph node metastasis and tumor differentiation. In vitro and in vivo assays showed miR-125b significantly promoted CRC migration and invasion. To elucidate the potential mechanism, cystic fibrosis transmembrane conductance regulator (CFTR) and cingulin (CGN) were defined as two target genes of miR-125b. On the one hand, miR-125b promoted epithelial-mesenchymal transition (EMT) and the production and secretion of urokinase plasminogen activator (uPA) by inhibiting CFTR; on the other hand, miR-125b activated Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) signaling by repressing CGN. Therefore, we provided a potential biomarker for CRC prevention and treatment in the future.

Abstract

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

Details

Title
miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN
Author
Zhang, Xiaohui 1 ; Li, Tingyu 2 ; Ya-Nan Han 3 ; Ge, Minghui 4 ; Wang, Pei 5 ; Sun, Lina 6 ; Liu, Hao 1 ; Cao, Tianyu 1 ; Nie, Yongzhan 1 ; Fan, Daiming 1   VIAFID ORCID Logo  ; Guo, Hao 4 ; Wu, Kaichun 1 ; Zhao, Xiaodi 1   VIAFID ORCID Logo  ; Lu, Yuanyuan 1 

 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China; [email protected] (X.Z.); [email protected] (Y.-N.H.); [email protected] (H.L.); [email protected] (T.C.); [email protected] (Y.N.); [email protected] (D.F.); [email protected] (K.W.) 
 Department of Gastroenterology, National Clinical Research Center for Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, Beijing 100853, China; [email protected] 
 State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an 710032, China; [email protected] (X.Z.); [email protected] (Y.-N.H.); [email protected] (H.L.); [email protected] (T.C.); [email protected] (Y.N.); [email protected] (D.F.); [email protected] (K.W.); Department of Gastroenterology, Xi’an Children’s Hospital, Xi’an 710003, China; [email protected] 
 State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing 210042, China; [email protected] (M.G.); [email protected] (H.G.) 
 Department of Gastroenterology, Ningxia Medical University, Yinchuan 750004, China; [email protected] 
 Department of Gastroenterology, Xi’an Children’s Hospital, Xi’an 710003, China; [email protected] 
First page
5710
Publication year
2021
Publication date
2021
Publisher
MDPI AG
e-ISSN
20726694
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2602019426
Copyright
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.