Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.
Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.
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纤毛损失通过激活甲羟戊酸途径使细胞对转化敏感
DOI：
10.1084/jem.20170399
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发表时间：
2018-01-02
期刊：
影响因子：
--
通讯作者：
Xie D
中科院分区：
文献类型：
--
作者：
Deng YZ;Cai Z;Shi S;Jiang H;Shang YR;Ma N;Wang JJ;Guan DX;Chen TW;Rong YF;Qian ZY;Zhang EB;Feng D;Zhou QL;Du YN;Liu DP;Huang XX;Liu LM;Chin E;Li DS;Wang XF;Zhang XL;Xie D
虽然在肿瘤发生的早期阶段经常观察到纤毛损失和细胞转化，但纤毛在细胞转化中的作用尚不清楚。在这项研究中，在癌细胞和胰腺癌组织中观察到破坏的纤毛发生，其通过激活甲羟戊酸（MVA）途径促进癌基因诱导的正常胰腺细胞（HPDE 6C 7）和NIH 3 T3细胞转化。纤毛发生的破坏通过与固醇调节元件结合转录因子2（SREBP 2）同步的连环蛋白-T细胞因子（TCF）信号传导上调MVA酶，并且在胰腺导管腺癌（PDAC）的小鼠模型和人PDAC样品中再现了由连环蛋白-TCF信号传导对MVA的调节。此外，通过消耗Tg 737破坏纤毛发生显著促进了PDAC小鼠模型中的肿瘤发生，这是由KrasG 12 D驱动的，其被MVA途径的抑制剂他汀抑制。总的来说，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，表明他汀类药物对胰腺癌治疗具有治疗潜力。
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 &bgr; catenin–T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by &bgr;-catenin–TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D, 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.
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影响因子：
64.8
作者：
Perera, RushikaM.;Stoykova, Svetlana;Nicolay, Brandon N.;Ross, Kenneth N.;Fitamant, Julien;Boukhali, Myriam;Lengrand, Justine;Deshpande, Vikram;Selig, Martin K.;Ferrone, Cristina R.;Settleman, Jeff;Stephanopoulos, Gregory;Dyson, Nicholas J.;Zoncu, Roberto;Ramaswamy, Sridhar;Haas, Wilhelm;Bardeesy, Nabeel
通讯作者：
Bardeesy, Nabeel
影响因子：
3
作者：
Pal, Kasturi;Mukhopadhyay, Saikat
通讯作者：
Mukhopadhyay, Saikat
影响因子：
64.8
作者：
Pampliega, Olatz;Orhon, Idil;Patel, Bindi;Sridhar, Sunandini;Diaz-Carretero, Antonio;Beau, Isabelle;Codogno, Patrice;Satir, Birgit H.;Satir, Peter;Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
45.3
作者：
Gutt, Ruchika;Tonlaar, Nathan;Liauw, Stanley L.
通讯作者：
Liauw, Stanley L.