Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility

P. D. Leotlela, M. S. Wade, P. H. Duray, M. J. Rhode, H. F. Brown, D. T. Rosenthal1, S. K. Dissanayake, R. Earley, E. Indig, B. J. Nickoloff, D. D. Taub, Olli Kallioniemi, P. Meltzer, P. J. Morin, A. T. Weeraratna

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Abstract

Serial analysis of gene expression followed by pathway analysis implicated the tight junction protein claudin-1 (CLDN1) in melanoma progression. Tight junction proteins regulate the paracellular transport of molecules, but staining of a tissue microarray revealed that claudin-1 was overexpressed in melanoma, and aberrantly expressed in the cytoplasm of malignant cells, suggesting a role other than transport. Indeed, melanoma cells in culture demonstrate no tight junction function. It has been shown that protein kinase C (PKC) can affect expression of claudin-1 in rat choroid plexus cells, and we observed a correlation between levels of activated PKC and claudin expression in our melanoma cells. To determine if PKC could affect the expression of CLDN1 in human melanoma, cells lacking endogenous claudin-1 were treated with 200 nM phorbol myristic acid (PMA). PKC activation by PMA caused an increase in CLDN1 transcription in 30 min, and an increase in claudin-1 protein by 12 h. Inhibition of PKC signaling in cells with high claudin-1 expression resulted in decreased claudin-1 expression. CLDN1 appears to contribute to melanoma cell invasion, as transient transfection of melanoma cells with CLDN1 increased metalloproteinase 2 (MMP-2) secretion and activation, and subsequently, motility of melanoma cells as demonstrated by wound-healing assays. Conversely, knockdown of CLDN1 by siRNA resulted in the inhibition of motility, as well as decreases in MMP-2 secretion and activation. These data implicate claudin-1 in melanoma progression.
Original languageEnglish
Pages (from-to)3846–3856
JournalOncogene
Volume26
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

Keywords

  • claudin, melanoma, PKC, motility, tissue array

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    Leotlela, P. D., Wade, M. S., Duray, P. H., Rhode, M. J., Brown, H. F., Rosenthal1, D. T., Dissanayake, S. K., Earley, R., Indig, E., Nickoloff, B. J., Taub, D. D., Kallioniemi, O., Meltzer, P., Morin, P. J., & Weeraratna, A. T. (2007). Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility. Oncogene, 26, 3846–3856. https://doi.org/10.1038/sj.onc.1210155