This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, X. Articles by Glick, A. Search for Related Content PubMed PubMed Citation Articles by Liu, X. Articles by Glick, A.

Smad7 but not Smad6 Cooperates with Oncogenic ras to Cause Malignant Conversion in a Mouse Model for Squamous Cell Carcinoma

Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland

Smad7 and Smad6 are inhibitory Smads that block transforming growth factor-ß (TGF-ß) 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-, heparin binding-EGF, amphiregulin, and EGF receptor tyrosine phosphorylation as well as the EGF-CFC growth factor cripto-1. TGF- 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-ß 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.

This article has been cited by other articles:

				L. De Rosa, D. Antonini, G. Ferone, M. T. Russo, P. B. Yu, R. Han, and C. Missero p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7 J. Biol. Chem., October 30, 2009; 284(44): 30574 - 30582. [Abstract] [Full Text] [PDF]

				X. Yan, Z. Liu, and Y. Chen Regulation of TGF-{beta} signaling by Smad7 Acta Biochim Biophys Sin, April 1, 2009; 41(4): 263 - 272. [Abstract] [Full Text] [PDF]

				H.-S. Jeon, T. Dracheva, S.-H. Yang, D. Meerzaman, J. Fukuoka, A. Shakoori, K. Shilo, W. D. Travis, and J. Jen SMAD6 Contributes to Patient Survival in Non-Small Cell Lung Cancer and Its Knockdown Reestablishes TGF-{beta} Homeostasis in Lung Cancer Cells Cancer Res., December 1, 2008; 68(23): 9686 - 9692. [Abstract] [Full Text] [PDF]

				L. L. Hoover and S. W. Kubalak Holding Their Own: The Noncanonical Roles of Smad Proteins Sci. Signal., November 18, 2008; 1(46): pe48 - pe48. [Abstract] [Full Text] [PDF]

				C. L. Kanies, J. J. Smith, C. Kis, C. Schmidt, S. Levy, K. S.A. Khabar, J. Morrow, N. Deane, D. A. Dixon, and R. D. Beauchamp Oncogenic Ras and Transforming Growth Factor-{beta} Synergistically Regulate AU-Rich Element-Containing mRNAs during Epithelial to Mesenchymal Transition Mol. Cancer Res., July 1, 2008; 6(7): 1124 - 1136. [Abstract] [Full Text] [PDF]

				A. Shukla, Y. Ho, X. Liu, A. Ryscavage, and A. B. Glick Cripto-1 Alters Keratinocyte Differentiation via Blockade of Transforming Growth Factor-{beta}1 Signaling: Role in Skin Carcinogenesis Mol. Cancer Res., March 1, 2008; 6(3): 509 - 516. [Abstract] [Full Text] [PDF]

				K. Jungert, A. Buck, M. Buchholz, M. Wagner, G. Adler, T. M. Gress, and V. Ellenrieder Smad-Sp1 complexes mediate TGF{beta}-induced early transcription of oncogenic Smad7 in pancreatic cancer cells Carcinogenesis, December 1, 2006; 27(12): 2392 - 2401. [Abstract] [Full Text] [PDF]

				J. Hulit, R. J. Lee, Z. Li, C. Wang, S. Katiyar, J. Yang, A. A. Quong, K. Wu, C. Albanese, R. Russell, et al. p27Kip1 Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/{beta}-Catenin Signaling. Cancer Res., September 1, 2006; 66(17): 8529 - 8541. [Abstract] [Full Text] [PDF]