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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Liu YN,Yin J,Barrett B,Sheppard-Tillman H,Li D,Casey OM,Fang L,Hynes PG,Ameri AH,Kelly Kdoi
10.1128/MCB.00008-15subject
Has Abstractpub_date
2015-06-01 00:00:00pages
1940-51issue
11eissn
0270-7306issn
1098-5549pii
MCB.00008-15journal_volume
35pub_type
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