Clinical Significance of Organic Anion Transporting Polypeptide Gene Expression in High-Grade Serous Ovarian Cancer
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 genes may allo...
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Published in | Frontiers in pharmacology Vol. 9; p. 842 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
07.08.2018
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Subjects | |
Online Access | Get full text |
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Summary: | 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
genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of
mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor,
and
(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 (
= 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)
with
implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation (
) with
and
. Combining LASSO Cox regression and univariate Cox regression analyses,
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;
= 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
, the network
as well as
. Furthermore, expression of
and
, which are important for PGE
degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that
and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Tristan M. Sissung, National Institutes of Health (NIH), United States; Mariza De Andrade, Mayo Clinic, United States These authors have contributed equally to this work. Edited by: Salvatore Salomone, Università degli Studi di Catania, Italy This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2018.00842 |