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Targeting of stromal versican by miR-144/199 inhibits multiple myeloma by downregulating FAK/STAT3 signalling.

ABSTRACT: The abnormal growth of malignant plasma cells in Multiple Myeloma (MM) requires bone marrow (BM) niche consisting of proteoglycans, cytokines, etc. Versican (VCAN), a chondroitin sulphate proteoglycan promotes progression in solid tumours but there is dearth of literature in MM. Hence, we studied the involvement of VCAN in MM and its regulation by microRNAs as a therapeutic approach. Thirty MM patients and 20 controls were recruited and BM stromal cells (BMSCs) were isolated by primary culture. Molecular levels of VCAN, miR-144, miR-199 & miR-203 were determined in study subjects and cell lines. The involvement of VCAN in myeloma pathogenesis was studied using BMSCs-conditioned medium (BMSCs-CM) and VCAN-neutralizing antibody or microRNA mimics. Elevated expression of VCAN was observed in patients especially in BM stroma while microRNA expression was significantly lower and showed negative correlation with VCAN. Moreover, BMSCs-CM showed the presence of VCAN which upon supplementing to MM cells alter parameters in favour of myeloma progression, however, this effect was neutralized by VCAN antibody or miR (miR-144 and miR-199) mimics. The downstream signalling of VCAN was found to activate FAK and STAT3 which subsides by using VCAN antibody or miR mimics. The neutralization of oncogenic effect of BMSCs-CM by VCAN blockage affirms its plausible role in progression of MM. VCAN was observed as a paracrine mediator in the cross-talk of BMSCs and myeloma cells in BM microenvironment. Therefore, these findings suggest exploring VCAN as novel therapeutic target and utilization of microRNAs as a therapy to regulate VCAN for better management of MM.

SUBMITTER: Gupta N

PROVIDER: S-EPMC6948970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiple myeloma (MM) is a hematological cancer causing from accumulated abnormal plasma cells. STAT3 overexpression in MM appears to be mediated by a variety of factors, and it may be associated with an adverse prognosis and play a role in microenvironment-dependent treatment resistance. Unfortunately, MM remains an incurable disease, as relapse is very common. Therefore, there is urgent need to develop new treatment options for MM. Radotinib is a novel anti-cancer drug, currently approved in South Korea for the treatment of chronic myeloid leukemia patients. It is an oral, multitargeted inhibitor of receptor tyrosine kinases, including BCR-ABL, c-KIT, PDGFR, and Src family kinases. However, little is known about the effects of radotinib on multiple myeloma cells. However, little is known about the effects of radotinib on multiple myeloma cells. But even tinip almost not known about the impact of multiple myeloma cells. Moreover, nothing is known about how it affects STAT3 and JAK2. In this study, we analyzed the effect of radotinib on multiple myeloma cells. Herein, Moreover, nothing is known about how it. Moreover, not all is known about how the affects STAT3 and JAK2. We investigated the effect of radotinib on the STAT3 signaling pathway in MM cells, including several MM cell lines and mouse models. So we investigated the effect of radotinib on MM cells, including several MM cell lines and mouse models. Interestingly, radotinib induced apoptosis, and inhibited cell proliferation in MM cells including RPMI-8226, MM.1S, U266B1, and IM-9 cells. Moreover, radotinib treatment significantly increased the number Annexin V-positive cells and G0/G1-phase cells. In addition, radotinib treatment in various MM cells strongly suppressed the activity and expression of STAT3 and JAK2 proteins. We also observed that diverse proteins related to the STAT3 signaling pathway, including c-Myc, Bcl-xL, Mcl-1, cyclin D1 and cyclin D3, were powerfully inhibited by radotinib treatment in MM cells. Furthermore, radotinib significantly suppressed MM cell growth in a xenograft animal model using IM-9 cells. In conclusion, radotinib may play an important role as a candidate agent for MM treatment.

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Targeting of stromal versican by miR-144/199 inhibits multiple myeloma by downregulating FAK/STAT3 signalling.

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