Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
J Exp Med. 2018 Jan 2;215(1):177-195. doi: 10.1084/jem.20170399. Epub 2017 Dec 13.
Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through β catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by β-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting dramatically promoted tumorigenesis in the PDAC mouse model, driven by , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.
尽管纤毛缺失和细胞转化在肿瘤发生的早期阶段经常观察到，但纤毛在细胞转化中的作用尚不清楚。在这项研究中，观察到癌细胞和胰腺癌组织中存在纤毛发生障碍，这通过激活甲羟戊酸（MVA）途径促进了致癌基因诱导的正常胰腺细胞（HPDE6C7）和 NIH3T3 细胞的转化。纤毛发生障碍通过β连环蛋白-T 细胞因子（TCF）信号上调 MVA 酶，与固醇调节元件结合转录因子 2（SREBP2）同步，并且在胰腺导管腺癌（PDAC）小鼠模型和人类 PDAC 样本中β-连环蛋白-TCF 信号对 MVA 的调节得到了重现。此外，通过耗尽 显著促进了 PDAC 小鼠模型中的肿瘤发生，这是由 驱动的，而 MVA 途径的抑制剂 statin 抑制了这种作用。总之，这项研究强调了纤毛通过激活 MVA 途径在控制转化早期步骤中的关键作用，表明 statin 对胰腺癌治疗具有潜在的治疗作用。
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