Bozok Çetintaş Vildan, Tetik Vardarlı Aslı, Düzgün Zekeriya, Tezcanlı Kaymaz Burçin, Açıkgöz Eda, Aktuğ Hüseyin, Kosova Can Buket, Gündüz Cumhur, Eroğlu Zuhal
Department of Medical Biology, Ege University School of Medicine, Izmir, Turkey.
Department of Embryology and Histology, Ege University School of Medicine, Izmir, Turkey.
Tumour Biol. 2016 Feb;37(2):1739-51. doi: 10.1007/s13277-015-3950-9. Epub 2015 Aug 28.
Platinum-based chemotherapies have long been used as a standard treatment in non-small cell lung cancer. However, cisplatin resistance is a major problem that restricts the use of cisplatin. Deregulated cell death mechanisms including apoptosis and autophagy could be responsible for the development of cisplatin resistance and miRNAs are the key regulators of these mechanisms. We aimed to analyse the effects of selected miRNAs in the development of cisplatin resistance and found that hsa-miR-15a-3p was one of the most significantly downregulated miRNAs conferring resistance to cisplatin in Calu1 epidermoid lung carcinoma cells. Only hsa-miR-15a-3p mimic transfection did not affect cell proliferation or cell death, though decreased cell viability was found when combined with cisplatin. We found that induced expression of hsa-miR-15a-3p via mimic transfection sensitised cisplatin-resistant cells to apoptosis and autophagy. Our results demonstrated that the apoptosis- and autophagy-inducing effects of hsa-miR-15a-3p might be due to suppression of BCL2, which exhibits a major connection with cell death mechanisms. This study provides new insights into the mechanism of cisplatin resistance due to silencing of the tumour suppressor hsa-miR-15a-3p and its possible contribution to apoptosis, autophagy and cisplatin resistance, which are the devil's triangle in determining cancer cell fate.
铂类化疗长期以来一直被用作非小细胞肺癌的标准治疗方法。然而，顺铂耐药是限制顺铂使用的一个主要问题。包括凋亡和自噬在内的细胞死亡机制失调可能是顺铂耐药产生的原因，而微小RNA（miRNAs）是这些机制的关键调节因子。我们旨在分析特定miRNAs在顺铂耐药形成中的作用，发现hsa-miR-15a-3p是Calu1肺表皮样癌细胞中对顺铂耐药最显著下调的miRNAs之一。单独转染hsa-miR-15a-3p模拟物不影响细胞增殖或细胞死亡，不过与顺铂联合使用时细胞活力会降低。我们发现通过模拟物转染诱导hsa-miR-15a-3p表达可使顺铂耐药细胞对凋亡和自噬敏感。我们的结果表明，hsa-miR-15a-3p的凋亡诱导和自噬诱导作用可能是由于抑制了BCL2，而BCL2与细胞死亡机制有主要联系。本研究为肿瘤抑制因子hsa-miR-15a-3p沉默导致顺铂耐药的机制及其对凋亡、自噬和顺铂耐药的可能作用提供了新的见解，而凋亡、自噬和顺铂耐药是决定癌细胞命运的“魔鬼三角”。
