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Post‐Transcriptional Regulation of the Na + ,HCO 3 ‐ ‐cotransporter NBCn1 (SLC4A7) by a Constitutively Active ErbB2 Receptor in MCF‐7 Breast Cancer Cells
Author(s) -
Gorbatenko Andrej,
Sigurdsson Haraldur,
PedrazCuesta Elena,
Pedersen Stine
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.578.6
Subject(s) - biology , downregulation and upregulation , untranslated region , receptor , messenger rna , three prime untranslated region , microbiology and biotechnology , cancer research , biochemistry , gene
Altered pH regulation is a fundamental characteristic of cancers. Net acid production is greatly increased in tumor cells, due to a shift from oxidative phosphorylation towards glycolytic metabolism. We previously showed that the Na + , HCO 3 ‐ cotransporter NBCn1 (SLC4A7) is strongly upregulated in MCF‐7 breast cancer cells by Krüppel‐like factor 4 (KLF4) upon expression of a truncated, constitutively active ErbB2 receptor (DNErbB2) (1). GWAS studies implicate a SNP (rs4973768) in the 3′ Untranslated Region (3′UTR) of NBCn1 in breast cancer development. We tested the function of the 3′UTR in regulation of NBCn1 expression by DNErbB2 signaling, and assessed the role of SNP. The NBCn1 3′UTR, cloned upstream renilla luciferase, downregulated it's activity in MCF‐7 cells, while DNErbB2 expression reversed the effect. Additionally, DNErbB2 signaling increased NBCn1 mRNA stability, when compared to control MCF‐7 cells, in an Actinomycin D mRNA stability assay. Further, we indentified a region between 865 bp and 1137 bp in the 3′UTR to be mainly responsible for downregulation of luciferase activity. This region contains a conserved seed site for miR‐200bc/429. Finally, introduction of SNP rs4973768 in the 3′UTR significantly downregulated luciferase activity in T47D cells (luminal A), while it had no effect in other cell lines tested. In conclusion, we have demonstrated that DNErbB2 controls NBCn1 expression post‐transcriptionally, identified the 3′UTR region involved, and shown that SNP rs4973768 may alter NBCn1 expression in some breast cancer subtypes.