ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer.
ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer.
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DOI：
10.1053/j.gastro.2016.06.005
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发表时间：
2016-09
期刊：
影响因子：
29.4
通讯作者：
Rustgi AK
中科院分区：
文献类型：
--
作者：
Heeg S;Das KK;Reichert M;Bakir B;Takano S;Caspers J;Aiello NM;Wu K;Neesse A;Maitra A;Iacobuzio-Donahue CA;Hicks P;Rustgi AK
ets转录因子ETV1参与胰腺发育过程中的上皮-间质转化（EMT），并在小鼠胰腺上皮内瘤变（PanIN）和胰腺导管腺癌（PDAC）中被诱导。我们研究了ETV1在PDAC基质扩张和转移中的功能，以及它对下游靶点Sparc的影响，Sparc编码PDAC基质中发现的一种基质细胞蛋白，该蛋白与侵袭性和转移以及患者预后不良有关。从Pdx1Cre中分离胰腺导管细胞；KrasG12D/+小鼠（PanIN）、Pdx1Cre、KrasG12D/+；KrasG12D/+;p53fl/+；Rosa26YFP小鼠（PDAC）、Pdx1Cre、KrasG12D/+；p53fl / +;Sparc - / -小鼠。细胞在三维类器官培养中生长，分析形态、增殖和侵袭。评估人PanIN和PDAC组织中ETV1的表达。小鼠原位移植etv1 -过表达PDAC细胞和对照细胞。原位异种移植物的分析显示，ETV1诱导的原发肿瘤明显大于对照组，基质扩张明显增加，腹水和转移明显增加。过表达ETV1的三维类器官的囊肿结构被破坏，接受了EMT，并且更具侵入性。在人PanINs中，ETV1的表达增加，在原发性和转移性pdac中更是如此。我们通过荧光素酶检测确定Sparc是ETV1的功能基因靶点，并且Sparc和ETV1蛋白在体内共定位。Sparc的破坏降低了体内ETV1过表达时基质扩张和转移的表型。我们确定Has2是ETV1的另一个下游因子；它可能介导ETV1透明质酸的显著扩张。相反，PDAC小鼠（Pdx1Cre;KrasG12D/+;p53fl/+;Rosa26YFP;Cre;Etv1fl/fl）中Etv1的破坏降低了基质中SPARC和透明质酸的水平。ETV1在小鼠胰腺癌的间质增生和转移进展中起关键作用，部分功能上通过SPACR2和HAS2介导。
The ETS-transcription factor ETV1 is involved in the epithelial–mesenchymal transition (EMT) during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on its downstream target Sparc, which encodes a matricellular protein found in the PDAC stroma that has been associated with invasiveness and metastasis and poor outcomes of patients. Pancreatic ductal cells were isolated from Pdx1Cre;KrasG12D/+ mice (PanIN), Pdx1Cre;KrasG12D/+;p53fl/+ and Pdx1Cre;KrasG12D/+;p53fl/+;Rosa26YFP mice (PDAC), and Pdx1Cre;KrasG12D/+; p53fl/+;Sparc-/- mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic transplants of ETV1-overexpressing PDAC and control cells were assessed in mice. Analyses of orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion and significantly more ascites and metastases. Three-dimensional organoids that overexpressed ETV1 had a disrupted cyst architecture, underwent the EMT, and were more invasive. ETV1 expression was increased in human PanINs and even more so in primary and metastatic PDACs. We identified Sparc as a functional gene target of ETV1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc reduced the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified Has2 as another downstream factor of ETV1; it may mediate ETV1's significant expansion of hyaluronic acid. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre;KrasG12D/+;p53fl/+;Rosa26YFP;Cre;Etv1fl/fl) reduced levels of SPARC and hyaluronic acid in the stroma. ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through SPACR2 and HAS2.
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影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
16.2
作者：
Patel, TD;Kramer, I;Snider, WD
通讯作者：
Snider, WD
DOI：
10.1158/1078-0432.ccr-15-2010
发表时间：
2016-06-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hingorani SR;Harris WP;Beck JT;Berdov BA;Wagner SA;Pshevlotsky EM;Tjulandin SA;Gladkov OA;Holcombe RF;Korn R;Raghunand N;Dychter S;Jiang P;Shepard HM;Devoe CE
通讯作者：
Devoe CE
影响因子：
29.4
作者：
Kanda M;Matthaei H;Wu J;Hong SM;Yu J;Borges M;Hruban RH;Maitra A;Kinzler K;Vogelstein B;Goggins M
通讯作者：
Goggins M
影响因子：
45.3
作者：
Infante, Jeffrey R.;Matsubayashi, Hiroyuki;Goggins, Michael
通讯作者：
Goggins, Michael