SET contributes to the epithelial-mesenchymal transition of pancreatic cancer.
SET contributes to the epithelial-mesenchymal transition of pancreatic cancer.
复制标题
DOI：
10.18632/oncotarget.19067
复制
发表时间：
2017-09-15
期刊：
影响因子：
--
通讯作者：
Govindarajan R
中科院分区：
文献类型：
--
作者：
Mody HR;Hung SW;Naidu K;Lee H;Gilbert CA;Hoang TT;Pathak RK;Manoharan R;Muruganandan S;Govindarajan R
胰腺癌的预后是灾难性的，因为80%-90%的诊断病例发生在已经出现转移的时候。上皮-间充质转化(EMT)的激活是转移的先决条件，因为它允许肿瘤细胞扩散到血流和次级器官。在这里，我们试图确定SET癌蛋白，一种PP2A的内源性抑制物，在EMT和胰腺肿瘤进展中的作用。在SET的两个主要亚型(亚型1和亚型2)中，侵袭性胰腺癌细胞株中SET亚型2的蛋白水平较高。在上皮细胞系中过表达SET亚型2和SET亚型1，通过诱导间充质特征和促进细胞的增殖、迁移、侵袭和集落形成，促进了EMT样特征。一直以来，间充质细胞系中SET异构体的敲除部分抵抗了这些特征，并促进了上皮特征。SET诱导的EMT可能是通过增加N-钙粘蛋白的过度表达、降低PP2A活性和/或增加关键的EMT驱动转录因子的表达来促进的。此外，SET过表达激活了rac1/JNK/c-jun信号通路，从而诱导了N-cadherin表达的转录激活。在体内，SET异构体2的过度表达与人PDAC中N-钙粘蛋白的增加以及在原位小鼠肿瘤模型中的肿瘤负担和转移能力显著相关。这些发现确定了SET在癌症中的新作用，并对SET的设计和靶向干预胰腺肿瘤进展具有一定的意义。
Pancreatic cancer has a devastating prognosis due to 80-90% of diagnostic cases occurring when metastasis has already presented. Activation of the epithelial-mesenchymal transition (EMT) is a prerequisite for metastasis because it allows for the dissemination of tumor cells to blood stream and secondary organs. Here, we sought to determine the role of SET oncoprotein, an endogenous inhibitor of PP2A, in EMT and pancreatic tumor progression. Among the two major isoforms of SET (isoform 1 and isoform 2), higher protein levels of SET isoform 2 were identified in aggressive pancreatic cancer cell lines. Overexpressing SET isoform 2, and to a lesser extent SET isoform 1, in epithelial cell lines promoted EMT-like features by inducing mesenchymal characteristics and promoting cellular proliferation, migration, invasion, and colony formation. Consistently, knockdown of SET isoforms in the mesenchymal cell line partially resisted these characteristics and promoted epithelial features. SET-induced EMT was likely facilitated by increased N-cadherin overexpression, decreased PP2A activity and/or increased expression of key EMT-driving transcription factors. Additionally, SET overexpression activated the Rac1/JNK/c-Jun signaling pathway that induced transcriptional activation of N-cadherin expression. In vivo, SET isoform 2 overexpression significantly correlated with increased N-cadherin in human PDAC and to tumor burden and metastatic ability in an orthotopic mouse tumor model. These findings identify a new role for SET in cancer and have implications for the design and targeting of SET for intervening pancreatic tumor progression.
登录
查看更多内容
DOI：
10.15252/embj.201490693
发表时间：
2015-08-13
期刊：
The EMBO journal
影响因子：
--
作者：
Sahu SK;Garding A;Tiwari N;Thakurela S;Toedling J;Gebhard S;Ortega F;Schmarowski N;Berninger B;Nitsch R;Schmidt M;Tiwari VK
通讯作者：
Tiwari VK
影响因子：
50.3
作者：
Neviani, P;Santhanam, R;Perrotti, D
通讯作者：
Perrotti, D
影响因子：
8
作者：
Maeda, M.;Johnson, E.;Johnson, K. R.
通讯作者：
Johnson, K. R.
影响因子：
3.3
作者：
Govindarajan R;Chakraborty S;Johnson KE;Falk MM;Wheelock MJ;Johnson KR;Mehta PP
通讯作者：
Mehta PP
DOI：
10.1158/1541-7786.mcr-13-0542
发表时间：
2014-06
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Farrell AS;Allen-Petersen B;Daniel CJ;Wang X;Wang Z;Rodriguez S;Impey S;Oddo J;Vitek MP;Lopez C;Christensen DJ;Sheppard B;Sears RC
通讯作者：
Sears RC