MicroRNA-135b regulates ERa, AR and HIF1AN and affects breast and prostate cancer cell growth

Aakulaa Anna (Corresponding Author), Suvi-Katri Leivonen, Petteri Hintsanen, Tero Aittokallio, Yvonne Ceder, Anne-Lise Børresen-Dale, Merja Perälä, Päivi Östling, Olli Kallioniemi

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Abstract

MicroRNAs (miRNAs) regulate a wide range of cellular signaling pathways and biological processes in both physiological and pathological states such as cancer. We have previously identified miR-135b as a direct regulator of androgen receptor (AR) protein level in prostate cancer (PCa). We wanted to further explore the relationship of miR-135b to hormonal receptors, particularly estrogen receptor a (ERa). Here we show that miR-135b expression is lower in ERa-positive breast tumors as compared to ERa-negative samples in two independent breast cancer (BCa) patient cohorts (101 and 1302 samples). Additionally, the miR-135b expression is higher in AR-low PCa patient samples (47 samples). We identify ERa as a novel miR-135b target by demonstrating miR-135b binding to the 3'UTR of the ERa and decreased ERa protein and mRNA level upon miR-135b overexpression in BCa cells. MiR-135b reduces proliferation of ERa-positive BCa cells MCF-7 and BT-474 as well as AR-positive PCa cells LNCaP and 22Rv1 when grown in 2D. To identify other genes regulated by miR-135b we performed gene expression studies and found a link to the hypoxia inducible factor 1a (HIF1a) pathway. We show that miR-135b influences the protein level of the inhibitor for hypoxia inducible factor 1a (HIF1AN) and is able to bind to HIF1AN 3'UTR. Our study demonstrates that miR-135b regulates ERa, AR and HIF1AN protein levels through interaction with their 3'UTR regions, and proliferation in ERa-positive BCa and AR-positive PCa cells.
Original languageEnglish
Pages (from-to)1287-1300
JournalMolecular Oncology
Volume9
Issue number7
DOIs
Publication statusPublished - 2015
MoE publication typeA1 Journal article-refereed

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Keywords

  • MicroRNA (miRNA)
  • Breast cancer (BCa)
  • Prostate cancer (PCa)
  • Estrogen receptor a (ERa)
  • Androgen receptor (AR)
  • Hypoxia inducible factor 1 alpha subunit inhibitor (HIF1AN)

Cite this

Anna, A., Leivonen, S-K., Hintsanen, P., Aittokallio, T., Ceder, Y., Børresen-Dale, A-L., Perälä, M., Östling, P., & Kallioniemi, O. (2015). MicroRNA-135b regulates ERa, AR and HIF1AN and affects breast and prostate cancer cell growth. Molecular Oncology, 9(7), 1287-1300. https://doi.org/10.1016/j.molonc.2015.03.001