Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer

Veronika Buxhofer-Ausch; Orsolya Német; Majdah Sheikh; Hajnalka Andrikovics; Angelika Reiner; Christoph Ausch; Diana Mechtcheriakova; Attila Tordai; Andreas Gleiss; Csilla Özvegy-Laczka; Walter Jäger; Theresia Thalhammer

doi:10.3892/ol.2020.12115

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer

Oncol Lett. 2020 Nov;20(5):252. doi: 10.3892/ol.2020.12115. Epub 2020 Sep 17.

Authors

Affiliations

¹ Department of Internal Medicine I with Hematology, Stem Cell Transplantation, Hemostaseology and Medical Oncology, Ordensklinikum Linz der Elisabethinen, A-4020 Linz, Austria.
² Medical Faculty, Johannes Kepler University Linz, A-4040 Linz, Austria.
³ Membrane Protein Research Group, Institute of Enzymology, Research Centre for Natural Sciences, H-1117 Budapest, Hungary.
⁴ Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, A-1090 Vienna, Austria.
⁵ Laboratory of Molecular Genetics, National Institute of Hematology and Infectious Diseases, Central Hospital of Southern Pest, H-1097 Budapest, Hungary.
⁶ Department of Pathology, Donauspital/Sozialmedizinisches Zentrum Ost, A-1220 Vienna, Austria.
⁷ Department of Surgery, Krankenhaus Göttlicher Heiland, A-1170 Vienna, Austria.
⁸ Institute of Pathophysiology, Semmelweis University, Faculty of Medicine, H-1085 Budapest, Hungary.
⁹ Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, A-1090 Vienna, Austria.
¹⁰ Department of Pharmaceutical Chemistry, University of Vienna, A-1090 Vienna, Austria.

Abstract

Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions (SLCO) genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in SLCO4A1 (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.

Keywords: colorectal cancer; colorectal cancer risk; polymorphic variants; rs1047099; rs34419428; single-nucleotide polymorphism; solute carrier; solute carrier organic anion transporter family member 4A1.