miRNA Signatures Associate with Pathogenesis and Progression of Osteosarcoma

Department of Orthopaedics and Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
Cancer Research (Impact Factor: 9.33). 02/2012; 72(7):1865-77. DOI: 10.1158/0008-5472.CAN-11-2663
Source: PubMed


Osteosarcoma remains a leading cause of cancer death in adolescents. Treatment paradigms and survival rates have not improved in two decades. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. Here we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a,miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p.
We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a.
Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish a miRNA signature associated with pathogenesis of osteosarcoma as well as critical pre-treatment biomarkers of metastasis and responsiveness to therapy. Cancer Res; 72(7); 1865-77. (c)2012 AACR.

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    • "MiRNAs play important roles in several cellular processes, such as proliferation, differentiation, apoptosis and development, by simultaneously controlling the expression levels of hundreds of genes [4,16]. MiRNAs have demonstrated far-reaching effects on the cellular biology of development and cancer [17,18]. Their role in osteosarcoma genesis remains largely unexplored. "
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    ABSTRACT: MicroRNAs (MiRNAs) are small non-coding RNAs (18-25nt) that regulate gene expression mainly through affecting post-transcriptional modification. Osteosarcoma is an aggressive sarcoma of the bone characterized by a high level of genetic instability and recurrent DNA deletions and amplifications. microRNAs (miRNAs) play an important role in cancer cell growth and migration, however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. In this paper, miR-199a and miR-34a were discussed the mechanisms of apoptosis using micrRNA mimics in human osteosarcoma cells. The results demonstrated that miR-199a and miR-34a could induce the apoptosis of human osteosarcoma cells via p53 signaling pathway.
    Bioscience Reports 06/2014; 34(4). DOI:10.1042/BSR20140084 · 2.64 Impact Factor
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    • "miR- 199b-5p, miR-183, miR-34a, miR-340 and miR-16 exert tumor suppressor effects in osteosarcomagenesis through suppression of the Notch pathway [9], the oncogenes Ezrin [10], c-Met [11], ROCK1 [12], and Raf1-MEK1/2-ERK1/2 signaling [13] in OS cells, respectively. A recent miRNA microarray analysis by Jones et al. [1] revealed higher miR-214 expression in OS tissues, compared with normal bone tissues. However, the precise role of miR-214 in OS cells remains unclear at present. "
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    ABSTRACT: Previous studies have shown that miR-214 functions either as an oncogene or a tumor suppressor in various human cancer types. The role of this microRNA in osteosarcoma (OS) is presently unclear. Here, we demonstrated that miR-214 is frequently upregulated in OS specimens, compared with noncancerous bone tissues. Bioinformatics analysis further revealed leucine zipper, putative tumor suppressor 1 (LZTS1) as a potential target of miR-214. Expression patterns of miR-214 were inversely correlated with those of LZTS1 mRNA and protein in OS tissues. Data from reporter assays showed that miR-214 directly binds to the 3’-untranslated region (3’-UTR) of LZTS1 mRNA and suppresses expression at both transcriptional and translational levels. In functional assays, miR-214 promoted OS cell proliferation, invasion and tumor growth in nude mice, which could be reversed by overexpression of LZTS1. Taken together, our data provide compelling evidence that miR-214 functions as an onco-miRNA in OS, and its oncogenic effects are mediated chiefly through downregulation of LZTS1.
    Biochemical and Biophysical Research Communications 06/2014; 449(2). DOI:10.1016/j.bbrc.2014.04.140 · 2.30 Impact Factor
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    • "MicroRNAs (miRNAs) are noncoding small RNAs, usually 18–25 nucleotides in length, which repress translation and cleave mRNA by base-pairing to the 3′-untranslated region (UTR) of the target genes [12]. Knowledge of individual miRNAs effecting developmental biology, cellular differentiation programs, and oncogenesis continues to grow [13]. Differences in the miRNA expression profiles detected between cancer cells and their normal counterparts have revealed that miRNAs are involved in the pathogenesis of cancer [14]. "
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    ABSTRACT: miRNAs are involved in osteosarcoma (OS) chemoresistance, and TWIST reportedly enhances cisplatin-induced OS cell apoptosis by inhibiting multiple signaling pathways. In this study, we profiled miRNAs differentially expressed in chemoresistant OS, with a focus to identify miRNAs that regulate TWIST expression and OS chemoresistance. OS patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (chemoresistant), and those who showed >=90% tumor necrosis were defined as good responders (control). miRNA microarray analysis was carried out with a discovery cohort (n = 12) of age-, sex- and tumor stage-matched chemoresistant and control OS patients. Among the up-regulated miRNAs in chemoresistant OS samples, miR-33a was verified to down-regulate TWIST expression, which was supported by an inverse miRNA-33a/TWIST expression trend in the validation cohort (n = 70), target-sequence-specific inhibition of TWIST-3[prime] untranslated region-luciferase reporter activity by miR-33a, and alteration of TWIST expression by overexpression or inhibition of miR-33a in human OS cell lines. In Saos-2 cells treated with cisplatin, inhibition of miR-33a by antagomir-33a markedly increased cell apoptosis, which was enhanced by overexpression of TWIST. The apoptosis-inducing effect of TWIST overexpression was reversed by overexpression of miR-33a. In MG-63 cells, overexpression of miR-33a significantly decreased cisplatin-induced cell apoptosis, which was enhanced by knockdown of TWIST. Antagomir-33a significantly increased cisplatin-induced cell apoptosis, which was reversed by knockdown of TWIST. We have demonstrated in this study that miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. Our in vitro data indicate that miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST; on the other hand, inhibition of miR-33a by antagomir-33a enhances cisplatin-induced apoptosis in OS cells by up-regulating TWIST expression. The findings suggest that inhibition of miR-33a/TWIST signaling could be a potential new strategy to enhance neoadjuvant chemotherapy for OS.
    Journal of Experimental & Clinical Cancer Research 01/2014; 33(1):12. DOI:10.1186/1756-9966-33-12 · 4.43 Impact Factor
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