AUTHOR=Svoboda Martin , Mungenast Felicitas , Gleiss Andreas , Vergote Ignace , Vanderstichele Adriaan , Sehouli Jalid , Braicu Elena , Mahner Sven , Jäger Walter , Mechtcheriakova Diana , Cacsire-Tong Dan , Zeillinger Robert , Thalhammer Theresia , Pils Dietmar 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00842

DOI=10.3389/fphar.2018.00842

ISSN=1663-9812

ABSTRACT=<p>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 <italic>SLCO</italic> genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of <italic>SLCO</italic> mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor, <italic>ESR1</italic> and <italic>ESR2</italic> (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., <xref ref-type="bibr" rid="B45">2012</xref>; Auer et al., <xref ref-type="bibr" rid="B3">2015</xref>, <xref ref-type="bibr" rid="B2">2017</xref>; Kurman and Shih Ie, <xref ref-type="bibr" rid="B30">2016</xref>; Karam et al., <xref ref-type="bibr" rid="B26">2017</xref>; Labidi-Galy et al., <xref ref-type="bibr" rid="B32">2017</xref>; Salomon-Perzynski et al., <xref ref-type="bibr" rid="B49">2017</xref>; Sukhbaatar et al., <xref ref-type="bibr" rid="B53">2017</xref>). The final value used (<italic>K</italic> = 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) <italic>SLCO2B1</italic> with <italic>ABCC3</italic> implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation (<italic>ABCB2/ABCB3</italic>) with <italic>ABCC3</italic> and <italic>HER-2</italic>. Combining LASSO Cox regression and univariate Cox regression analyses, <italic>SLCO5A1</italic> 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; <italic>p</italic> = 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 <italic>SLCO5A1</italic>, the network <italic>ABCB2/ABCB3/ABCC4/HER2</italic> as well as <italic>ESR1</italic>. Furthermore, expression of <italic>SLCO2A1</italic> and <italic>PGDH</italic>, which are important for PGE<sub>2</sub> degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that <italic>SLCOs</italic> and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies.</p>