Date Published: February 27, 2019
Publisher: Public Library of Science
Author(s): Weiwei Gong, Yueyang Liu, Christof Seidl, Tobias Dreyer, Enken Drecoll, Matthias Kotzsch, Holger Bronger, Julia Dorn, Viktor Magdolen, Henning Ulrich.
Overexpression of several members of the kallikrein-related peptidase (KLK) family, including KLK4, has been reported in ovarian cancer tissue, consistent with the fact that elevated levels of KLK protein are often also found in serum and in effusion fluids of ovarian cancer patients. In the present study, we quantitatively analyzed KLK4 tumor tissue mRNA expression levels in a homogeneous cohort including 138 patients of advanced high-grade serous ovarian cancer (FIGO stage III/IV). Age as well as ascites fluid volume were found to be significantly associated with KLK4 mRNA expression levels. In univariate Cox regression analysis, the clinical factors residual tumor mass and ascites fluid volume represented univariate predictors for both overall survival (OS) and progression-free survival (PFS). Furthermore, elevated KLK4 mRNA expression levels were significantly linked with reduced OS (p = 0.001), but not with PFS. The results concerning the association of KLK4 mRNA expression with OS were validated in a publicly available Affymetrix-based mRNA data set from The Cancer Genome Atlas (n = 252) applying the Kaplan-Meier Plotter tool (p = 0.047). In multivariable analyses, elevated KLK4 mRNA values turned out as an additional, independent predictive marker for shortened OS (p = 0.006), whereas residual tumor mass, but not ascites fluid volume, remained an independent indicator for both OS and PFS (p < 0.001 and p = 0.002, respectively). The results of the present study, obtained in a well-defined, homogenous cohort of patients afflicted with advanced high-grade serous ovarian cancer, are in line with previous reports describing high KLK4 levels as an unfavorable marker in ovarian cancer patients.
Epithelial ovarian cancer still is the leading cause of death among patients with gynecological malignancies . Due to the lack of obvious symptoms, approximately 75% of patients are diagnosed at advanced stages of epithelial ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage IIb-IV) , with 5-year survival rates of 17–36% . Moreover, the poor prognosis of the patients afflicted with ovarian cancer originates from inefficient primary debulking surgery and rapid development of chemo-resistance . Therefore, valid tumor markers for prognosis and prediction of therapy response are urgently needed.
In the present retrospective study, we analyzed the mRNA expression levels of KLK4 in a homogenous cohort of 138 patients suffering from advanced high-grade serous ovarian cancer (FIGO stage III/IV) by qPCR. Moreover, the impact of KLK4 mRNA expression on clinical outcome was evaluated by univariate and multivariable Cox regression analysis. In previous studies, KLK4 protein was demonstrated to be upregulated in serous ovarian cancer, as compared with the expression in normal ovary tissues [5,27]. Obiezu and co-workers found that KLK4 mRNA was more frequently expressed in advanced-stage and high-grade ovarian cancers, in comparison with patients with early stage and lower grade ovarian cancers, suggesting that elevated KLK4 expression is correlated with more aggressive tumor subtypes . Still, according to the data from The Cancer Genome Atlas (TCGA) (https://www.proteinatlas.org/), the majority of ovarian cancer tissues display low expression levels of KLK4 mRNA. In accordance with these data, in the current study KLK4 mRNA was detectable at low levels in most of the advanced high-grade serous ovarian cancer samples as well (Fig 1).
In the present study, we found a significant association of elevated KLK4 mRNA expression levels with shortened OS analyzing a homogenous cohort of advanced high-grade serous ovarian cancer patients (FIGO stage III/IV). Strikingly, upon addition of KLK4 mRNA into the multivariable model we showed that KLK4 remains an independent unfavorable predictive biomarker for OS in ovarian cancer. In the context with previous findings indicating an important tumor biological role of KLK4 in regulation of cell proliferation, adhesion, migration, and invasion, KLK4 may represent an attractive novel target for tumor therapy in ovarian cancer.