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- Title
Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas.
- Authors
Holgren, C.; Dougherty, U.; Edwin, F.; Cerasi, D.; Taylor, I.; Fichera, A.; Joseph, L.; Bissonnette, M.; Khare, S.
- Abstract
Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/extracellular signal-regulated kinase (ERK) pathways. Sprouty is downregulated 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 upregulated 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 upregulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants showed strong upregulation 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 small interfering RNA (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 showed increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to the liver from cecal orthotopic implants, suggesting that 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 upregulation.
- Subjects
COLON cancer; ADENOCARCINOMA; BREAST cancer; LIVER cancer; PROSTATE cancer; TUMOR suppressor genes; MET receptor; CELL proliferation
- Publication
Oncogene, 2010, Vol 29, Issue 38, p5241
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2010.264