MiR-520d-5p directly targets TWIST1 and downregulates the metastamiR miR-10b

// Pinchas Tsukerman 1 , Rachel Yamin 1 , Einat Seidel 1 , Saleh Khawaled 1 , Dominik Schmiedel 1 , Tomer Bar-Mag 1 , Ofer Mandelboim 1 1 The Lautenberg Center for General and Tumor Immunology, The Hebrew University, The BioMedical Research Institute, Israel Canada, Hadassah Medical School, Jerusalem, Israel Correspondence to: Ofer Mandelboim, e-mail: oferm@ekmd.huji.ac.il Keywords: TWIST1, miR-10b, mir-520d Received: August 14, 2014      Accepted: October 01, 2014      Published: November 07, 2014 ABSTRACT MicroRNAs are key players in most biological processes. Some microRNAs are involved in the genesis of tumors and are therefore termed oncomiRs, while others, termed metastamiRs, play a significant role in the formation of cancer metastases. Previously, we identified ten different cellular microRNAs that downregulate the expression of MICB, a ligand of the activating NK receptor NKG2D. Interestingly, several of the ten MICB-targeting microRNAs, such as miR-10b, are involved in tumor formation and metastasis. In this work, we identify a complex interplay between these different microRNAs. Specifically, we demonstrate that three of the MICB-targeting microRNAs: miR-20a, miR-17-5p and miR-93, also target the same site in the 3′UTR of TWIST1, a transcription factor implicated in cancer metastasis. Additionally, we show that miR-520d-5p targets a different site in the 3′UTR of TWIST1. We next show that the miR-520d-5p-mediated decrease of TWIST1 expression results in reduced expression of one of its targets, miR-10b, and in the restoration of E-Cadherin expression, which in turn results in reduced cellular motility and invasiveness. Finally, we show that miR-520d-5p leads to reduced proliferation of tumor cells, and that high levels of miR-520d-5p correlate with higher survival rates of cancer patients.