MiR-34c-5p Inhibition Affects Bax/Bcl2 Expression and Reverses Bortezomib Resistance in Multiple Myeloma Cells

IF 0.9 4区医学

Indian Journal of Hematology and Blood Transfusion Pub Date : 2024-04-11 DOI:10.1007/s12288-024-01742-w

Emad Matour, Zari Tahannejad Asadi, Ahmad Ahmadzadeh Deilami, Seyed Saeed Azandeh, Behrouz Taheri

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Abstract

Developing resistance to anticancer drugs complicates the clinical treatment of multiple myeloma patients. Previous studies revealed a link between the unfolded protein response (UPR) and miRNAs with acquired drug resistance. This study aimed to determine the expression profile of XBP1, hsa-miR-34c-5p, hsa-miR-214, and hsa-miR-30c-2* in resistant and sensitive multiple myeloma cell lines to a proteasome inhibitor, bortezomib. After establishing bortezomib-resistant cells, the expression level of XBP1, hsa-miR-214, hsa-miR-34c-5p, and hsa-miR-30c-2* in both cell lines were assessed by qRT-PCR. Hsa-miR-34c-5p was suppressed to study its effect on the expression profile of Bax/Bcl-2. Statistical analysis was done by t-test in two clinically resistant and sensitive cells to bortezomib. MTT assay confirmed the creation of the resistant cell line. The qRT-PCR screening showed a significant difference between XBP1 and miR-34c-5p levels in resistant and sensitive cells. Following hsa-miR-34c-5p blockage, while Bax was overexpressed, Bcl-2 expression was reduced in the resistant cell line, overcoming cells resistant to bortezomib. Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.

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抑制 MiR-34c-5p 可影响多发性骨髓瘤细胞中 Bax/Bcl2 的表达并逆转硼替佐米的抗药性

对抗癌药物产生耐药性使多发性骨髓瘤患者的临床治疗变得更加复杂。先前的研究显示，未折叠蛋白反应（UPR）和 miRNA 与获得性耐药性之间存在联系。本研究旨在确定XBP1、hsa-miR-34c-5p、hsa-miR-214和hsa-miR-30c-2*在对蛋白酶体抑制剂硼替佐米耐药和敏感的多发性骨髓瘤细胞系中的表达谱。在建立硼替佐米耐药细胞后，通过 qRT-PCR 评估了两种细胞系中 XBP1、hsa-miR-214、hsa-miR-34c-5p 和 hsa-miR-30c-2* 的表达水平。抑制 Hsa-miR-34c-5p 以研究其对 Bax/Bcl-2 表达谱的影响。通过 t 检验对两种对硼替佐米具有临床耐药性和敏感性的细胞进行了统计分析。MTT 检测证实了耐药细胞系的产生。qRT-PCR 筛查显示，耐药细胞和敏感细胞的 XBP1 和 miR-34c-5p 水平存在显著差异。在阻断 hsa-miR-34c-5p 后，耐药细胞系中 Bax 表达过高，而 Bcl-2 表达降低，从而克服了细胞对硼替佐米的耐药性。我们的研究结果表明，miR-34c-5p 在硼替佐米敏感和耐药的 MM 细胞中表达不同。抑制miR-34c-5p可通过调节Bax/Bcl-2的表达，使耐药细胞对硼替佐米重新敏感，这表明该miRNA调控细胞凋亡和耐药性，可能是克服MM蛋白酶体抑制剂耐药性的一个有希望的治疗靶点。

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Indian Journal of Hematology and Blood Transfusion Medicine-Hematology

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期刊介绍： Indian Journal of Hematology and Blood Transfusion is a medium for propagating and exchanging ideas within the medical community. It publishes peer-reviewed articles on a variety of aspects of clinical hematology, laboratory hematology and hemato-oncology. The journal exists to encourage scientific investigation in the study of blood in health and in disease; to promote and foster the exchange and diffusion of knowledge relating to blood and blood-forming tissues; and to provide a forum for discussion of hematological subjects on a national scale. The Journal is the official publication of The Indian Society of Hematology & Blood Transfusion.