Differential roles of insulin-like growth factor receptor- and insulin receptor-mediated signaling in the phenotypes of hepatocellular carcinoma cells.
Intrahepatic and extrahepatic metastases are common findings in hepatocellular carcinoma (HCC). Insulin-like growth factor 2 (IGF2) expression is frequently induced in HCC, and serum IGF2 levels correlate with the presence of extrahepatic metastases. Yet, the role of IGF-induced signaling in the dissemination of HCC remains unclear. We have previously observed elevated IGF2 levels in tumors with metastatic potential in an HCC mouse model. Here, we demonstrate that inhibition of IGF2, or its receptor IGF1R, impairs the migration and invasion activities of murine HCC cells. Furthermore, inhibition of IGF1R also impairs the ability of HCC cells to colonize the lungs after introduction into the circulation through the tail vein but does not impair subcutaneous tumor growth. Collectively, these findings suggest that IGF1R-mediated signaling plays a causative role in tumor dissemination but is not required for tumor growth per se. Although previous studies indicate that IGF ligands can signal through IGF1R/insulin receptor (IR) heterodimers, and IR-A homodimers, we demonstrate that the IR is not required for invasion and metastasis by HCC cells. Finally, we identify matrix metalloproteinase 2 as a mediator of the invasive phenotype downstream of IGF1R-induced signaling. Thus, our studies demonstrate the importance of IGF2-induced signaling in the dissemination of HCC cells.
Chen
Ya-Wen
YW
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Boyartchuk
Victor
V
Lewis
Brian C
BC
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011972:Receptor, Insulin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
C513121:IGF2 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9