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.
Highlights
Breast cancer is the most frequent malignancy occurring in women and the second leading cause of cancer mortality in women worldwide
Our previous study showed that miR-373 promotes breast cancer metastasis [11]
These observations indicate that miR-373 promotes cancer metastasis by inducing epithelial-to-mesenchymal transition (EMT)
Summary
Breast cancer is the most frequent malignancy occurring in women and the second leading cause of cancer mortality in women worldwide. 90% of breast cancer-associated deaths result from the distant metastasis of primary tumors [1]. Metastasis is a complex process comprising multiple sequential steps and the regulation of multiple factors. Local invasion is considered an initial, indispensable step during the process of distant metastasis from primary tumors. The epithelialmesenchymal transition (EMT) is a crucial step in the cancer metastasis process [2, 3]. MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs consisting of 20-24 nucleotides that suppress gene expression at the post-transcriptional level by blocking mRNA translation or degrading target mRNAs [4, 5]. MiRNAs are involved in both the promotion and suppression of cancer metastasis [6,7,8]
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