Smad4 regulates claudin-1 expression in a transforming growth factor-β-independent manner in colon cancer cells

Sheng Ru Shiou, Amar Bahadur Singh, Krishnan Moorthy, Pran K. Datta, M. Kay Washington, R. Daniel Beauchamp, Punita Dhawan

Research output: Contribution to journalArticle

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Abstract

We have recently reported that the expression of a tight junction protein, claudin-1, is increased during colon carcinogenesis and particularly metastatic colorectal cancer. Manipulation of claudin-1 levels in colon cancer cells showed a positive correlation between claudin-1 expression and tumor growth and metastasis. However, the mechanisms underlying the increased claudin-1 expression in colorectal cancer remains unknown. The tumor suppressor Smad4 is a central intracellular signal transduction component of the transforming growth factor-β (TGF-β) family of cytokines. Loss of Smad4 protein expression is correlated with poor prognosis and is frequently observed in invasive and metastatic colorectal carcinoma. In the present study, we report an inverse relationship between Smad4 and claudin-1 expression in human colorectal carcinoma tumor samples and in human colon cancer cell lines. We found that the expression of Smad4 in Smad4-deficient but claudin-1-positive SW480 or HT29 colon cancer cell lines down-regulates claudin-1 expression through transcriptional repression by modulating β-catenin/T-cell factor/lymphocyte enhancer factor activity. Furthermore, this Smad4-dependent inhibition of claudin-1 expression is independent of TGF-β signaling because Smad4 expression alone is insufficient to restore TGF-β signaling in the SW480 cells, and the selective TGF-β receptor kinase inhibitor LY364947 did not prevent the Smad4 suppression of claudin-1 protein expression in either SW480 or HT29 cells. Taken together, these findings suggest a novel mechanism underlying Smad4 tumor-suppressive function through regulation of a potential metastatic modulator, claudin-1, in a TGF-β-independent manner.

Original languageEnglish (US)
Pages (from-to)1571-1579
Number of pages9
JournalCancer Research
Volume67
Issue number4
DOIs
StatePublished - Feb 15 2007

Fingerprint

Claudin-1
Transforming Growth Factors
Colonic Neoplasms
Colorectal Neoplasms
Smad4 Protein
Zonula Occludens-1 Protein
Claudins
TCF Transcription Factors
Cell Line
Catenins
Neoplasms
HT29 Cells
Growth Factor Receptors
Signal Transduction
Colon
Carcinogenesis
Phosphotransferases
Down-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Smad4 regulates claudin-1 expression in a transforming growth factor-β-independent manner in colon cancer cells. / Shiou, Sheng Ru; Singh, Amar Bahadur; Moorthy, Krishnan; Datta, Pran K.; Washington, M. Kay; Beauchamp, R. Daniel; Dhawan, Punita.

In: Cancer Research, Vol. 67, No. 4, 15.02.2007, p. 1571-1579.

Research output: Contribution to journalArticle

Shiou, Sheng Ru ; Singh, Amar Bahadur ; Moorthy, Krishnan ; Datta, Pran K. ; Washington, M. Kay ; Beauchamp, R. Daniel ; Dhawan, Punita. / Smad4 regulates claudin-1 expression in a transforming growth factor-β-independent manner in colon cancer cells. In: Cancer Research. 2007 ; Vol. 67, No. 4. pp. 1571-1579.
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