PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways
PLAC8 Localizes to the Inner Plasma Membrane of Pancreatic Cancer Cells and Regulates Cell Growth and Disease Progression through Critical Cell-Cycle Regulatory Pathways
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DOI：
10.1158/0008-5472.can-15-0216
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发表时间：
2016-01-01
期刊：
影响因子：
11.2
通讯作者：
Buchholz, Malte
中科院分区：
文献类型：
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作者：
Kaistha, Brajesh P.;Lorenz, Holger;Buchholz, Malte
胰腺导管腺癌（PDAC）是所有实体瘤中预后最差的，并且通常对目前可用的化疗和/或放疗方案（包括靶向分子治疗）具有强烈抗性。因此，阐明胰腺癌侵袭行为的分子机制是开发新治疗方法的必要前提。我们先前在全基因组搜索与胰腺肿瘤进展相关的靶基因中鉴定了胎盘特异性蛋白8（PLAC 8，onzin），并证明PLAC 8在晚期肿瘤前病变和侵袭性人类PDAC中强烈异位表达。然而，PLAC 8的分子功能仍不清楚，并且越来越多的证据表明其作用是高度保守的，与其他细胞系统相反，PLAC 8蛋白定位于胰腺癌细胞质膜的内表面，在那里它以时间和空间稳定的方式与特定的膜结构相互作用。PLAC 8表达的抑制通过减弱细胞周期进程强烈抑制胰腺癌细胞生长，这与中央细胞周期调节因子CDKN 1A、视网膜母细胞瘤蛋白和细胞周期蛋白D1（CCND 1）的转录和/或翻译后修饰有关，但不影响自噬。此外，Plac 8缺陷显著抑制胰腺癌基因工程小鼠模型中的肿瘤形成。总之，我们的研究结果确立了PLAC 8作为PDAC中肿瘤进展的中心介导因子，以及作为诊断和治疗靶向的有希望的候选基因。（C）2015年AACR。
Pancreatic ductal adenocarcinoma (PDAC) carries the most dismal prognosis of all solid tumors and is generally strongly resistant to currently available chemo- and/or radiotherapy regimens, including targeted molecular therapies. Therefore, unraveling the molecular mechanisms underlying the aggressive behavior of pancreatic cancer is a necessary prerequisite for the development of novel therapeutic approaches. We previously identified the protein placenta-specific 8 (PLAC8, onzin) in a genome-wide search for target genes associated with pancreatic tumor progression and demonstrated that PLAC8 is strongly ectopically expressed in advanced preneoplastic lesions and invasive human PDAC. However, the molecular function of PLAC8 remained unclear, and accumulating evidence suggested its role is highly strate that in contrast to other cellular systems, PLAC8 protein localizes to the inner face of the plasma membrane in pancreatic cancer cells, where it interacts with specific membranous structures in a temporally and spatially stable manner. Inhibition of PLAC8 expression strongly inhibited pancreatic cancer cell growth by attenuating cell-cycle progression, which was associated with transcriptional and/or posttranslational modification of the central cell-cycle regulators CDKN1A, retinoblastoma protein, and cyclin D1 (CCND1), but did not impact autophagy. Moreover, Plac8 deficiency significantly inhibited tumor formation in genetically engineered mouse models of pancreatic cancer. Together, our findings establish PLAC8 as a central mediator of tumor progression in PDAC and as a promising candidate gene for diagnostic and therapeutic targeting. (C)2015 AACR.