Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India.
Mol Cell Biochem. 2021 Jun;476(6):2551-2559. doi: 10.1007/s11010-020-04038-5. Epub 2021 Mar 1.
The continuous rise in relapse rate and mortality for multiple myeloma (MM) demands an effective treatment option. The microRNAs are emerging nowadays for their promising therapeutic potential. Earlier, we reported involvement of Versican (VCAN) in myeloma pathogenesis which could be inhibited by miR-144 and miR-199 in stroma. However, there is dearth of literature showcasing the direct effect of these miRs in association with VCAN in MM. Expression of miR-144 and miR-199 was determined in myeloma cell lines (RPMI8226 & U266). These miRs were inhibited by small oligos to elucidate changes in expression of VCAN along with variation in parameters such as proliferation, apoptosis, migration and invasion in vitro. Moreover, effect on certain downstream signaling cascades was also evaluated. Lastly, interaction of miRs with VCAN was assessed by reporter luciferase assay. microRNAs expression were found significantly elevated in myeloma cells in comparison to stromal levels reported previously. The antagomirs-mediated inhibition of miR-144 and miR-199 significantly induced VCAN expression in myeloma cells along with alteration in myeloma-associated parameters in favor of myeloma pathogenesis with downstream activation of FAK/STAT3 signaling. Interestingly, miR-144 found to have direct binding with VCAN 3' UTR while miR-199 possess different mechanism. The inhibition of miR-144 and miR-199 contributed in myeloma progression via upregulation of VCAN in vitro affirming the translational significance of VCAN and associated microRNAs in MM. These miRs, hence might be employed for targeting VCAN and might emerge as an effective therapy for the better outcome of MM in clinical settings in future.
多发性骨髓瘤（MM）的复发率和死亡率持续上升，这需要一种有效的治疗选择。microRNAs 因其有希望的治疗潜力而受到关注。此前，我们报道了 Versican（VCAN）在骨髓瘤发病机制中的作用，基质中的 miR-144 和 miR-199 可以抑制其作用。然而，目前缺乏这些 microRNAs 与 VCAN 直接相关在 MM 中作用的文献。在骨髓瘤细胞系（RPMI8226 和 U266）中测定了 miR-144 和 miR-199 的表达。通过小寡核苷酸抑制这些 microRNAs，阐明了在体外与 VCAN 的表达变化以及增殖、凋亡、迁移和侵袭等参数的变化。此外，还评估了对某些下游信号通路的影响。最后，通过报告荧光素酶测定评估了 microRNAs 与 VCAN 的相互作用。与之前报道的基质水平相比，骨髓瘤细胞中的 microRNAs 表达明显升高。miR-144 和 miR-199 的反义寡核苷酸抑制显著诱导骨髓瘤细胞中 VCAN 的表达，同时改变骨髓瘤相关参数，有利于骨髓瘤发病机制，下游激活 FAK/STAT3 信号通路。有趣的是，miR-144 被发现与 VCAN 3'UTR 有直接结合，而 miR-199 则具有不同的机制。miR-144 和 miR-199 的抑制通过体外上调 VCAN 促进骨髓瘤进展，证实了 VCAN 及其在 MM 中的相关 microRNAs 的翻译意义。这些 microRNAs 可能用于靶向 VCAN，并可能在未来成为改善 MM 临床疗效的有效治疗方法。
