Abstract

Myc oncogenic transcription factor is known to inhibit tumor suppressive microRNAs (miRNAs), resulting in greater expression of their target protein related to cell cycle, invasion or anti-apoptotic factors in human cancer cells. To explore possible oncogenic factors in Ewing’s sarcoma (ES), we conducted microarray-based approach to profile the changes in the expression of miRNAs and its downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). Three miRNAs, let-7a, miR-16 and miR-29b were significantly down-regulated, whereas c-Myc and cyclin D2 (CCND2) were significantly up-regulated in all tested ES cells compared with hMSCs. To verify that let-7a, miR-16 and miR-29b were the targets of c-Myc in ES cell lines, we transfected siRNA against c-Myc and confirmed the coordinate up-regulation of let-7a, miR-16 and miR-29b through the repression of c-Myc. The ES cells transfected with c-Myc-siRNA and let-7a, miR-16 and miR-29b exhibited the inhibition of the cell cycle progression. The increased expression of let-7a, miR-16 and miR-29b resulted in the reduction of CCND2 protein expression. We also demonstrated that c-Myc-siRNA treatment of ES cells was associated with the decreased expression of CCND2 as a down-stream of three miRNAs. Furthermore, the introduction of let-7a, miR-16 and miR-29b in ES cells could inhibit the c-Myc-mediated up-regulation of CCND2 resulted in the prevention of cell cycle progression. In addition, the transfection of let-7a, miR-16 and miR-29b in ES cells suppressed tumor growth ex vivo treatment. These findings suggests that the up-regulation of c-Myc inhibited the expression of let-7a, miR-16 and miR-29b subsequently induced CCND2 expression in ES cells. The present study might identify a novel oncogenic axis that c-Myc regulates the expression of CCND2 via let-7a, miR-16 and miR-29b, leading to the development new therapeutic targets for ES.

Highlights

  • Ewing’ sarcoma (ES) is the second most common bone cancer, most often occurring in children, adolescents, and young adults

  • MiRNAs are single-stranded non-coding single stranded RNAs (18–24 nucleotides) that are capable of inhibiting gene expression at the post-transcriptional level referred to as RNA interference (RNAi) [5]. miRNAs exhibit sequence specific interaction with the 3’-untranslated region (UTR) of cognate mRNA targets, causing degradation of mRNAs and suppression of translation [6]. miRNAs have identified as key regulators of multiple physiological and pathological processes, including cell proliferation, apoptosis, and cancer [7,8]

  • Featured miRNAs have been shown to act as critical factors for tumorigenesis or tumor suppressors emphasizing the importance of identification of miRNAs that function in the regulation of tumor progression

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Summary

Introduction

Ewing’ sarcoma (ES) is the second most common bone cancer, most often occurring in children, adolescents, and young adults. C-Myc controls the cell cycle by operating the levels of several regulators of progression through G1 such as cyclins and CDKs. c-Myc controls the production of many non-coding RNAs, including micro-RNAs (miRNAs), and these miRNAs are likely to contribute substantially to the biologic and pathologic functions of c-Myc [4]. MiRNAs are single-stranded non-coding single stranded RNAs (18–24 nucleotides) that are capable of inhibiting gene expression at the post-transcriptional level referred to as RNA interference (RNAi) [5]. MiRNAs have identified as key regulators of multiple physiological and pathological processes, including cell proliferation, apoptosis, and cancer [7,8]. MiRNAs can either regulate or act as oncogenes [9,10] or tumor suppressor genes [11] at the post-transcriptional level In the past decade, emerging evidences have demonstrated a diverse function of miRNAs in the establishment and progression of human tumors. miRNAs can either regulate or act as oncogenes [9,10] or tumor suppressor genes [11] at the post-transcriptional level

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