Synergistic role of Sprouty2 inactivation and c-Met up-regulation in mouse and human hepatocarcinogenesis.
Sprouty2 (Spry2), a negative feedback regulator of the Ras/mitogen-activated protein kinase (MAPK) pathway, is frequently down-regulated in human hepatocellular carcinoma (HCC). We tested the hypothesis that loss of Spry2 cooperates with unconstrained activation of the c-Met protooncogene to induce hepatocarcinogenesis via in vitro and in vivo approaches. We found coordinated down-regulation of Spry2 protein expression and activation of c-Met as well as its downstream effectors extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene homolog (AKT) in a subset of human HCC samples with poor outcome. Mechanistic studies revealed that Spry2 function is disrupted in human HCC via multiple mechanisms at both transcriptional and post-transcriptional level, including promoter hypermethylation, loss of heterozygosity, and proteosomal degradation by neural precursor cell expressed, developmentally down-regulated 4 (NEDD4). In HCC cell lines, Spry2 overexpression inhibits c-Met-induced cell proliferation as well as ERK and AKT activation, whereas loss of Spry2 potentiates c-Met signaling. Most importantly, we show that blocking Spry2 activity via a dominant negative form of Spry2 cooperates with c-Met to promote hepatocarcinogenesis in the mouse liver by sustaining proliferation and angiogenesis. The tumors exhibited high levels of activated ERK and AKT, recapitulating the subgroup of human HCC with a clinically aggressive phenotype.


CONCLUSIONS
The occurrence of frequent genetic, epigenetic, and biochemical events leading to Spry2 inactivation provides solid evidence that Spry2 functions as a tumor suppressor gene in liver cancer. Coordinated deregulation of Spry2 and c-Met signaling may be a pivotal oncogenic mechanism responsible for unrestrained activation of ERK and AKT pathways in human hepatocarcinogenesis.
Lee
Susie A
SA
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Ladu
Sara
S
Evert
Matthias
M
Dombrowski
Frank
F
De Murtas
Valentina
V
Chen
Xin
X
Calvisi
Diego F
DF
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000209:etiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C485561:SPRY2 protein, human; D019859:Proto-Oncogene Proteins c-met; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse