Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ARHI is an imprinted tumor suppressor gene and is downregulated in various malignancies. However, ARHI expression, function, and mechanisms of action in prostate cancer have not been reported. Here, we report that ARHI mRNA and protein levels were downregulated in prostate cancer tissues compared with adjacent normal tissues. Overexpression of ARHI inhibited cell proliferation, colony formation, invasion, and induced apoptosis. Further studies on a new mechanism of ARHI downregulation showed a significant inverse relationship between ARHI and miR-221 and 222, which were upregulated in prostate cancer cell lines. Transfection of miR-221 and 222 inhibitors into PC-3 cells caused a significant induction of ARHI expression. A direct interaction of miR-221 or 222 with a target site on the 3'UTR of ARHI was confirmed by a dual luciferase pMIR-REPORT assay. Finally, we also found that genistein upregulates ARHI by downregulating miR-221 and 222 in PC-3 cells. In conclusion, ARHI is a tumor suppressor gene downregulated in prostate cancer, and overexpression of ARHI can inhibit cell proliferation, colony formation, and invasion. This study demonstrates for the first time that prostate cancer cells have decreased level of ARHI which could be caused by direct targeting of 3'UTR of ARHI by miR221/222. Genistein, a potential nontoxic chemopreventive agent, restores expression of ARHI and may be an important dietary therapeutic agent for treating prostate cancer.
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PMID:MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer. 2107 79

The immediate molecular mechanisms behind invasive melanoma are poorly understood. Recent studies implicate microRNAs (miRNAs) as important agents in melanoma and other cancers. To investigate the role of miRNAs in melanoma, we subjected human melanoma cell lines to miRNA expression profiling, and report a range of variations in several miRNAs. Specifically, compared with expression levels in melanocytes, levels of miR-211 were consistently reduced in all eight non-pigmented melanoma cell lines we examined; they were also reduced in 21 out of 30 distinct melanoma samples from patients, classified as primary in situ, regional metastatic, distant metastatic, and nodal metastatic. The levels of several predicted target mRNAs of miR-211 were reduced in melanoma cell lines that ectopically expressed miR-211. In vivo target cleavage assays confirmed one such target mRNA encoded by KCNMA1. Mutating the miR-211 binding site seed sequences at the KCNMA1 3'-UTR abolished target cleavage. KCNMA1 mRNA and protein expression levels varied inversely with miR-211 levels. Two different melanoma cell lines ectopically expressing miR-211 exhibited significant growth inhibition and reduced invasiveness compared with the respective parental melanoma cell lines. An shRNA against KCNMA1 mRNA also demonstrated similar effects on melanoma cells. miR-211 is encoded within the sixth intron of TRPM1, a candidate suppressor of melanoma metastasis. The transcription factor MITF, important for melanocyte development and function, is needed for high TRPM1 expression. MITF is also needed for miR-211 expression, suggesting that the tumor-suppressor activities of MITF and/or TRPM1 may at least partially be due to miR-211's negative post transcriptional effects on the KCNMA1 transcript. Given previous reports of high KCNMA1 levels in metastasizing melanoma, prostate cancer and glioma, our findings that miR-211 is a direct posttranscriptional regulator of KCNMA1 expression as well as the dependence of this miRNA's expression on MITF activity, establishes miR-211 as an important regulatory agent in human melanoma.
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PMID:The regulation of miRNA-211 expression and its role in melanoma cell invasiveness. 2107 71

Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3'UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer.
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PMID:MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2. 2122 45

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, primarily at the post-transcriptional level. Growing evidence suggests that miRNAs function as oncogenes or tumor suppressors in human cancers. The down-regulation of miR-145 has been reported in many types of human cancer, including prostate cancer (PC), suggesting that miR-145 functions as a tumor suppressor. Using the PC cell lines, PC3 and DU145, gain-of-function assays revealed that miR-145 transfection inhibited cell proliferation, migration and invasion. Fascin homolog 1 (FSCN1), an actin-bundling protein, is a candidate target gene of miR-145 based on genome-wide gene expression analysis. A luciferase reporter assay showed a significantly decreased signal at two miR-145 target sites at the 3'UTR of FSCN1, suggesting that miR-145 directly regulates FSCN1. In FSCN1 loss-of-function assays, cell growth, migration and invasion were all inhibited, implying that FSCN1 is associated with the progression of PC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the potential mechanisms of prostate carcinogenesis.
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PMID:Restoration of miR-145 expression suppresses cell proliferation, migration and invasion in prostate cancer by targeting FSCN1. 2125 69

Enabling the transduction of therapeutic gene expression exclusively in diseased sites is the key to developing more effective treatments for advanced prostate cancer using viral-based therapy. While prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by lentiviruses with envelope proteins engineered to bind to this therapeutic antibody. More importantly, after intravenous injection, this trastuzumab-bound lentivirus is able to target castration-resistant prostate tumor xenografts, albeit with low efficiency. This proof of principle opens up multiple possibilities for the prevention and treatment of prostate cancer using a viral-based therapy. However, to be safe and more effective, the viral vectors must target prostate cancer cells more selectively and efficiently. A higher degree of specificity and efficiency of cancer cell targeting can be achieved by engineering viral vectors to bind to a specific cell surface marker and by controlling the expression of the therapeutic payload at transcriptional level, with a tissue-specific promoter, and at the translational level, with a regulatory sequences inserted into either the 5'UTR or 3'UTR regions of the therapeutic gene(s). The latter would be designed to ensure that translation of this mRNA occurs exclusively in malignant cells. Furthermore, in order to obtain a potent anti-tumor effect, viral vectors would be engineered to express pro-apoptotic genes, intra-cellar antibodies/nucleotide aptamers to block critical proteins, or siRNAs to knockdown essential cellular mRNAs. Alternatively, controlled expression of an essential viral gene would restore replication competence to the virus and enable selective oncolysis of tumor cells. Successful delivery of such bioengineered viruses may provide a more effective way to treat advanced prostate cancer.
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PMID:Bioengineered viral vectors for targeting and killing prostate cancer cells. 2132 34

Androgen receptor (AR) is expressed in all stages of prostate cancer progression, including in castration-resistant tumors. Eliminating AR function continues to represent a focus of therapeutic investigation, but AR regulatory mechanisms remain poorly understood. To systematically characterize mechanisms involving microRNAs (miRNAs), we conducted a gain-of function screen of 1129 miRNA molecules in a panel of human prostate cancer cell lines and quantified changes in AR protein content using protein lysate microarrays. In this way, we defined 71 unique miRNAs that influenced the level of AR in human prostate cancer cells. RNA sequencing data revealed that the 3'UTR of AR (and other genes) is much longer than currently used in miRNA target prediction programs. Our own analyses predicted that most of the miRNA regulation of AR would target an extended 6 kb 3'UTR. 3'UTR-binding assays validated 13 miRNAs that are able to regulate this long AR 3'UTR (miR-135b, miR-185, miR-297, miR-299-3p, miR-34a, miR-34c, miR-371-3p, miR-421, miR-449a, miR-449b, miR-634, miR-654-5p, and miR-9). Fifteen AR downregulating miRNAs decreased androgen-induced proliferation of prostate cancer cells. In particular, analysis of clinical prostate cancers confirmed a negative correlation of miR-34a and miR-34c expression with AR levels. Our findings establish that miRNAs interacting with the long 3'UTR of the AR gene are important regulators of AR protein levels, with implications for developing new therapeutic strategies to inhibit AR function and androgen-dependent cell growth.
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PMID:Systematic analysis of microRNAs targeting the androgen receptor in prostate cancer cells. 2134 91

It is commonly agreed that there is an association of chronic inflammation with tumorigenesis. COX-2, a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth; thus, overexpression of COX-2 is often found in tumor tissues. Therefore, a better understanding of the regulatory mechanism(s) of COX-2 could lead to novel targeted cancer therapies. In this study, we investigated the mechanism of microRNA-101 (miR-101)-regulated COX-2 expression and the therapeutic potential of exogenous miR-101 for COX-2-associated cancer. A stably expressing exogenous miR-101 prostate cancer cell line (BPH1(CmiR101)) was generated by using lentiviral transduction as a tool for in vitro and in vivo studies. We found that miR-101 inhibited COX-2 posttranscriptional expression by directly binding to the 3'-untranslated region (3'-UTR) of COX-2 mRNA. The regulatory function of miR-101 was also confirmed by using antisense DNA. As a result, exogenous miR-101 is able to effectively suppress the growth of cultured prostate cancer cells and prostate tumor xenografts. The average tumor weight was significantly lower in the BPH1(CmiR101) group (0.22 g) than the BPH1(Cvec) group (0.46 g). Expression levels of the cell growth regulators, such as cyclin proteins, PCNA (proliferating cell nuclear antigen), EGFR (epidermal growth factor receptor), were also studied. In conclusion, COX-2 is a direct target in miR-101 regulation of posttranscription. Exogenous miR-101 suppresses the proliferation and growth of prostate cancer cells in vitro and in vivo. These data suggest that exogenous miR-101 may provide a new cancer therapy by directly inhibiting COX-2 expression.
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PMID:Enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway in vivo. 2143 74

Recently, a C>T polymorphism (rs1434536) in a miR-125b binding site in the 3' untranslated region (3'UTR) of bone morphogenetic protein membrane receptor type IB gene (BMPR1B) has been found to contribute to cancer susceptibility. To investigate whether it plays an important role in the development of prostate cancer in southern Chinese Han population, we performed a case-control study. 247 prostate cancer and 278 control subjects were included in the cancer association study and dual-luciferase reporter assay was used to test the binding ability of miR-125b to BMPR1B-C or -T vectors. The effect of CT/TT genotype on prostate cancer risk was found to be significant for localized disease (OR=1.60, 95% CI=1.01-2.53, P=0.044) and among subgroups of aged>70 years (OR=1.90, 95% CI=1.15-3.15, P=0.015) compared with CC genotype. Moreover, C-allele gave a reduced luciferase activity relative to T-allele in dual-luciferase reporter assay. Our findings show that rs1434536 in the 3'UTR of BMPR1B gene affects the binding ability of miR-125b to BMPR1B mRNA and contributes to the genetic predisposition to localized prostate cancer and patients aged>70 years.
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PMID:A miR-125b binding site polymorphism in bone morphogenetic protein membrane receptor type IB gene and prostate cancer risk in China. 2155 65

Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post-transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3'UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches.
Prostate Cancer Prostatic Dis 2011 Dec
PMID:Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer. 2182 97

In this study, we have taken advantage of over-expression of eukaryotic translation initiation factor 4E (eIF4E) in prostate cancer cells to design a viral-based targeting system of prostate cancer. Three different lengths of 5'-untranslated regions (5'UTRs) derived from either fibroblast growth factor-2 (FU-FGF2-GW) or ornithine decarboxylase (FU-ODC149-GW and FU-ODC274-GW) were inserted upstream of enhanced green fluorescent protein (GFP) gene in a lentiviral backbone. Both nonmalignant control (PNT1B and BPH-1) and neoplastic (LNCaP, C4-2, DU145 and PC-3) prostate cell lines were transfected with each plasmid or virus alone, or in the presence of siRNA against eIF4E, and their expression was monitored via GFP protein levels. Two 5'UTRs (FU-FGF2-GW and FU-ODC-GW) were selected as being most sensitive to eIF4E status. Lentiviruses containing these sequences were injected directly into the prostates of PTEN(-/-) (tumor-bearing) and control mice. Immunofluorescence data and western blot analyses determined that a lentivirus containing a 5'UTR derived from FGF-2 is the best candidate for directing selective gene expression in the prostate tumors of PTEN(-/-) mice in vivo. This study demonstrates that judicious selection of a complex 5'UTR can enhance selective targeting of viral-based gene therapies for prostate cancer.
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PMID:Fibroblast growth factor and ornithine decarboxylase 5'UTRs enable preferential expression in human prostate cancer cells and in prostate tumors of PTEN(-/-) transgenic mice. 2192 43


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