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.

Sprouty keeps bowel kinases regular in colon cancer, while miR-21 targets Sprouty

“…In this regard, two recently published studies indicate that at least some colonic adenocarcinomas have increased expression of Spry2, and that under some circumstances Spry2 can actually enhance transformation. 22,23 The apparent contradiction between these studies and the current report likely results from the specific growth factor receptor signaling repertoire active within the tumors studied and in the culture conditions of in vitro models.…”

Activation of Membrane Androgen Receptors in Colon Cancer Inhibits the Prosurvival Signals Akt/Bad In Vitro and In Vivo and Blocks Migration via Vinculin/Actin Signaling

“…This assumption is fully supported by the in vitro and in vivo results presented here, which support the argument that the in vitro findings reported previously are not simply a side effect of mAR activation. Akt has been also shown to play a major role in the invasive potential of colon cancer cells in response to a variety of stimuli, for example, heregulin (28), PAK1 (29) and Sprouty-2 (30). Moreover, inhibition of Akt-dependent pathways has been linked to reduced cell motility in colon cancer (21), whereas mAR stimulation downregulates p-Akt (16 and this work), and mAR-dependent activation has been shown to block cell motility and invasion in prostate cancer cells (1).…”

SPROUTY-2 represses the epithelial phenotype of colon carcinoma cells via upregulation of ZEB1 mediated by ETS1 and miR-200/miR-150

“…7 Moreover, in HT-29 and LS-174T cells SPRY2 increases the level of c-MET and HGF-stimulated ERK and AKT phosphorylation, promoting cell migration and invasion. 8 Further supporting a tumorigenic role, SPRY2 is upregulated in KRAS mutant colorectal cancer, 9 and in melanoma cells harbouring N-RAS or B-RAF mutations. 10,11 RNA expression repository databases show upregulation of SPRY2 expression in colorectal tumors versus others neoplasias.…”

“…7 Likewise, SPRY2 RNA and protein levels are higher in colon adenocarcinomas than in normal adjacent mucosa. 8 In SW480-ADH colon cancer cells SPRY2 represses CDH1/E-cadherin and counteracts the adhesive phenotype induced by 1α,25-dihydroxyvitamin D 3 . 7 Moreover, in HT-29 and LS-174T cells SPRY2 increases the level of c-MET and HGF-stimulated ERK and AKT phosphorylation, promoting cell migration and invasion.…”