Rodríguez-García Yaiza, Martínez-Moreno Mónica, Alonso Lola, Sánchez-Vencells Anna, Arranz Alicia, Dagà-Millán Roger, Sevilla-Movilla Silvia, Valeri Antonio, Martínez-López Joaquin, Teixidó Joaquin
Department of Molecular Biomedicine Centro de Investigaciones Biológicas Margarita Salas (CSIC) Madrid Spain.
Genetic and Molecular Epidemiology Group Spanish National Cancer Research Centre and CIBERONC Madrid Spain.
EJHaem. 2023 Jul 25;4(3):631-638. doi: 10.1002/jha2.756. eCollection 2023 Aug.
The α4β1 integrin regulates the trafficking of multiple myeloma (MM) cells and contributes to MM disease progression. MicroRNAs (miRNAs) can have both tumor suppressor and oncogenic roles and thus are key controllers of tumor evolution, and have been associated with different phases of MM pathogenesis. Using small RNAseq analysis, we show here that α4β1-dependent MM cell adhesion regulates the expression of forty different miRNAs, therefore expanding our current view of the α4β1 involvement in MM cell biology. Specific upregulation of miR-324-5p and miR-331-3p in cells attached to α4β1 ligands was confirmed upon silencing the α4 integrin subunit, and their increased levels found to be dependent on Erk1/2- and PI3K-Akt-, but not Src-dependent signaling. Enhanced miR-324-5p expression upon α4β1-mediated MM cell adhesion aimed the hedgehog (Hh) component , revealing that the miR-324-5p- module represents a α4β1-regulated pathway that could control Hh-dependent cellular responses in myeloma. Our results open new therapy research avenues around the α4β1 contribution to MM progression that deserve to be investigated.
α4β1整合素调节多发性骨髓瘤（MM）细胞的运输，并促进MM疾病进展。微小RNA（miRNA）兼具肿瘤抑制和致癌作用，因此是肿瘤演变的关键调控因子，且与MM发病机制的不同阶段相关。通过小RNA测序分析，我们在此表明，α4β1依赖性MM细胞黏附调节40种不同miRNA的表达，从而拓展了我们目前对α4β1参与MM细胞生物学的认识。在沉默α4整合素亚基后，证实了黏附于α4β1配体的细胞中miR-324-5p和miR-331-3p的特异性上调，且发现它们水平的升高依赖于Erk1/2和PI3K-Akt信号通路，而非Src依赖性信号通路。α4β1介导的MM细胞黏附后miR-324-5p表达增强靶向了刺猬（Hh）信号通路成分，表明miR-324-5p-信号模块代表了一条α4β1调节的通路，该通路可能控制骨髓瘤中Hh依赖性细胞反应。我们的研究结果围绕α4β1对MM进展的作用开辟了新的治疗研究途径，值得深入研究。
