MiR-373 drives the epithelial-to-mesenchymal transition and metastasis via the miR-373-TXNIP-HIF1α-TWIST signaling axis in breast cancer

Abstract

// De Chen 1,4,* , Bian-Li Dang 2,* , Jin-zhou Huang 2,* , Min Chen 2 , Di Wu 3 , Man-Li Xu 2 , Rong Li 3 and Guang-Rong Yan 1,2,4 1 Biomedicine Research Center and Department of Surgery, The Third Affiliated Hospital of Guangzhou Medicine University, Guangzhou, China 2 Institutes of Life and Health Engineering, Jinan University, Guangzhou, China 3 Cancer Center, Nanfang Hospital, Southern Medical University, Guangzhou, China 4 Key Laboratory for Major Obstetric Diseases of Guangdong Province and Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medicine University, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Guang-Rong Yan, email: // Rong Li, email: // Keywords : miR-373, EMT, TXNIP, ROS, TWIST Received : April 22, 2015 Accepted : June 23, 2015 Published : July 01, 2015 Abstract Our previous proteomics study revealed that thioredoxin-interacting protein (TXNIP) was down-regulated by miR-373. However, little is known of the mechanism by which miR-373 decreases TXNIP to stimulate metastasis. In this study, we show that miR-373 promotes the epithelial-to-mesenchymal transition (EMT) in breast cancer. MiR-373 suppresses TXNIP by binding to the 3’UTR of TXNIP, which in turn, induces cancer cell EMT and metastasis. TXNIP co-expression, but not the TXNIP-3’UTR, reverses the enhancement of EMT, migration, invasion and metastasis induced by miR-373. MiR-373 stimulates EMT, migration and invasion through TXNIP-dependent reactive oxygen species (ROS) reduction. Mechanistically, miR-373 up-regulates and activates the HIF1α-TWIST signaling axis via the TXNIP pathway. Consequently, TWIST induces miR-373 expression by binding to the promoter of the miR-371-373 cluster. Clinically, miR-373 is negatively associated with TXNIP and positively associated with HIF1α and TWIST, and activation of the miR-373-TXNIP-HIF1α-TWIST signaling axis is correlated with a worse outcome in patients with breast cancer. This signaling axis may be an independent prognostic factor for patients with breast cancer.