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Inhibition of miR-144/199 promote myeloma pathogenesis via upregulation of versican and FAK/STAT3 signaling

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Abstract

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.

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Acknowledgements

The fellowship of Ms. Nidhi Gupta was granted by the Council of Scientific and Industrial Research (CSIR), India (Grant Number: 09/006(0451)/2015-EMR-I). The funding for this work was supported by the All India Institute of Medical Sciences (AIIMS), New Delhi, India (Grant Number: A-489).

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Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India

    Nidhi Gupta, Raman Kumar & Alpana Sharma

  2. Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, India

    Raman Kumar

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  1. Nidhi Gupta
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  2. Raman Kumar
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  3. Alpana Sharma
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Contributions

NG and AS contributed to the study conception and design. NG performed all the experiments, data acquisition and analysis. RK helped in methodology and data analysis. AS provided all the necessary expertise and instrumentation facilities to carry out the work. The first draft of the manuscript was written by NG and edited by AS. All authors have read and approved the final manuscript.

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Correspondence to Alpana Sharma.

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Gupta, N., Kumar, R. & Sharma, A. Inhibition of miR-144/199 promote myeloma pathogenesis via upregulation of versican and FAK/STAT3 signaling. Mol Cell Biochem 476, 2551–2559 (2021). https://doi.org/10.1007/s11010-020-04038-5

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