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

Xiying Shang, Xinjian Lin, Edwin Alvarez, Gerald Manorek, Stephen B. Howell

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The extent of tight junction (TJ) formation is one of many factors that regulate motility, invasion, and metastasis. Claudins are required for the formation and maintenance of TJs. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are highly expressed in the majority of ovarian cancers.We report here that CLDN3 and CLDN4 each serve to constrain the growth of human 2008 cancer xenografts and limit metastatic potential. Knockdown of CLDN3 increased in vivo growth rate by 2.3-fold and knockdown of CLDN4 by 3.7-fold in the absence of significant change in in vitro growth rate. Both types of tumors exhibited increase in birth rate as measured by Ki67 staining and decrease in death rate as reflected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Knockdown of either claudin did not alter expression of other TJ protein but did reduce TJ formation asmeasured by transepithelial resistance and paracellular flux of dextran, enhance migration and invasion in in vitro assays, and increase lung colonization following intravenous injection. Knockdown of CLDN3 and CLDN4 increased total lung metastatic burden by 1.7-fold and 2.4-fold, respectively. Loss of either CLDN3 or CLDN4 resulted in down-regulation of E-cadherin mRNA and protein, increased inhibitory phosphorylation of glycogen synthase kinase-3β (GSK-3β), and activation of β-catenin pathway signaling as evidenced by increases in nuclear β-catenin, the dephosphorylated form of the protein, and transcriptional activity of β-catenin/T-cell factor (TCF).We conclude that both CLDN3 and CLDN4 mediate interactions with other cells in vivo that restrain growth and metastatic potential by sustaining expression of E-cadherin and limiting β-catenin signaling.

Original languageEnglish (US)
Pages (from-to)974-985
Number of pages12
JournalNeoplasia (United States)
Volume14
Issue number10
DOIs
StatePublished - Oct 2012

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Claudin-3
Claudin-4
Tight Junction Proteins
Catenins
Neoplasm Metastasis
Growth
Neoplasms
Tight Junctions
Cadherins
Claudins
Staining and Labeling
TCF Transcription Factors
Glycogen Synthase Kinase 3
Lung
DNA Nucleotidylexotransferase
Birth Rate
Dextrans
Heterografts
Intravenous Injections
Ovarian Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases. / Shang, Xiying; Lin, Xinjian; Alvarez, Edwin; Manorek, Gerald; Howell, Stephen B.

In: Neoplasia (United States), Vol. 14, No. 10, 10.2012, p. 974-985.

Research output: Contribution to journalArticle

Shang, X, Lin, X, Alvarez, E, Manorek, G & Howell, SB 2012, 'Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases', Neoplasia (United States), vol. 14, no. 10, pp. 974-985. https://doi.org/10.1593/neo.12942
Shang, Xiying ; Lin, Xinjian ; Alvarez, Edwin ; Manorek, Gerald ; Howell, Stephen B. / Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases. In: Neoplasia (United States). 2012 ; Vol. 14, No. 10. pp. 974-985.
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