Human kallikrein-related peptidase 6 (KLK6) and 13 (KLK13) are involved in ovarian carcinoma pathogenesis

White, Nicole (2010) Human kallikrein-related peptidase 6 (KLK6) and 13 (KLK13) are involved in ovarian carcinoma pathogenesis. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

It is estimated in 2009 that 2500 Canadian women were diagnosed and 1750 women lost their lives to epithelial ovarian cancer. This malignancy has a high mortality rate because the majority of women are diagnosed in late stage disease where the 5 year survival rate is only 20%. Late diagnosis is a result of the lack of an effective screening marker. Currently, CA125 is the only marker that is used for ovarian cancer patients and it is used primarily to monitor disease recurrence after treatment. Unfortunately, CA125 lacks the sensitivity and specificity to be used for early detection of ovarian cancer. Recently, a new group of genes, the human kallikrein-related peptidase (KLK) family, has been implicated in ovarian cancer and are being investigated as potential new biomarkers for the malignancy. In particular, KLK 13 has been shown to have increased expression in ovarian cancer. KLK13 has increased expression in the ovarian cancer cell lines CAOV-3, OVCAR-3, and SKOV-3 when compared to the IOSE cell line and is involved in cell motility. Increased KLK13 expression increases migration in the epithelial cell lines IOSE and Mv1Lu. Also, when KLK13 expression was decreased in the ovarian cancer cell line SKOV-3, which has high endogenous KLK13 expression levels, there was a decrease in cellular migration. Increased KLK13 expression in IOSE cells increased cellular invasion through the basement membrane. These data together suggest KLK 13 plays a role in ovarian carcinogenesis and may be a potential therapeutic target. In order to see if KLK expression had any prognostic significance in ovarian cancer patients, paraffin embedded ovarian cancer samples were analyzed for KLK6 and KLK13 mRNA expression. High expression levels of both KLK6 and KLK13 were associated with invasive ovarian cancer. Also, high KLK6 expression was associated with late stage ovarian cancer and serous histological type. Both KLK6 and KLK13 were also shown to be markers of poor prognosis as patients with high kallikrein expression were more likely to have a recurrence than patients with low KLK expression. When KLK6, KLK13 and Mucl6 were assessed for the ability to detect ovarian cancer, the genes detected 56%, 50%, and 56%, respectively, early stage (Stage I and II) ovarian cancer patients. When all three markers were used in combination, the sensitivity of the test improved to 84%. There was no significant change in the specificity or positive predictive value, but the negative predictive value increased from 33% using the individual markers to 58% when all three markers were combined. These data together suggest KLK6 and KLK 13 are involved in ovarian cancer tumorigenesis. Both KLK6 and KLK13 are potential new markers and possible therapeutic targets for ovarian carcinoma.

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