Antimetastatic Role of Smad4 Signaling in Colorectal Cancer

Bixiang Zhang, Sunil Krishna Halder, Nilesh D. Kashikar, Yong Jig Cho, Arunima Datta, D. Lee Gorden, Pran K. Datta

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Transforming growth factor (TGF)-β signaling occurs through Smads 2/3/4, which translocate to the nucleus to regulate transcription; TGF-β has tumor-suppressive effects in some tumor models and pro-metastatic effects in others. In patients with colorectal cancer (CRC), mutations or reduced levels of Smad4 have been correlated with reduced survival. However, the function of Smad signaling and the effects of TGF-β-receptor kinase inhibitors have not been analyzed during CRC metastasis. We investigated the role of TGF-β/Smad signaling in CRC progression. Methods: We evaluated the role of TGF-β/Smad signaling on cell proliferation, migration, invasion, tumorigenicity, and metastasis in Smad4-null colon carcinoma cell lines (MC38 and SW620) and in those that transgenically express Smad4. We also determined the effects of a TGF-β-receptor kinase inhibitor (LY2109761) in CRC tumor progression and metastasis in mice. Results: TGF-β induced migration/invasion, tumorigenicity, and metastasis of Smad4-null MC38 and SW620 cells; incubation with LY2109761 reversed these effects. In mice, LY2109761 blocked metastasis of CRC cells to liver, inducing cancer cell expression of E-cadherin and reducing the expression of the tumorigenic proteins matrix metalloproteinase-9, nm23, urokinase plasminogen activator, and cyclooxygenase-2. Transgenic expression of Smad4 significantly reduced the oncogenic potential of MC38 and SW620 cells; in these transgenic cells, TGF-β had tumor suppressor, rather than tumorigenic, effects. Conclusions: TGF-β/Smad signaling suppresses progression and metastasis of CRC cells and tumors in mice. Loss of Smad4 might underlie the functional shift of TGF-β from a tumor suppressor to a tumor promoter; inhibitors of TGF-β signaling might be developed as CRC therapeutics.

Original languageEnglish (US)
JournalGastroenterology
Volume138
Issue number3
DOIs
StatePublished - Jan 1 2010

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Transforming Growth Factors
Colorectal Neoplasms
Neoplasm Metastasis
Growth Factor Receptors
Neoplasms
Phosphotransferases
Plasminogen Activators
Matrix Metalloproteinase 9
Urokinase-Type Plasminogen Activator
Cadherins
Cyclooxygenase 2
Liver Neoplasms
Carcinogens
Cell Movement
Colon
Cell Proliferation
Carcinoma
Cell Line
Mutation

Keywords

  • Metastasis
  • TGF-β
  • TGF-β Receptor Kinase Inhibitor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Zhang, B., Halder, S. K., Kashikar, N. D., Cho, Y. J., Datta, A., Gorden, D. L., & Datta, P. K. (2010). Antimetastatic Role of Smad4 Signaling in Colorectal Cancer. Gastroenterology, 138(3). https://doi.org/10.1053/j.gastro.2009.11.004

Antimetastatic Role of Smad4 Signaling in Colorectal Cancer. / Zhang, Bixiang; Halder, Sunil Krishna; Kashikar, Nilesh D.; Cho, Yong Jig; Datta, Arunima; Gorden, D. Lee; Datta, Pran K.

In: Gastroenterology, Vol. 138, No. 3, 01.01.2010.

Research output: Contribution to journalArticle

Zhang, B, Halder, SK, Kashikar, ND, Cho, YJ, Datta, A, Gorden, DL & Datta, PK 2010, 'Antimetastatic Role of Smad4 Signaling in Colorectal Cancer', Gastroenterology, vol. 138, no. 3. https://doi.org/10.1053/j.gastro.2009.11.004
Zhang B, Halder SK, Kashikar ND, Cho YJ, Datta A, Gorden DL et al. Antimetastatic Role of Smad4 Signaling in Colorectal Cancer. Gastroenterology. 2010 Jan 1;138(3). https://doi.org/10.1053/j.gastro.2009.11.004
Zhang, Bixiang ; Halder, Sunil Krishna ; Kashikar, Nilesh D. ; Cho, Yong Jig ; Datta, Arunima ; Gorden, D. Lee ; Datta, Pran K. / Antimetastatic Role of Smad4 Signaling in Colorectal Cancer. In: Gastroenterology. 2010 ; Vol. 138, No. 3.
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