miRNA Signatures Associate with Pathogenesis and Progression of Osteosarcoma

Abstract

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.

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

“…Most patients with osteosarcoma are diagnosed at a late stage, and many patients need radiotherapy or/and chemotherapy 5, 6, 7, 8. However, the response to chemotherapy is usually poor in these patients 9, 10, 11, 12.…”

CORR Insights®: MicroRNA Regulates Vascular Endothelial Growth Factor Expression in Chondrosarcoma Cells

“…Normal chondrocytes, chondrosarcoma, and osteosarcoma have been shown to express miRNA-181a [1,2,6,9]. The current study has made an important contribution in terms of how it demonstrates a pathogenic role for miR181a, particularly in terms of the upregulation of VEGF, and how it may respond to hypoxia in chondrosarcoma cells.…”

“…Previous studies [1,2,6,9] demonstrated that miRNA-181a is neither cell nor tumor specific. Normal chondrocytes, chondrosarcoma, and osteosarcoma have been shown to express miRNA-181a [1,2,6,9].…”

“…Previous research [5] demonstrated the roles of miRNAs in tumor initiation, invasion, angiogenesis, apoptosis, and metastasis, among other areas. A number of articles [1][2][3][4][5][6][7][8][9] have investigated miRNAs in sarcomas. Yoshitaka and colleagues [9] evaluated the miRNA expressions in clinical samples from human conventional chondrosarcoma tissue, cell lines, and nontumorous articular chondrocytes.…”

Bone marrow stroma-derived miRNAs as regulators, biomarkers and therapeutic targets of bone metastasis

“…34,35 Given the profound effect that regulated miRNA expression has on bone marrow cell differentiation and activity, it is perhaps not surprising that misregulation of miRNAs has also been linked to a number of bone-related pathologies, including miRNAs as biomarkers for bone metastasis progression A Aleč ković and Y Kang [36][37][38] and osteosarcoma. [39][40][41][42][43] Importantly, misregulated miRNAs have been proposed as potential biomarkers of the specific bone-related diseases as they may accurately reflect the disease state of the bone. Because osteoporosis is caused by an imbalance between bone formation and resorption, misregulated bone marrow miRNAs represent promising indicators of assessment of bone fragility and provide potential therapeutic options to restore homeostasis.…”