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Elucidation of the Pax‐5/ miRNA interactome and its oncogenic effects in cancer cells
Author(s) -
Robichaud Gilles Andre,
Harquail Jason,
Beauregard AnniePier,
Hannay Brandon
Publication year - 2019
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.2019.33.1_supplement.368.12
Subject(s) - microrna , biology , oncogene , polyadenylation , cancer , untranslated region , cancer research , three prime untranslated region , alternative splicing , interactome , messenger rna , cancer cell , rna splicing , genetics , rna , gene , cell cycle
The Pax‐5 oncogene has consistently been associated to B cell cancer lesions and more recently solid tumors including breast carcinoma. Although Pax‐5 downstream activity is relatively well characterized, aberrant Pax‐5 expression in a cancer specific context is poorly understood. To investigate the regulation of Pax‐5 expression, we studied micro‐RNAs (miRNAs) and mRNA polymorphism in cancer cells. Using bioinformatics and next‐generation sequencing, we found that miRNAs 484 and 210 are aberrantly expressed in breast cancer and predicted to target Pax‐5 mRNA. Through conditional modulation of these miRNAs, we demonstrate that miRNA‐484 and 210 inhibit Pax‐5 expression and regulate Pax‐5‐associated cancer processes. In validation, we show that these effects are reversible by either Pax‐5 recombinant overexpression; or, selective miRNA inhibition. On the other hand, upon our analysis of the Pax‐5 transcript, we found that not only is the 3′UTR submitted to alternative polyadenylation; but also, alternative splicing of the Pax‐5 mRNA 3′UTR. These transcript polymorphism events lead to the shortening of the Pax‐5 3′UTR which resulted in greater oncogene translation frequency. More importantly, we also found that Pax‐5 transcripts characterized with shorter 3′UTRs were associated with advanced staging of cancer lesions. Our findings identify novel molecular mechanisms, which account for Pax‐5 aberrant expression and function in cancer cells. These findings will further elucidate Pax‐5 ‐mediated cancer processes and may provide new avenues for therapeutic intervention. Support or Funding Information This work was supported by grants from the New Brunswick (NB) Innovation Foundation, the Canadian Breast Cancer Foundation, the Canadian Breast Cancer Society/QEII Foundation, the NB Health Research Foundation and by the Beatrice Hunter Cancer Research Institute This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .