Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Department of Hematology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
RNA Biol. 2020 Jan;17(1):98-111. doi: 10.1080/15476286.2019.1669405. Epub 2019 Sep 29.
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.
多发性骨髓瘤（MM）中恶性浆细胞的异常生长需要由蛋白聚糖、细胞因子等组成的骨髓（BM）龛。软骨素硫酸蛋白聚糖 Versican（VCAN）促进实体瘤的进展，但在 MM 中文献匮乏。因此，我们研究了 VCAN 在 MM 中的作用及其作为治疗方法被 microRNAs 调节的情况。招募了 30 名 MM 患者和 20 名对照者，并通过原代培养分离 BM 基质细胞（BMSCs）。在研究对象和细胞系中测定了 VCAN、miR-144、miR-199 和 miR-203 的分子水平。使用 BMSCs 条件培养基（BMSCs-CM）和 VCAN 中和抗体或 microRNA 模拟物研究 VCAN 在骨髓瘤发病机制中的作用。观察到患者，尤其是 BM 基质中 VCAN 的表达升高，而 microRNA 的表达明显降低，且与 VCAN 呈负相关。此外，BMSCs-CM 中存在 VCAN，向 MM 细胞补充后会改变有利于骨髓瘤进展的参数，但这种作用可被 VCAN 抗体或 miR（miR-144 和 miR-199）模拟物中和。发现 VCAN 的下游信号激活 FAK 和 STAT3，而使用 VCAN 抗体或 miR 模拟物可使其减弱。通过阻断 VCAN 来中和 BMSCs-CM 的致癌作用，证实其在 MM 进展中具有潜在作用。VCAN 被观察为 BM 微环境中 BMSCs 和骨髓瘤细胞之间的旁分泌介质。因此，这些发现表明探索 VCAN 作为新的治疗靶标，以及利用 microRNAs 作为调节 VCAN 的治疗方法，以更好地管理 MM。
