Smad7 but not Smad6 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma.
Smad7 and Smad6 are inhibitory Smads that block transforming growth factor-beta (TGF-beta) superfamily signal transduction. Smad7 is overexpressed in chemically induced mouse epidermal tumors, where oncogenic activation of c-ras is a frequent event. To test the role of Smad7 overexpression in tumor progression, we used retroviruses to transduce Smad7 or Smad6 and v-ras(Ha) into primary mouse keratinocytes. By itself, Smad7 transiently enhanced keratinocyte proliferation, blocked normal differentiation, and induced keratin 8, a marker of malignant conversion, but did not cause tumor formation. Smad7 extended the in vitro life span, suppressed senescence, and increased transformation frequency 3-fold of primary keratinocytes coexpressing v-ras(Ha). Smad7/v-ras(Ha) coinfected keratinocytes rapidly progressed to squamous cell carcinomas in vivo, whereas pBabe/v-ras(Ha)- or Smad6/v-ras(Ha)-transduced keratinocytes formed only benign papillomas. Smad7/v-ras(Ha) tumors had elevated proliferation and defective nuclear localizaton of Smad2, Smad3, and Smad5, whereas only Smad5 was altered in Smad6/v-ras(Ha) tumors. Smad7 overexpression in vitro induced epidermal growth factor (EGF)-like growth factors TGF-alpha, heparin binding-EGF, amphiregulin, and EGF receptor tyrosine phosphorylation as well as the EGF-CFC growth factor cripto-1. TGF-alpha and cripto-1 were also overexpressed in Smad7/v-ras(Ha) tumors. These results suggest that Smad7 overexpression accelerates tumor progression through inhibition of TGF-beta superfamily signaling and up-regulation of the EGF-like superfamily of growth factors. This is the first demonstration that Smad7 overexpression can cause malignant conversion in a multistage cancer model and suggests that it may have an important role in the pathogenesis of human cancer.
Liu
Xin
X
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute/NIH, Building 37, Bethesda, MD 20892, USA.
Lee
Jennifer
J
Cooley
Margaret
M
Bhogte
Ervind
E
Hartley
Stephan
S
Glick
Adam
A
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D011905:Genes, ras / Q000502:physiology*; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010212:Papilloma / Q000235:genetics / Q000473:pathology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta