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
Summary
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
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
