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Gene expression profiling of noncancerous prostate epithelial cells (RWPE-1) following pre-miR-424 transfection

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60201 | GEO | 2017/12/31

SECONDARY ACCESSION(S): PRJNA257736

REPOSITORIES: GEO

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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.

Project description:The proto-oncogenes ETV1, ETV4, and ETV5 encode members of the E26 transformation-specific (ETS) transcription factor family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COnstitutive Photomorphogenic-1 (COP1, also called RFWD2) as a tumor suppressor that negatively regulates ETV1, ETV4, and ETV5. ETV1, which is the member mutated more frequently in prostate cancer, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs (degrons) and was 50-fold more stable than wild-type ETV1. Almost all patient translocations eliminate these ETV1 degrons, implying that translocations rendering ETV1 insensitive to COP1 confer a significant selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 levels and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. The combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, relatively rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein expression, and abnormally elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a bona fide tumor suppressor whose down-regulation promotes prostatic epithelial cell proliferation and tumorigenesis. LNCap prostate cancer cell line were treated with 5 different sets of siRNAs: (1) control siRNA; (2) COP1 (RFWD2) siRNA; (3) COP1 siRNA + ETV1 siRNA; (4) COP1 siRNA + c-JUN siRNA; (5) COP1 siRNA + ETV1 siRNA + c-JUN siRNA. The experiments were conducted in two batches; each batch has its own control siRNA group, so that the batch effect can be properly modelled. Each group has 4-6 replicates; there are 31 samples in total.

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Gene expression profiling of noncancerous prostate epithelial cells (RWPE-1) following pre-miR-424 transfection

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