NEW ROLE OF HYPDXIA IN PATHOPHYSIOLOGY OF MULTIPLE MYELOMA THROUGH MIR-210

Bone is one of the most common sites of complication in multiple myeloma (MM) progression and bone remodeling gets definitively perturbed during disease progression. Hypoxia and miR-210 play an important role in hematological malignancies. In an attempt to elucidate the specificity of the pathways of hypoxia and miR-210 in suppression of osteoblastic differentiation in MM patients, we examined the effect of miR-210 and hypoxia on expression of important cytokines and genes of myeloma cells. Differentiation of BM-MSCs towards osteoblastic cells in response to microvesicles (MVs) was also investigated. Finally, we proposed a molecular model on how HIF-1 alpha may promote bone lesions in MM patients. To validate the effect of miR-210 and HIF-1 alpha on targeted genes, the shRNA of HIF-1 alpha and off-hsa-miR-210 were transfected into RPMI-8226 cells. BM-MSCs were cultured in osteoblastic inducer and 50 mu g/mL of MVs derived from both hypoxic and normoxic myeloma cells. We designed an in vitro study to establish the effects of HIF-1 alpha and miR-210 on the crosstalk between MM and osteoblasts. We here showed that hypoxia-induced miR-210 increased the mRNA expression of VLA-4, CXCR4, IL-6 and TGF-beta in myeloma cells. MiR-210 is mandatory for the hypoxia-increased resistance of MM cells to melphalan. Moreover, MVs derived from hypoxic myeloma cells substantially decreased osteoblast differentiation. Considered comprehensively, our findings explain one of the reasons of bone loss that occurs at the sites of MM and a nascent crosstalk model in MM pathogenesis.