Home LiteratureArticle Details
PMID: 19841536 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation.

The Journal of clinical investigation ·Vol. 119 ·No. 11 ·2009-11-00 ·Pages 3408-19

Bornstein S, White R, Malkoski S, Oka M, Han G, Cleaver T, Reh D, Andersen P, Gross N, Olson S, Deng C, Lu SL, Wang XJ

Abstract

Smad4 is a central mediator of TGF-beta signaling, and its expression is downregulated or lost at the malignant stage in several cancer types. In this study, we found that Smad4 was frequently downregulated not only in human head and neck squamous cell carcinoma (HNSCC) malignant lesions, but also in grossly normal adjacent buccal mucosa. To gain insight into the importance of this observation, we generated mice in which Smad4 was deleted in head and neck epithelia (referred to herein as HN-Smad4-/- mice) and found that they developed spontaneous HNSCC. Interestingly, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited increased genomic instability, which correlated with downregulated expression and function of genes encoding proteins in the Fanconi anemia/Brca (Fanc/Brca) DNA repair pathway linked to HNSCC susceptibility in humans. Consistent with this, further analysis revealed a correlation between downregulation of Smad4 protein and downregulation of the Brca1 and Rad51 proteins in human HNSCC. In addition to the above changes in tumor epithelia, both normal head and neck tissue and HNSCC from HN-Smad4-/- mice exhibited severe inflammation, which was associated with increased expression of TGF-beta1 and activated Smad3. We present what we believe to be the first single gene-knockout model for HNSCC, in which both HNSCC formation and invasion occurred as a result of Smad4 deletion. Our results reveal an intriguing connection between Smad4 and the Fanc/Brca pathway and highlight the impact of epithelial Smad4 loss on inflammation.

MeSH Terms
Animals Carcinoma, Squamous Cell/genetics,pathology,physiopathology DNA Repair/genetics Down-Regulation Fanconi Anemia Complementation Group Proteins/metabolism Gene Deletion Genes, BRCA1 Genomic Instability/genetics Head and Neck Neoplasms/genetics,pathology,physiopathology Humans Inflammation/genetics,physiopathology Mice Mice, Inbred C57BL Mice, Knockout Rad51 Recombinase/metabolism Smad4 Protein/genetics,metabolism
Chemicals
Fanconi Anemia Complementation Group Proteins Smad4 Protein Rad51 Recombinase
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Bornstein Sophia
Department of Otolaryngology, Oregon Health & Science University (OHSU), Portland, Oregon, USA.
White Ruth
Malkoski Stephen
Oka Masako
Han Gangwen
Cleaver Timothy
Reh Douglas
Andersen Peter
Gross Neil
Olson Susan
Deng Chuxia
Lu Shi-Long
Wang Xiao-Jing
References (60)
60 references, click to expand
  1. Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice.
    Development. 2003 Dec;130(24):6143-53 PMID: 14597578
  2. Cancer targets in the Ras pathway.
    Cold Spring Harb Symp Quant Biol. 2005;70:461-7 PMID: 16869784
  3. Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation.
    Am J Respir Cell Mol Biol. 2002 Aug;27(2):160-9 PMID: 12151307
  4. Receptor-associated Mad homologues synergize as effectors of the TGF-beta response.
    Nature. 1996 Sep 12;383(6596):168-72 PMID: 8774881
  5. Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma.
    Genes Dev. 2006 May 15;20(10):1331-42 PMID: 16702406
  6. The Fanconi Anemia/BRCA pathway: new faces in the crowd.
    Genes Dev. 2005 Dec 15;19(24):2925-40 PMID: 16357213
  7. DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma.
    Cancer Res. 1996 Jun 1;56(11):2519-21 PMID: 8653689
  8. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma.
    Oncogene. 2005 Jun 16;24(26):4232-42 PMID: 15824737
  9. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.
    Immunity. 2006 Feb;24(2):179-89 PMID: 16473830
  10. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival.
    Oncogene. 2004 Jan 29;23(4):1000-4 PMID: 14647419
  11. Decreased Smad4 expression in the transforming growth factor-beta signaling pathway during progression of esophageal squamous cell carcinoma.
    Cancer. 2002 Aug 15;95(4):737-43 PMID: 12209716
  12. Synergistic function of Smad4 and PTEN in suppressing forestomach squamous cell carcinoma in the mouse.
    Cancer Res. 2006 Jul 15;66(14):6972-81 PMID: 16849541
  13. Downregulation of Fanconi anemia genes in sporadic head and neck squamous cell carcinoma.
    ORL J Otorhinolaryngol Relat Spec. 2007;69(4):218-25 PMID: 17409780
  14. The Fanconi anaemia/BRCA pathway.
    Nat Rev Cancer. 2003 Jan;3(1):23-34 PMID: 12509764
  15. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage.
    Oncogene. 2005 Mar 31;24(14):2289-97 PMID: 15735739
  16. Mouse models for human head and neck squamous cell carcinomas.
    Head Neck. 2006 Oct;28(10):945-54 PMID: 16721744
  17. TGF-beta and cancer.
    Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):29-40 PMID: 16289860
  18. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice.
    Oncogene. 2000 Apr 6;19(15):1868-74 PMID: 10773876
  19. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.
    Mol Cell. 2001 Feb;7(2):249-62 PMID: 11239454
  20. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer.
    Nat Rev Cancer. 2003 Nov;3(11):807-21 PMID: 14557817
  21. Head and neck cancer.
    N Engl J Med. 2001 Dec 27;345(26):1890-900 PMID: 11756581
  22. Persistent activation of the Akt pathway in head and neck squamous cell carcinoma: a potential target for UCN-01.
    Clin Cancer Res. 2004 Jun 15;10(12 Pt 1):4029-37 PMID: 15217935
  23. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells.
    Mol Cell. 1999 Mar;3(3):389-95 PMID: 10198641
  24. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes.
    Cell. 1998 Mar 6;92(5):645-56 PMID: 9506519
  25. Identification of novel prognosticators of outcome in squamous cell carcinoma of the head and neck.
    J Clin Oncol. 2004 Oct 1;22(19):3965-72 PMID: 15459219
  26. Presence of multiple incontiguous deleted regions at the long arm of chromosome 18 in head and neck cancer.
    Clin Cancer Res. 1998 Mar;4(3):539-44 PMID: 9533520
  27. Oncogenes and tumour suppressors take on centrosomes.
    Nat Rev Cancer. 2007 Dec;7(12):911-24 PMID: 18004399
  28. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas.
    Cancer Cell. 2007 Mar;11(3):229-43 PMID: 17349581
  29. Microenvironmental genomic alterations and clinicopathological behavior in head and neck squamous cell carcinoma.
    JAMA. 2007 Jan 10;297(2):187-95 PMID: 17213402
  30. Targeted disruption of Smad4 in mouse epidermis results in failure of hair follicle cycling and formation of skin tumors.
    Cancer Res. 2005 Oct 1;65(19):8671-8 PMID: 16204035
  31. Transforming growth factor-beta induces development of the T(H)17 lineage.
    Nature. 2006 May 11;441(7090):231-4 PMID: 16648837
  32. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1.
    Science. 1996 Jan 19;271(5247):350-3 PMID: 8553070
  33. Tumor formation in mice with conditional inactivation of Brca1 in epithelial tissues.
    Oncogene. 2003 Aug 21;22(35):5415-26 PMID: 12934101
  34. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia.
    Arch Otolaryngol Head Neck Surg. 2003 Jan;129(1):106-12 PMID: 12525204
  35. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion.
    Nat Genet. 2007 Apr;39(4):467-75 PMID: 17369830
  36. Inducible activation of oncogenic K-ras results in tumor formation in the oral cavity.
    Cancer Res. 2004 Aug 1;64(15):5054-8 PMID: 15289303
  37. Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4.
    Cancer Lett. 2007 Jan 8;245(1-2):163-70 PMID: 16478646
  38. Distinct roles of individual Smads in skin carcinogenesis.
    Mol Carcinog. 2007 Aug;46(8):660-4 PMID: 17477360
  39. Clinical significance of MMP-2 and MMP-9 in patients with oral cancer.
    Head Neck. 2007 Jun;29(6):564-72 PMID: 17252594
  40. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.
    Genes Dev. 2006 Nov 15;20(22):3130-46 PMID: 17114584
  41. Genome-wide profiling of oral squamous cell carcinoma by array-based comparative genomic hybridization.
    Laryngoscope. 2006 May;116(5):735-41 PMID: 16652080
  42. Cancer-associated transforming growth factor beta type II receptor gene mutant causes activation of bone morphogenic protein-Smads and invasive phenotype.
    Cancer Res. 2008 Mar 15;68(6):1656-66 PMID: 18339844
  43. Functional proteomics of transforming growth factor-beta1-stimulated Mv1Lu epithelial cells: Rad51 as a target of TGFbeta1-dependent regulation of DNA repair.
    EMBO J. 2002 Mar 1;21(5):1219-30 PMID: 11867550
  44. Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer.
    Clin Cancer Res. 1999 Jun;5(6):1369-79 PMID: 10389921
  45. Inflammation: gearing the journey to cancer.
    Mutat Res. 2008 Jul-Aug;659(1-2):15-30 PMID: 18485806
  46. Hair follicle defects and squamous cell carcinoma formation in Smad4 conditional knockout mouse skin.
    Oncogene. 2006 Jan 12;25(2):207-17 PMID: 16170355
  47. Gene expression of differentiation-specific keratins (4/13 and 1/10) in normal human buccal mucosa.
    Lab Invest. 1998 Jul;78(7):787-95 PMID: 9690557
  48. Overexpression of transforming growth factor beta1 in head and neck epithelia results in inflammation, angiogenesis, and epithelial hyperproliferation.
    Cancer Res. 2004 Jul 1;64(13):4405-10 PMID: 15231647
  49. Smad4 and transforming growth factor beta1 expression in patients with squamous cell carcinoma of the esophagus.
    Clin Cancer Res. 2002 Jun;8(6):1838-42 PMID: 12060625
  50. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer.
    Nature. 2006 Jun 22;441(7096):1015-9 PMID: 16791201
  51. Genetic abnormalities associated with nodal metastasis in head and neck cancer.
    Head Neck. 2004 Jan;26(1):10-5 PMID: 14724901
  52. TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch.
    EMBO J. 2009 Jan 21;28(2):88-98 PMID: 19096363
  53. Identification of new minimally lost regions on 18q in head and neck squamous cell carcinoma.
    Cancer Res. 2000 Jul 1;60(13):3397-403 PMID: 10910046
  54. A distinct expression of CC chemokines by macrophages in nasopharyngeal carcinoma: implication for the intense tumor infiltration by T lymphocytes and macrophages.
    Hum Pathol. 2001 Jan;32(1):42-9 PMID: 11172294
  55. Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder.
    EMBO J. 2004 Apr 21;23(8):1770-81 PMID: 15057277
  56. Smad3 knockout mice exhibit a resistance to skin chemical carcinogenesis.
    Cancer Res. 2004 Nov 1;64(21):7836-45 PMID: 15520189
  57. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology.
    Clin Cancer Res. 2007 Mar 1;13(5):1383-8 PMID: 17332279
  58. Overexpression of mammalian Rad51 does not stimulate tumorigenesis while a dominant-negative Rad51 affects centrosome fragmentation, ploidy and stimulates tumorigenesis, in p53-defective CHO cells.
    Oncogene. 2003 Oct 23;22(48):7587-92 PMID: 14576820
  59. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice.
    J Clin Invest. 2006 Jul;116(7):1843-52 PMID: 16767220
  60. Profiling early head and neck cancer.
    Nat Rev Cancer. 2005 Feb;5(2):127-35 PMID: 15685196
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI38854
Published
2009-11-00
Epub
2009-00-19
Pages
3408-19
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2769185
Subset
IM
Grants
NCI NIH HHS · K08 CA131483 · United States
NIDCR NIH HHS · R01 DE015953 · United States
External Links
PubMed source DOI: 10.1172/JCI38854 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2