Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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HIP1 mediates prostate carcinogenesis and progression through STAT3 signalling

ABSTRACT: Overexpression of HIP1 has been associated with fibroblast transformation, increasing grades of prostate cancer (CaP), and biochemical relapse. Here we demonstrate cellular transformation and phenotypic effects of HIP1 overexpression in a benign prostate epithelial cell line to be dependent on STAT3 signalling. In vivo xenografts confirmed the cellular transformation phenotype and revealed serum GDF15 to be a marker of CaP in our model. STAT3 signalling was in part, dependent on HIP1 expression, in a highly invasive, metastatic and androgen receptor (AR) negative DU145 cell line, Immunohistochemistry of a large prostate tissue microarray (TMA) revealed increased HIP1 and reciprocal GDF15 expression to adversely affect outcome warranting further studies to assess HIP1 and GDF15 as biomarkers for detection and prognostication of CaP. Gene expression of PNT1a cells stably overexpressing HIP1 protein and LNCaP cells transiently overexpressing HIP1 protein were compared with their respective empty vector control cell lines using the illumina expression array platform. There were six biological replicates for each of the four different groups.

ORGANISM(S): Homo sapiens

SUBMITTER: Roslin Russell

PROVIDER: E-GEOD-35211 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MicroRNAs (miRNAs) play important roles in cell differentiation and self-renewal controlling post-transcriptional processing of mRNAs and attenuating production of the encoded proteins. Here, we unveil a novel oncogenic pathway leading to activation of STAT3 signaling through miRNA-mediated silencing of the E3 ubiquitin ligase COP1. miRNA profiling showed that miR-424 was upregulated in prostate cancer compared to normal prostate and specifically associated with reduced level of the ETS factor ESE3/EHF in an aggressive subgroup of tumors. MiR-424 was significantly elevated also in other epithelial cancers and amplified in 1-3% of various cancers. In normal prostate epithelial cells miR-424 was repressed by ESE3/EHF and when upregulated promoted oncogenic and cancer stem cell (CSC) properties. Conversely, ablation of miR-424 in metastatic prostate cancer cells reduced CSC self-renewal and prevented in vivo tumour initiation and metastatic spread. miR-424 targeted the 3' UTR of COP1 mRNA and reduced COP1 protein level. COP1 induced STAT3 ubiquitylation and degradation by the ubiquitin-proteasome system (UPS). Therefore, reduced levels of COP1 in prostate cancer cells, resulted in accumulation and increased STAT3 signaling. COP1 knockdown and over-expression phenocopied the effects of miR-424 deregulation on oncogenic phenotypes and STAT3 signalling, while STAT3 knockdown prevented the transforming effects of miR-424. Consistently, expression of EHF/ESE3 and RFWD2/COP1 were highly correlated in human prostate cancers and other epithelial tumors. Furthermore, miR-424 induced genes were enriched of STAT3 targets, converged with those induced by COP1 loss in mouse embryos and were associated with adverse prognosis in prostate and other epithelial cancers. In primary prostate tumours, low COP1 and high STAT3 protein level were also significantly associated and predictive of biochemical relapse. Collectively, this study reveals a novel miRNA-activated oncogenic axis in prostate cancer. Targeting miR-424 or miR-424 dependent pathways may represent a unique approach to attack a key node in tumorigenesis.

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HIP1 mediates prostate carcinogenesis and progression through STAT3 signalling

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