SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer

Stephanie Koller; Jonatan Kendler; Jasmine Karacs; Andrea Wolf; Caroline Kreuzinger; Isabel Von Der Decken; Felicitas Mungenast; Diana Mechtcheriakova; Wolfgang Schreiner; Andreas Gleiss; Walter Jäger; Dan Cacsire Castillo-Tong; Theresia Thalhammer

doi:10.3389/fphar.2022.946348

SLCO4A1 expression is associated with activated inflammatory pathways in high-grade serous ovarian cancer

Front Pharmacol. 2022 Aug 29:13:946348. doi: 10.3389/fphar.2022.946348. eCollection 2022.

Affiliations

¹ Department of Obstetrics and Gynecology, Translational Gynecology Group, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
² Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
³ Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
⁴ Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria.

Abstract

Patients with high-grade serous ovarian cancer (HGSOC) have a very poor overall survival. Current therapeutic approaches do not bring benefit to all patients. Although genetic alterations and molecular mechanisms are well characterized, the molecular pathological conditions are poorly investigated. Solute carrier organic anion transporter family member 4A1 (SLCO4A1) encodes OATP4A1, which is an uptake membrane transporter of metabolic products. Its expression may influence various signaling pathways associated with the molecular pathophysiological conditions of HGSOC and consequently tumor progression. RNA sequencing of 33 patient-derived HGSOC cell lines showed that SLCO4A1 expression was diverse by individual tumors, which was further confirmed by RT-qPCR, Western blotting and immunohistochemistry. Gene Set Enrichment Analysis revealed that higher SLCO4A1 level was associated with inflammation-associated pathways including NOD-like receptor, adipocytokine, TALL1, CD40, NF-κB, and TNF-receptor 2 signaling cascades, while low SLCO4A1 expression was associated with the mitochondrial electron transport chain pathway. The overall gene expression pattern in all cell lines was specific to each patient and remained largely unchanged during tumor progression. In addition, genes encoding ABCC3 along with SLCO4A1-antisense RNA 1, were associated with higher expression of the SLCO4A1, indicating their possible involvement in inflammation-associated pathways that are downstream to the prostaglandin E2/cAMP axis. Taken together, increased SLCO4A1/OATP4A1 expression is associated with the upregulation of specific inflammatory pathways, while the decreased level is associated with mitochondrial dysfunction. These molecular pathophysiological conditions are tumor specific and should be taken into consideration by the development of therapies against HGSOC.

Keywords: ABCC3; NF-kB; OATP4A1; SLCO4A1; SLCO4A1-AS1; high-grade serous ovarian cancer; inflammatory signaling pathways.