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Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases

Xiying Shang1, Xinjian Lin, Edwin Alvarez

  • 1Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.

Neoplasia (New York, N.Y.)
|October 26, 2012
PubMed

Insights

Claudin-3 and claudin-4 proteins are crucial for ovarian cancer. Their reduced expression accelerates tumor growth and metastasis by affecting E-cadherin and beta-catenin signaling pathways.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Metastasis

Background:

  • Tight junction (TJ) formation regulates cancer cell motility, invasion, and metastasis.
  • Claudins are essential proteins for TJ formation and maintenance.
  • Claudin-3 (CLDN3) and claudin-4 (CLDN4) are highly expressed in most ovarian cancers.

Purpose of the Study:

  • To investigate the role of CLDN3 and CLDN4 in constraining ovarian cancer xenograft growth and limiting metastatic potential.
  • To elucidate the molecular mechanisms by which CLDN3 and CLDN4 influence cancer progression.

Main Methods:

  • Gene knockdown of CLDN3 and CLDN4 in human 2008 cancer xenografts.
  • In vivo growth rate and metastatic potential assessment.
  • Analysis of cell proliferation (Ki67) and apoptosis (TUNEL).
  • Measurement of transepithelial electrical resistance and paracellular flux.
  • In vitro migration and invasion assays.
  • Western blotting and RT-PCR for E-cadherin, GSK-3β, and β-catenin pathway components.

Main Results:

  • CLDN3 and CLDN4 knockdown significantly increased in vivo tumor growth rate (2.3-fold and 3.7-fold, respectively) without affecting in vitro growth.
  • Knockdown led to increased cell proliferation and decreased apoptosis in xenografts.
  • Reduced TJ integrity, enhanced cell migration and invasion, and increased lung colonization were observed upon claudin knockdown.
  • Loss of CLDN3/CLDN4 resulted in decreased E-cadherin expression and activation of the β-catenin signaling pathway.
  • Knockdown of CLDN3 and CLDN4 increased lung metastatic burden by 1.7-fold and 2.4-fold, respectively.

Conclusions:

  • CLDN3 and CLDN4 constrain ovarian cancer growth and metastasis in vivo.
  • These claudins maintain E-cadherin expression and limit β-catenin pathway activation, thereby restricting tumor progression.
  • Targeting CLDN3 and CLDN4 may offer therapeutic strategies for ovarian cancer treatment.

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