miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.
miRNA-193a-5p repression of p73 controls Cisplatin chemoresistance in primary bone tumors.
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DOI：
10.18632/oncotarget.10950
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发表时间：
2016-08-23
期刊：
影响因子：
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通讯作者：
Ory B
中科院分区：
文献类型：
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作者：
Jacques C;Calleja LR;Baud'huin M;Quillard T;Heymann D;Lamoureux F;Ory B
骨肉瘤和尤文肉瘤是两种最常见的骨肉瘤，主要位于四肢的长骨，主要影响青少年和青壮年。顺铂是目前治疗这些侵袭性癌症的药物库中的一种选择。不幸的是，对这种药物的耐药性仍然是患者复发的主要原因。因此，需要更好地了解这些药物诱导癌细胞死亡的分子途径，以及更好地描述化疗耐药的起源，以提高当前治疗的成功率。此外，由于P53在骨肉瘤中经常发生突变，这些癌症中的其他途径必须介导药物诱导的细胞死亡。在这里，我们首次证明了TAp73β，一种P53家族蛋白，与顺铂诱导的骨肉瘤细胞凋亡有关。此外，虽然癌细胞对这类药物产生的获得性耐药性可能有多种来源，但现在人们普遍认为，涉及microRNAs(MiRNAs)的表观遗传机制是其中之一。我们发现miRNA-193a-5p通过抑制TAp73β来调节骨肉瘤细胞的存活率、克隆形成能力和顺铂诱导的细胞凋亡。总之，这些结果揭示了miR-193a-5p参与了骨肉瘤顺铂耐药的过程，并为在这些恶性肿瘤中靶向miR-193a-5p/TAp73β轴提供的新的治疗机会开辟了道路。
Osteosarcoma and Ewing Sarcoma are the two most common types of Bone Sarcomas, principally localized at the long bones of the extremities and mainly affecting adolescents and young adults. Cisplatin is one of the current options in the therapeutic arsenal of drugs available to cure these aggressive cancers. Unfortunately, chemoresistance against this agent is still a major cause of patient relapse. Thus, a better understanding of the molecular pathways by which these drugs induce cancer cell death, together with a better delineation of the origins of chemoresistance are required to improve the success rate of current treatments. Furthermore, as p53 is frequently mutated in Bone Sarcomas, other pathways in these cancers must mediate drug-induced cell death. Here, we demonstrate for the first time that TAp73β, a p53-family protein, is implicated in Cisplatin-induced apoptosis of Bone Sarcomas'. Furthermore, while acquired resistance developed by cancer cells against such drugs can have multiple origins, it is now well accepted that epigenetic mechanisms involving microRNAs (miRNAs) are one of them. We show that miRNA-193a-5p modulates the viability, the clonogenic capacity and the Cisplatin-induced apoptosis of the Bone Sarcoma cells through inhibition of TAp73β. Collectively, these results shed light on the involvement of miR-193a-5p in Cisplatin chemoresistance of Bone Sarcomas', and they open the road to new therapeutic opportunities provided by targeting the miR-193a-5p/TAp73β axis in the context of these malignancies.