title: A functional role for Smad7 in sustaining colon cancer cell growth and survival.
abstract: Initially identified as an inhibitor of transforming growth factor (TGF)-β mainly owing to its ability to bind TGF-β receptor type I and abrogate TGF-β-driven signaling, Smad7 can interact with additional intracellular proteins and regulate TGF-β-independent pathways, thus having a key role in the control of neoplastic processes in various organs. Genome-wide association studies have shown that common alleles of Smad7 influence the risk of colorectal cancer (CRC), even though the contribution of Smad7 in colon carcinogenesis is not fully understood. In this study, we assessed the expression and role of Smad7 in human and mouse models of sporadic CRC. We document a significant increase of Smad7 in human CRC relative to the surrounding nontumor tissues and show that silencing of Smad7 inhibits the growth of CRC cell lines both in vitro and in vivo after transplantation into immunodeficient mice. Knockdown of Smad7 results in enhanced phosphorylation of the cyclin-dependent kinase (CDK)2, accumulation of CRC cells in S phase and enhanced cell death. Smad7-deficient CRC cells have lower levels of CDC25A, a phosphatase that dephosphorylates CDK2, and hyperphosphorylated eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, knockdown of Smad7 associates with inactivation of eIF2α, lower CDC25A expression and diminished fraction of proliferating cells in human CRC explants, and reduces the number of intestinal tumors in Apc(min/+) mice. Altogether, these data support a role for Smad7 in sustaining colon tumorigenesis.
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Stolfi
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: De Simone
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Colantoni
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Franzè
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ribichini
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Fantini
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Caruso
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: Department of Surgery, University of 'Tor Vergata', Rome, Italy.
authors.forename: G S
authors.initials: GS
authors.lastname: Sica
authors.affiliation: Department of Surgery, University of 'Tor Vergata', Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Sileri
authors.affiliation: Centre for Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK.
authors.forename: T T
authors.initials: TT
authors.lastname: MacDonald
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pallone
authors.affiliation: Department of Systems Medicine, University of 'Tor Vergata', Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D016654:Genes, RAG-1; D015316:Genetic Therapy; D045325:HCT116 Cells; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D016376:Oligonucleotides, Antisense; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases