Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis

Yen Nien Liu, JuanJuan Yin, Ben Barrett, Heather Sheppard-Tillman, Dongmei Li, Orla M. Casey, Lei Fang, Paul G. Hynes, Amir H. Ameri, Kathleen Kelly

Research output: Contribution to journalArticle

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Abstract

Bone metastasis is the hallmark of progressive and castration-resistant prostate cancers. MicroRNA 1 (miR-1) levels are decreased in clinical samples of primary prostate cancer and further reduced in metastases. SRC has been implicated as a critical factor in bone metastasis, and here we show that SRC is a direct target of miR-1. In prostate cancer patient samples, miR-1 levels are inversely correlated with SRC expression and a SRC-dependent gene signature. Ectopic miR-1 expression inhibited extracellular signal-regulated kinase (ERK) signaling and bone metastasis in a xenograft model. In contrast, SRC overexpression was sufficient to reconstitute bone metastasis and ERK signaling in cells expressing high levels of miR-1. Androgen receptor (AR) activity, defined by an AR output signature, is low in a portion of castration-resistant prostate cancer. We show that AR binds to the miR-1-2 regulatory region and regulates miR-1 transcription. Patients with low miR-1 levels displayed correlated low canonical AR gene signatures. Our data support the existence of an AR-miR-1-SRC regulatory network. We propose that loss of miR-1 is one mechanistic link between low canonical AR output and SRC-promoted metastatic phenotypes.

Original languageEnglish
Pages (from-to)1940-1951
Number of pages12
JournalMolecular and Cellular Biology
Volume35
Issue number11
DOIs
Publication statusPublished - 2015

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Bone Neoplasms
MicroRNAs
Androgens
Prostatic Neoplasms
Neoplasm Metastasis
Androgen Receptors
Bone and Bones
Castration
Extracellular Signal-Regulated MAP Kinases
Nucleic Acid Regulatory Sequences
Heterografts
Genes
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis. / Liu, Yen Nien; Yin, JuanJuan; Barrett, Ben; Sheppard-Tillman, Heather; Li, Dongmei; Casey, Orla M.; Fang, Lei; Hynes, Paul G.; Ameri, Amir H.; Kelly, Kathleen.

In: Molecular and Cellular Biology, Vol. 35, No. 11, 2015, p. 1940-1951.

Research output: Contribution to journalArticle

Liu, YN, Yin, J, Barrett, B, Sheppard-Tillman, H, Li, D, Casey, OM, Fang, L, Hynes, PG, Ameri, AH & Kelly, K 2015, 'Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis', Molecular and Cellular Biology, vol. 35, no. 11, pp. 1940-1951. https://doi.org/10.1128/MCB.00008-15
Liu, Yen Nien ; Yin, JuanJuan ; Barrett, Ben ; Sheppard-Tillman, Heather ; Li, Dongmei ; Casey, Orla M. ; Fang, Lei ; Hynes, Paul G. ; Ameri, Amir H. ; Kelly, Kathleen. / Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis. In: Molecular and Cellular Biology. 2015 ; Vol. 35, No. 11. pp. 1940-1951.
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