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编者按：近年来，乳腺癌的分子靶向治疗不断取得进展。不过，分子靶向治疗对于乳腺癌患者五年生存率的改善尚未达到预期，尤其对于缺乏治疗靶点的三阴性乳腺癌患者。 2018年5月15日，英国《自然》旗下《癌基因》在线发表上海交通大学医学院附属仁济医院和上海儿童医学中心的研究报告，发现针对一种长链非编码核糖核酸（PVT1）可以抑制三阴性乳腺癌的发生和发展。 核糖核酸（RNA）为遗传信息载体之一。众所周知，细胞内主要有五种RNA：核糖体rRNA、信使mRNA、转运tRNA、微小miRNA、长链非编码lncRNA。lncRNA为长度大于200个核苷酸的转录物，并不编码蛋白质，但是能够发挥重要的调控作用，因此越来越受重视。 该研究发现，PVT1可以通过加强KLF5转录因子→β联蛋白的信号转导，从而促使三阴性乳腺癌发生。PVT1表达水平上调可见于临床三阴性乳腺癌。该研究通过针对三阴性乳腺癌细胞PVT1的遗传学方法，发现耗尽PVT1以后，抑制了三阴性乳腺癌细胞的增殖、克隆形成、原位异种移植肿瘤生长。其具体机制为：PVT1与KLF5结合，并通过BRCA1相关蛋白1（BAP1）增加KLF5稳定性，从而上调β联蛋白的信号转导，促使三阴性乳腺癌发生。PVT1、KLF5、β联蛋白还被发现共同表达于临床三阴性乳腺癌标本。 因此，该研究结果发现了诱发三阴性乳腺癌的新信号转导通路，并且将PVT1作为新的靶点，为改善三阴性乳腺癌的治疗奠定了基础。 Oncogene. 2018 May 15. [Epub ahead of print] LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling. Jianming Tang, Yanxin Li, Youzhou Sang, Bo Yu, Deguan Lv, Weiwei Zhang, Haizhong Feng. Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistically, PVT1 binds with KLF5 and increases its stability via BAP1, which upregulates beta-catenin signaling, resulting in enhanced TNBC tumorigenesis. PVT1, KLF5, and beta-catenin were also revealed to be co-expressed in clinical TNBC samples. Our findings uncover a new singaling pathway to mediate TNBC, and provide PVT1 as a new target for improving treatment of TNBC. DOI: 10.1038/s41388-018-0310-4
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