Chemotherapy-Induced miRNA-29c/Catenin-δ Signaling Suppresses Metastasis in Gastric Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-04, Vol.75 (7), p.1332-1344
• Main Authors: Wang, Yuxuan, Liu, Changzheng, Luo, Min, Zhang, Zhengyi, Gong, Jianan, Li, Jingjing, You, Lei, Dong, Lei, Su, Rui, Lin, Haishuang, Ma, Yanni, Wang, Fang, Wang, Yi, Chen, Jie, Zhang, Junwu, Jia, Hongyan, Kong, Yan, Yu, Jia
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Catenins - metabolism; Cell Line, Tumor; Cell Movement; Cisplatin - pharmacology; Gene Expression - drug effects; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - mortality; Lung Neoplasms - secondary; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; Neoplasm Invasiveness; Neoplasm Transplantation; rho GTP-Binding Proteins - metabolism; RNA Interference; Stomach Neoplasms - drug therapy; Stomach Neoplasms - metabolism; Stomach Neoplasms - mortality; Stomach Neoplasms - pathology; Taxoids - pharmacology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-0787

Chemotherapy has improved the survival of patients with gastric cancer by unknown mechanisms. In this study, we showed that cisplatin and docetaxel used in gastric cancer treatment increase the expression of miRNA-29 (miR-29) family members and decrease the expression of their oncogenic targets, mediating a significant part of the efficacious benefits of these chemotherapeutic agents. In particular, patients with gastric cancer who experienced recurrences after chemotherapy tended to exhibit low levels of miR-29c expression in their tumors, suggesting that miR-29c activation may contribute to the chemotherapeutic efficacy. Enforced expression of miR-29s in gastric cancer cells inhibited cell invasion in vitro and in vivo by directly targeting catenin-δ (CTNND1). Drug treatment suppressed gastric cancer cell invasion by restoring miR-29c-mediated suppression of catenin-δ and RhoA signaling. In parallel, drug treatment also activated several tumor-suppressive miRNAs, thereby decreasing expression of their oncogenic effector targets. Overall, our findings defined a global mechanism for understanding the efficacious effects of cytotoxic chemotherapy in gastric cancer.