Piccolella Margherita, Cristofani Riccardo, Tedesco Barbara, Chierichetti Marta, Ferrari Veronica, Casarotto Elena, Cozzi Marta, Crippa Valeria, Rusmini Paola, Galbiati Mariarita, Poletti Angelo, Messi Elio
Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, Italy.
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Front Oncol. 2021 May 31;11:652085. doi: 10.3389/fonc.2021.652085. eCollection 2021.
Breast cancer (BC) is a serious and widespread disease for which different treatments have been developed. In addition to the classic therapies, the treatment with retinoic acid (RA) is still being clinically investigated. RA reduces cancer cells proliferation and migration, but its molecular mechanism of action is not clear. In tumor development, autophagy promotes cancer cell survival and prevents apoptosis. Small heat shock protein B8 (HSPB8) acts together with its co-chaperone BCL-2 associated athanogene 3 (BAG3) stimulating BC proliferation and migration. We analyzed whether direct correlations exist between RA and HSPB8 or BAG3 and how this may play a role in BC. We measured HSPB8 and BAG3 gene expression in MCF-7 BC cells and we analyzed the potential correlation between the antiproliferative and antimigratory effect of RA with the expression level of HSPB8. We found that in MCF-7 cells RA reduces both HSPB8 and BAG3 gene expression and it alters the mitotic spindle organization. Notably, the effects of RA on HSPB8 levels are exerted at both transcriptional and translational levels. RA effects are possibly mediated by miR-574-5p that targets the HSPB8 transcript. Our results suggest that therapeutic doses of RA can efficiently counteract the adverse effects of HSPB8 in BC progression.
乳腺癌（BC）是一种严重且广泛传播的疾病，针对该疾病已开发出不同的治疗方法。除了经典疗法外，维甲酸（RA）治疗仍在进行临床研究。RA可降低癌细胞的增殖和迁移能力，但其分子作用机制尚不清楚。在肿瘤发展过程中，自噬可促进癌细胞存活并防止细胞凋亡。小分子热休克蛋白B8（HSPB8）与其共伴侣分子BCL-2相关抗凋亡基因3（BAG3）共同作用，刺激乳腺癌细胞的增殖和迁移。我们分析了RA与HSPB8或BAG3之间是否存在直接关联，以及这在乳腺癌中可能发挥何种作用。我们检测了MCF-7乳腺癌细胞中HSPB8和BAG3的基因表达，并分析了RA的抗增殖和抗迁移作用与HSPB8表达水平之间的潜在相关性。我们发现，在MCF-7细胞中，RA可降低HSPB8和BAG3的基因表达，并改变有丝分裂纺锤体的组织。值得注意的是，RA对HSPB8水平的影响在转录和翻译水平均有体现。RA的作用可能是由靶向HSPB8转录本的miR-574-5p介导的。我们的结果表明，治疗剂量的RA可有效对抗HSPB8在乳腺癌进展中的不利影响。
