Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas.
Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas.
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DOI：
10.1038/onc.2010.264
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发表时间：
2010-09-23
期刊：
影响因子：
8
通讯作者：
Khare, S.
中科院分区：
文献类型：
--
作者：
Holgren, C.;Dougherty, U.;Edwin, F.;Cerasi, D.;Taylor, I.;Fichera, A.;Joseph, L.;Bissonnette, M.;Khare, S.
Sprouty通过抑制Ras/ERK通路负调节受体酪氨酸激酶信号。Sprouty在乳腺癌、前列腺癌和肝癌中下调，似乎起着肿瘤抑制剂的作用。然而，Sprouty在结肠肿瘤中的作用尚未研究。Sprouty-2蛋白和mRNA转录在人结肠腺癌中显著上调。引人注目的是，c-Met受体在具有增加的sprougty-2的肿瘤中也上调。为了阐明sprouty-2和c-Met之间的潜在因果关系，用纯化的TAT-sprouty-2蛋白转导K-ras突变HCT-116结肠癌细胞或用全长人sprouty-2基因稳定转染。Sprouty-2的上调通过加速细胞周期转换显著增加细胞增殖。Sprouty-2转染子表现出强烈的上调c-Met蛋白和mRNA转录和肝细胞生长因子刺激ERK和Akt磷酸化，增强细胞迁移和侵袭。与此相反，c-Met的siRNA敲低显着降低细胞增殖，迁移和sprouty-2转染细胞的侵袭。此外，在亲本HT-29和LS-174 T结肠癌细胞中通过siRNA敲低sprougty-2也降低了细胞侵袭。Sprouty-2转染子形成了明显更大的肿瘤异种移植物，并表现出增殖和血管生成增加，细胞凋亡抑制。Sprouty-2肿瘤从盲肠原位移植物转移到肝脏，表明Sprouty-2也可能增强转移信号。因此，在结肠癌中，发芽作为致癌基因发挥作用，其作用部分由c-Met上调介导。
Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/ERK pathways. Sprouty is down-regulated in breast, prostate and liver cancers and appears to function as a tumor suppressor. The role of Sprouty in colonic neoplasia, however, has not been investigated. Sprouty-2 protein and mRNA transcripts were significantly up-regulated in human colonic adenocarcinomas. Strikingly, the c-Met receptor was also upregulated in tumors with increased sprouty-2. To delineate a potential causal relationship between sprouty-2 and c-Met, K-ras mutant HCT-116 colon cancer cells were transduced with purified TAT-sprouty-2 protein or stably transfected with full-length human sprouty-2 gene. Sprouty-2 up-regulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants demonstrated strong up-regulation of c-Met protein and mRNA transcripts and hepatocyte growth factor stimulated ERK and Akt phosphorylation and enhanced cell migration and invasion. In contrast, knockdown of c-Met by siRNA significantly decreased cell proliferation, migration and invasion in sprouty-2 transfectants. Further, knockdown of sprouty-2 by siRNA in parental HT-29 and LS-174T colon cancer cells also decreased cell invasion. Sprouty-2 transfectants formed significantly larger tumor xenografts and demonstrated increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to liver from cecal orthotopic implants suggesting sprouty-2 might also enhance metastatic signals. Thus in colon cancer sprouty functions as an oncogene and its effects are mediated in part by c-Met up-regulation.
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