Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer

Frontiers in Pharmacology

Walter Jäger¹  Elena Braicu²  Jalid Sehouli²  Sven Mahner³  Felicitas Mungenast⁴  Diana Mechtcheriakova⁴  Theresia Thalhammer⁴  Martin Svoboda⁴  Dietmar Pils⁵  Ignace Vergote⁶  Adriaan Vanderstichele⁶  Andreas Gleiss⁷  Robert Zeillinger⁸  Dan Cacsire-Tong⁹ 

[1] Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria;Department of Gynecology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Berlin Institute of Health, Humboldt-Universität zu Berlin, Berlin, Germany;Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria;Department of Surgery, Medical University of Vienna, Vienna, Austria;Division of Gynaecological Oncology, Department of Gynaecology and Obstetrics, Leuven Cancer Institute, University Hospital Leuven, Katholieke Universiteit Leuven, Leuven, Belgium;Institute of Clinical Biometrics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria;Molecular Oncology Group, Department of Obstetrics and Gynaecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;Translational Gynecology Group, Department of Obstetrics and Gynaecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria;

关键词: high-grade serous ovarian cancer;    SLCO;    OATP;    transporter;    overall survival;    estrogens;   

DOI  :  10.3389/fphar.2018.00842

来源: DOAJ

【 摘 要 】

High-grade serous ovarian cancer (HGSOC) is considered the most deadly and frequently occurring type of ovarian cancer and is associated with various molecular compositions and growth patterns. Evaluating the mRNA expression pattern of the organic anion transporters (OATPs) encoded by SLCO genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of SLCO mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor, ESR1 and ESR2 (coding for estrogen receptors ERα and ERß) and HER-2 were assessed using RT-qPCR. The expression levels were assessed in a cohort of 135 HGSOC patients to elucidate the independent impact of the expression pattern on the overall survival (OS). For identification of putative regulatory networks, Graphical Gaussian Models were constructed from the expression data with a tuning parameter K varying between meaningful borders (Pils et al., 2012; Auer et al., 2015, 2017; Kurman and Shih Ie, 2016; Karam et al., 2017; Labidi-Galy et al., 2017; Salomon-Perzynski et al., 2017; Sukhbaatar et al., 2017). The final value used (K = 4) was determined by maximizing the proportion of explained variation of the corresponding LASSO Cox regression model for OS. The following two networks of directly correlated genes were identified: (i) SLCO2B1 with ABCC3 implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation (ABCB2/ABCB3) with ABCC3 and HER-2. Combining LASSO Cox regression and univariate Cox regression analyses, SLCO5A1 coding for OATP5A1, an estrogen metabolite transporter located in the cytoplasm and plasma membranes of ovarian cancer cells, was identified as significant and independent prognostic factor for OS (HR = 0.68, CI 0.49–0.93; p = 0.031). Furthermore, results indicated the benefits of patients with high expression by adding 5.1% to the 12.8% of the proportion of explained variation (PEV) for clinicopathological parameters known for prognostic significance (FIGO stage, age and residual tumor after debulking). Additionally, overlap with previously described signatures that indicated a more favorable prognosis for ovarian cancer patients was shown for SLCO5A1, the network ABCB2/ABCB3/ABCC4/HER2 as well as ESR1. Furthermore, expression of SLCO2A1 and PGDH, which are important for PGE2 degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that SLCOs and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies.

【 授权许可】

Unknown