MicroRNA‐135b regulates ERα, AR and HIF1AN and affects breast and prostate cancer cell growth. Issue 7 (21st March 2015)

• Record Type: Journal Article
• Authors: Aakula, Anna; Leivonen, Suvi-Katri; Hintsanen, Petteri; Aittokallio, Tero; Ceder, Yvonne; Børresen-Dale, Anne-Lise; Perälä, Merja; Östling, Päivi; Kallioniemi, Olli
• Is Part Of: Molecular oncology. Volume 9:Issue 7(2015:Aug.)
• Page Start: 1287
• Page End: 1300
• Publication Date: 2015-03-21
• Subjects: MicroRNA (miRNA) -- Breast cancer (BCa) -- Prostate cancer (PCa) -- Estrogen receptor α (ERα) -- Androgen receptor (AR) -- Hypoxia inducible factor 1 alpha subunit inhibitor (HIF1AN); Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2015.03.001
• Languages: English
• ISSNs: 1574-7891

Abstract

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 α (ERα). Here we show that miR‐135b expression is lower in ERα‐positive breast tumors as compared to ERα‐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 ERα as a novel miR‐135b target by demonstrating miR‐135b binding to the 3′UTR of the ERα and decreased ERα protein and mRNA level upon miR‐135b overexpression in BCa cells. MiR‐135b reduces proliferation of ERα‐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 1α (HIF1α) pathway. We show that miR‐135b influences the protein level of the inhibitor for hypoxia inducible factor 1α (HIF1AN) and is able to bind to HIF1AN 3′UTR. Our study demonstrates that miR‐135b regulates ERα, AR and HIF1AN protein levels through interaction with their 3′UTR regions, and proliferation in ERα‐positive BCa and AR‐positive PCa cells. Highlights: MiR‐135b is studied in breast (BCa) and prostate cancer (PCa). ERα is identified as a novel miR‐135b target by interaction to the 3′UTR in BCa. MiR‐135b expression inversely correlates with ERα protein in BCa patient cohorts. MiR‐135b regulates ERα, AR and HIF1AN protein levels through 3′UTR binding. MiR‐135b inhibits growth of ERα+ BCa cells and AR+ PCa cells.