Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis

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

doi:10.1128/mcb.00008-15

Cited by 46 publications

(39 citation statements)

References 44 publications

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“…We previously showed that activated AR can directly target miR-1 and that miR-1 functions as an inhibitor of prostate cancer bone metastasis. 20 Accordingly, we analyzed the relationships between the genes associated with high miR-1 expression and androgen-responsive gene signatures 27 in the Taylor Prostate Cancer Dataset. 28 By using a bioinformatics approach, GSEA, we determined an association between KLF4 expression and AR-induced miR-1 expression (Supplementary Figures S3A,B).…”

Section: Resultsmentioning

confidence: 99%

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KLF4 functions as an activator of the androgen receptor through reciprocal feedback

Suau

et al. 2016

Oncogenesis

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In prostate cancer, Krüppel-like factor 4 (KLF4) depletion occurs frequently, suggesting a role as suppressor tumor. KLF4 is a transcription factor associated with androgen receptor (AR) expression; however, its cellular functions and signaling regulation mechanism remain largely unknown. In this study, we demonstrated that activated AR binds to the KLF4 promoter and enhances KLF4 expression, which reciprocally targets the AR promoter, thus sustaining KLF4 activity. Ectopic KLF4 expression in androgen-independent prostate cancer cells induced AR expression and decreased cell proliferation, invasion and bone metastasis. We previously showed that increased microRNA (miR)-1 expression is associated with reduced bone metastasis of prostate cancer cells. Here we observed that KLF4 targets the primary miR-1-2 stem-loop promoter and stimulates miR-1 expression. In clinical prostate cancer specimens, KLF4 levels were positively correlated with miR-1 and AR levels. These data suggest that the loss of KLF4 expression is one mechanistic link between aggressive prostate cancer progression and low canonical AR output through miR-1 inactivation.

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Section: Resultsmentioning

confidence: 99%

“…19 Notably, we demonstrated that miR-1 expression suppresses experimental bone metastasis and that miR-1 is directly and positively modulated by AR signaling. 20 …”

Section: Introductinonmentioning

confidence: 99%

KLF4 functions as an activator of the androgen receptor through reciprocal feedback

Suau

et al. 2016

Oncogenesis

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“…This cell line was characterized and used to study molecular mechanisms of prostate cancer metastasis previously in multiple peer-reviewed articles (15–20). Cells expressing miR-1 or the control miR were generated as described previously (14, 20). EGFR was subcloned into the pFUGW lentiviral vector and an IRES-mCherry reporter with a puromycin-selectable marker.…”

Section: Methodsmentioning

confidence: 99%

EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating miR-1 and Activating TWIST1

et al. 2015

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Dysregulation of the EGFR signaling axis enhances bone metastases in many solid cancers. However, the relevant downstream effector signals in this axis are unclear. miR-1 was recently shown to function as a tumor suppressor in prostate cancer cells, where its expression correlated with reduced metastatic potential. In this study, we demonstrated a role for EGFR translocation in regulating transcription of miR-1-1, which directly targets expression of TWIST1. Consistent with these findings, we observed decreased miR-1 levels that correlated with enhanced expression of activated EGFR and TWIST1 in a cohort of human prostate cancer specimens and additional datasets. Our findings support a model in which nuclear EGFR acts as a transcriptional repressor to constrain the tumor-suppressive role of miR-1 and sustain oncogenic activation of TWIST1, thereby leading to accelerated bone metastasis.

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“…miR-1 is reduced in primary prostate cancer compared with normal tissue, and levels are further decreased in metastatic disease (Liu et al 2015). Indeed, in aggressive prostate cancer mouse models, loss of miR-1 enhances mesenchymal commitment, invasiveness and tumourigenesis .…”

Section: Global Mirna Profiling Reveals a Signature Specific For Smalmentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis

Cited by 46 publications

References 44 publications

KLF4 functions as an activator of the androgen receptor through reciprocal feedback

KLF4 functions as an activator of the androgen receptor through reciprocal feedback

EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating miR-1 and Activating TWIST1

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

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