Downregulation of Human Kallikrein 10 <i> (KLK10/NES1)</i> by CpG Island Hypermethylation in Breast, Ovarian and Prostate Cancers

Vol. 26, No. 6, 2005

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Research Article

Downregulation of Human Kallikrein 10 (KLK10/NES1) by CpG Island Hypermethylation in Breast, Ovarian and Prostate Cancers
Michael Sidiropoulos^{a, b}, Georgios Pampalakis^c, Georgia Sotiropoulou^c, Dionyssios Katsaros^d, Eleftherios P. Diamandis^{a, b}

^aDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital, and
^bDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada,
^cDepartment of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece, and
^dDepartment of Gynecology, Gynecologic Oncology Unit, University of Turin, Turin, Italy

Address of Corresponding Author

Tumor Biol 2005;26:324-336 (DOI: 10.1159/000089290)

Key Words

Breast cancer
CpG islands
KLK10/NES1
Methylation
Ovarian cancer
Prostate cancer

Abstract

Objective: The human kallikrein 10 (KLK10)/normal epithelial cell-specific-1 (NES1) gene is highly expressed in normal mammary, ovary and prostate cells, but its expression is dramatically decreased in cancer cell lines. Recently, it has been shown that CpG island hypermethylation of the KLK10 gene is responsible for the tumor-specific loss of KLK10 gene expression in certain breast cancer cell lines. Method: We examined the role of CpG island hypermethylation in the tumor-specific loss of KLK10 expression in breast, ovarian and prostate cancers. We treated cells with the demethylating agent 5-aza-2'-deoxycytidine (dC) and monitored changes in KLK10 mRNA by RT-PCR and secreted hK10 protein expression by ELISA. The following cell lines were used: MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-1, T-47D and BT-474 (breast); BG-1, MDAH-2774, HTB-75, HTB-161, PA-1 and ES-2 (ovary), and LNCaP and PC-3 (prostate). Results: Upregulation of KLK10 mRNA levels, which was accompanied by an increase in secreted hK10 protein concentration, was observed for a subset of breast, ovarian, and prostate tumor cell lines after 5-aza-2'-dC. Genomic sequencing of sodium-bisulfite-treated DNA demonstrated that CpG sites within the KLK10 gene exon 3 were highly methylated. Hypermethylation of exon 3 CpG regions was also detected in primary ovarian cancers. Conclusion: These data suggest that CpG island hypermethylation plays an important role in the downregulation of kallikrein 10 mRNA and protein expression, but it cannot explain the pattern of expression of this gene in all cell lines or tissue tested.

Author Contacts

Dr. E.P. Diamandis
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital
600 University Avenue
Toronto, Ont. M5G 1X5 (Canada)
Tel. +1 416 586 8443, Fax +1 416 586 8628, E-Mail ediamandis@mtsinai.on.ca

Article Information

Received: March 13, 2005
Accepted after revision: June 8, 2005
Published online: October 26, 2005
Number of Print Pages : 13
Number of Figures : 5, Number of Tables : 3, Number of References : 36

Medline Abstract (ID 16254462)

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