Activated KrasG¹²D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin.
Activated KrasG¹²D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin.
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DOI：
10.1038/bjc.2011.31
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发表时间：
2011-03-15
影响因子：
8.8
通讯作者：
Batra, S. K.
中科院分区：
文献类型：
--
作者：
Rachagani, S.;Senapati, S.;Chakraborty, S.;Ponnusamy, M. P.;Kumar, S.;Smith, L. M.;Jain, M.;Batra, S. K.
胰腺癌（PC）在Kras原癌基因中含有一个激活的点突变（KrasG 12 D），该点突变已被证明可促进PC的发展。本研究旨在探讨致癌基因KrasG 12 D等位基因对PC细胞侵袭性和转移潜力的影响。我们通过稳定表达KrasG 12 D等位基因特异性的shRNA来沉默CD 18/HPAF和ASPC 1细胞系中致癌基因KrasG 12 D等位基因的表达。KrasG 12 D敲低细胞表现出运动性显著降低（P<0.0001），浸润（P<0.0001），锚定依赖性（P<0.0001）和锚定非依赖性生长（P<0.0001），增殖（P<0.005）和细胞倍增时间增加（P<0.005），并且原位植入裸鼠后转移发生率降低。KrasG 12 D等位基因的敲除导致E-钙粘蛋白（mRNA和蛋白质）在体外和体内的表达显著增加。这与phoshpo-ERK-1/2、NF-κB和MMP-9以及转录因子如δ EF 1、Snail和ETV 4的表达减少有关。此外，在KrasG 12 D敲低的细胞中，参与细胞存活、侵袭和转移的几种蛋白质的表达降低。这项研究的结果表明，KrasG 12 D等位基因促进PC细胞的转移，部分通过下调E-cadherin。
Pancreatic cancer (PC) harbours an activated point mutation (KrasG12D) in the Kras proto-oncogene that has been demonstrated to promote the development of PC. This study was designed to investigate the effect of the oncogenic KrasG12D allele on aggressiveness and metastatic potential of PC cells. We silenced the oncogenic KrasG12D allele expression in CD18/HPAF and ASPC1 cell lines by stable expression of shRNA specific to the KrasG12Dallele. The KrasG12D knockdown cells exhibited a significant decrease in motility (P<0.0001), invasion (P<0.0001), anchorage-dependent (P<0.0001) and anchorage-independent growth (P<0.0001), proliferation (P<0.005) and an increase in cell doubling time (P<0.005) in vitro and a decrease in the incidence of metastases upon orthotopic implantation into nude mice. The knockdown of the KrasG12D allele led to a significant increase in the expression of E-cadherin (mRNA and protein) both in vitro and in vivo. This was associated with a decrease in the expression of phoshpo-ERK-1/2, NF-κB and MMP-9, and transcription factors such as δEF1, Snail and ETV4. Furthermore, the expression of several proteins involved in cell survival, invasion and metastasis was decreased in the KrasG12D knockdown cells. The results of this study suggest that the KrasG12D allele promotes metastasis in PC cells partly through the downregulation of E-cadherin.
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影响因子：
5.2
作者：
Chaturvedi, Pallavi;Singh, Ajay P.;Batra, Surinder K.
通讯作者：
Batra, Surinder K.
影响因子：
64.5
作者：
ALMOGUERA, C;SHIBATA, D;PERUCHO, M
通讯作者：
PERUCHO, M
影响因子：
3.8
作者：
Heinemann, Volker;Boeck, Stefan;Hinke, Axel;Labianca, Roberto;Louvet, Christophe
通讯作者：
Louvet, Christophe
影响因子：
8
作者：
Eger, A;Aigner, K;Foisner, R
通讯作者：
Foisner, R
影响因子：
10.5
作者：
Aguirre, AJ;Bardeesy, N;DePinho, RA
通讯作者：
DePinho, RA