MicroRNA-1252-5p Associated with Extracellular Vesicles Enhances Bortezomib Sensitivity in Multiple Myeloma Cells by Targeting Heparanase

Author(s)

Rodrigues-Junior, Dorival Mendes ^{[1, 2]} ; de Andrade Pelarin, Maria Fernanda ^[1] ; Nader, Helena Bonciani ^[1] ; Vettore, Andre Luiz ^[3] ; Silva Pinhal, Maria Aparecida ^{[4, 1]}

Affiliation

^[1] Univ Fed Sao Paulo UNIFESP, Dept Biochem, Rua Tres de Maio 100, BR-04044020 Sao Paulo, SP - Brazil

^[2] Uppsala Univ, Inst Med Biochem & Microbiol, Uppsala - Sweden

^[3] Univ Fed Sao Paulo UNIFESP, Dept Biol Sci, Diadema - Brazil

^[4] Fac Med ABC, Dept Biochem, Santo Andre, SP - Brazil

• Document type: Journal article
• Source: ONCOTARGETS AND THERAPY; v. 14, p. 455-467, 2021.
• Web of Science Citations: 0

Abstract

Introduction: Multiple myeloma (MM) remains an incurable disease, and patient survival requires a better understanding of this malignancy's molecular aspects. Heparanase (HPSE) is highly expressed in aggressive MM cells and related to tumor growth, metastasis, and bortezomib (BTZ) resistance. Thus, targeting HPSE seems to be a promising approach for MM treatment, and because microRNAs (miRNAs) have emerged as potential regulators of HPSE expression, the use of extracellular vesicles (EVs) can allow the efficient delivery of therapeutic miRNAs. Methods: We used prediction algorithms to identify potential miRNAs that regulate negatively HPSE expression. RT-qPCR was performed to assess miRNAs and HPSE expression in MM lines (U266 and RPMI-8226). Synthetic miRNA mimics were electroporated in MM cells to understand the miRNA contribution in HPSE expression, glycosaminoglycans (GAGs) profile, cell proliferation, and cell death induced by BTZ. EVs derived from HEK293T cells were engineered with miRNAs to evaluate their therapeutic potential combined with BTZ. Results: It revealed a direct association between BTZ sensitivity, HPSE, and miR-1252-5p expressions. Moreover, overexpression of miR-1252-5p significantly reduced HPSE expression and HPSE enzymatic activity in MM cells. The higher level of miR-1252-5p was correlated with a reduction of cell viability and higher sensitivity to BTZ. Further, EVs carrying miR-1252-5p increased MM cells' sensitivity to BTZ treatment. Conclusion: These results showed that miR-1252-5p could negatively regulate HPSE in MM, indicating the use of EVs carrying miR-1252-5p as a potential novel BTZ sensitization approach in MM cells. (AU)

• FAPESP's process: 15/09182-0 - NEW APPROACHES FOR IDENTIFICATION OF PROGNOSIS MARKERS FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA
• Grantee: Andre Luiz Vettore de Oliveira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/01357-8 - Heparan sulfate, heparanase and HER2 binding peptides with potential antineoplastic effect
• Grantee: Maria Aparecida da Silva Pinhal
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/03964-6 - Glycosaminoglycans and proteoglycans: interplay between structure and function
• Grantee: Helena Bonciani Nader
• Support Opportunities: Research Projects - Thematic Grants