Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas

Abstract

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.