Downregulation of microRNA-26a is associated with metastatic potential and the poor prognosis of osteosarcoma patients

Abstract

Abstract. Accumulating evidence indicates that microRNAs are involved in multiple processes in cancer development and progression. microRNA-26a (miR-26a) has been identified as a tumor suppressor and its downregulation is associated with poor prognosis in several types of human cancer. However, the specific function of miR-26a in osteosarcoma remains unclear.In the present study, we found that the expression of miR-26a in osteosarcoma tissues and cell lines was much lower than that in the normal controls, respectively. In addition, downregulation of miR-26a more frequently occurred in osteosarcoma specimens with adverse clinical stage and with the presence of distant metastasis. Moreover, multivariate survival analyses demonstrated that loss of miR-26a is an independent prognostic factor for both disease-free and overall survival in osteosarcoma. In addition, restoration of miR-26a expression inhibited the invasion and migration in osteosarcoma cells, and miR-26a directly inhibited enhancer of zeste homolog 2 (EZH2) expression by targeting its 3'-UTR. Moreover, EZH2 was upregulated and inversely correlated with miR-26a expression in the osteosarcoma tissues. Thus, for the first time, we provide convincing evidence that downregulation of miR-26a is associated with tumor aggressiveness and tumor metastasis, and miR-26a inhibits cell migration and invasion by targeting the EZH2 gene in osteosarcoma. Thus, miR-26a is an independent prognostic marker for osteosarcoma patients. IntroductionOsteosarcoma, mainly arising from the metaphysis of the long bones, is the most common primary malignancy of bone in adolescents and young adults, with an estimated worldwide yearly incidence rate of 4 million (1,2). Despite current therapeutic strategies combining adjuvant chemotherapy, surgery and sometimes radiotherapy, the prognosis of osteosarcoma patients remains poor, since ~80% of patients eventually develop recurrent metastatic osteosarcoma following surgical treatment (3), and the 5-year survival rate of these patients is only 50-60% (4). Although recent developments in molecular biology have provided insight into the molecular mechanisms of osteosarcoma, the fundamental molecular mechanisms underlying metastasis in osteosarcoma have not been fully elucidated. Therefore, it is essential to identify metastasisassociated molecules as effective drug targets and to enhance the understanding of the mechanisms underlying the metastasis of osteosarcoma.MicroRNAs (miRNAs) are small non-coding RNAs 18-25 nucleotides in length, transcribed from non-proteincoding genes or introns, which regulate gene expression through repressing translation and cleaving their target mRNAs by binding to complementary sites in their 3'-untranslated region (3'-UTR). It has been demonstrated that aberrant expression of miRNAs cause them to function as tumor suppressors or oncogenes according to the roles of their target genes (5,6). Particularly, miRNAs can regulate various cellular processes of tumor cells, including differentiation, progression, apopt...

A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

“…Interestingly, the top three most significantly enriched upstream regulators were microRNAs (miRNAs) implicated in human osteosarcoma, namely the genes encoding miR-181 ( P = 2.18 × 10 −5 ), miR-17-5p ( P = 3.42 × 10 −5 ) and miR-26a-5p ( P = 3.06 × 10 −7 ) ( Fig. 3b and Supplementary Table 4 ) 40–42 . The remaining top regulators were MAPK7 ( P = 7.64 × 10 −5 ) and WT1 ( P = 8.50 × 10 −5 ), both implicated in osteosarcoma as prognostic markers of poor outcome 43,44 .…”

“…The fact that the majority of SB-mutagenized tumors had loss of Trp53 function and the loss of TP53 in many human osteosarcomas strongly suggest that loss of both these genes is a cooperative event driving osteosarcomagenesis 14 . Additionally, copy number loss of PTEN has been observed in >60% of human osteosarcomas, and oncogenic miRNAs implicated in osteosarcoma target PTEN 40–42,46 . To validate this cooperation in osteosarcoma and generate a new model genetically relevant to human disease, we combined conditional Pten (loxP-flanked exons 4 and 5) and Trp53 R270H alleles with Sp7-cre mice (Trp53-Pten mice) 40,46,47 .…”

MicroRNA-26a modulates transforming growth factor beta-1-induced proliferation in human fetal lung fibroblasts

“…The error bars represent the standard error. ⁄ p < 0.05, ⁄⁄ p < 0.01. prognosis in osteosarcoma patients [23]. miRNA-26a expression levels are lower in human nasopharyngeal carcinoma (NPC) specimens, and its overexpression significantly reduces cell-cycle related enhancer of EZH2 and Cyclin D2 [16].…”

MiR-100 Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion and Enhances Chemosensitivity by Targeting IGFIR

“…[4][5][6] Studies have reported that several miRNAs were dysregulated in osteosarcoma tissues or cell lines, including miR-17, miR-26a, miR-126, and miR-145. [7][8][9] MicroRNAs also play a role in chemoresistance of osteosarcoma. Recent studies found that miR-33a is upregulated in chemoresistant osteosarcoma and could promote osteosarcoma cell resistance to cisplatin via downregulating twist.…”