miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN

Cancers

Tingyu Li¹  Pei Wang²  Lina Sun³  Xiaodi Zhao⁴  Xiaohui Zhang⁴  Tianyu Cao⁴  Yongzhan Nie⁴  Daiming Fan⁴  Yuanyuan Lu⁴  Kaichun Wu⁴  Ya-Nan Han⁴  Hao Liu⁴  Hao Guo⁵  Minghui Ge⁵ 

[1] Department of Gastroenterology, National Clinical Research Center for Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, Beijing 100853, China;Department of Gastroenterology, Ningxia Medical University, Yinchuan 750004, China;Department of Gastroenterology, Xi’an Children’s Hospital, Xi’an 710003, China;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;State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing 210042, China;

关键词: colorectal cancer;    migration;    invasion;    metastasis;    miRNA;   

DOI  :  10.3390/cancers13225710

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown