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      Genetic and Epigenetic Regulation of the Organic Cation Transporter 3, SLC22A3


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          Human organic cation transporter 3 ( OCT3, SLC22A3) mediates the uptake of many important endogenous amines and basic drugs in a variety of tissues. OCT3 is identified as one of the important risk loci for prostate cancer and is markedly under-expressed in aggressive prostate cancers. The goal of this study was to identify genetic and epigenetic factors in the promoter region that influence the expression level of OCT3. Haplotypes that contained the common variants, g.-81G>delGA (rs60515630) (minor allele frequency (MAF) 11.5% in African American) and g.-2G>A (rs555754) (MAF>30% in all ethnic groups) showed significant increases in luciferase reporter activities and exhibited stronger transcription factor binding affinity than the haplotypes that contained the major alleles. Consistent with the reporter assays, OCT3 mRNA expression levels were significantly higher in Asian ( P<0.001) and Caucasian ( P<0.05) liver samples from individuals who were homozygous for g.-2A/A in comparison with those homozygous for the g.-2G/G allele. Studies revealed that the methylation level in the basal promoter region of OCT3 was associated with OCT3 expression level and tumorigenesis capability in various prostate cancer cell lines. The methylation level of the OCT3 promoter was higher in 62% of prostate tumor samples compared with matched normal samples. Our studies demonstrate that genetic polymorphisms in the proximal promoter region of OCT3 alter the transcription rate of the gene and may be associated with altered expression levels of OCT3 in human liver. Aberrant methylation contributes to the reduced expression of OCT3 in prostate cancer.

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          Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.

          We identify the SLC22A3-LPAL2-LPA gene cluster as a strong susceptibility locus for coronary artery disease (CAD) through a genome-wide haplotype association (GWHA) study. This locus was not identified from previous genome-wide association (GWA) studies focused on univariate analyses of SNPs. The proposed approach may have wide utility for analyzing GWA data for other complex traits.
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            A molecular correlate to the Gleason grading system for prostate adenocarcinoma.

            Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17 beta4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.
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              Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment.

              Unlike most other malignancies, prostate cancer metastasizes preferentially to the skeleton and elicits osteoblastic reactions. We present a hypothesis, based upon results obtained from our laboratory and others, on the nature of progression of prostate cancer cells and their predilection to growth and metastasis in the bone microenvironment. We propose the hypothesis that osseous metastatic prostate cancer cells must be osteomimetic in order to metastasize, grow, and survive in the skeleton. The reciprocal interaction between prostate cancer and bone stromal growth factors, including basic fibroblast growth factor (bFGF), hepatocyte growth factor/scatter factor (HGF/SF), and especially the insulin growth factor (IGF) axis initiates bone tropism, and is enhanced by prostate secreted endothelin-1 (ET-1) and urokinase-type plasminogen activator (uPA). Growth factors and peptides that have differentiating activity, such as transforming growth factor beta (TGF-beta), parathyroid hormone-related protein (PTH-rp), and the bone morphogenetic proteins (BMPs), can shift local homeostasis to produce the characteristic blastic phenotype, via interaction with prostate-secreted human kalikrein 2 (hK2), and prostate-specific antigen (PSA). This proposal asserts that altering the expression of certain critical transcription factors, such as Cbfa and MSX in prostate cancer cells, which presumably are under the inductive influences of prostate or bone stromal cells, can confer profiles of gene expression, such as osteopontin (OPN), osteocalcin (OC), and bone sialoprotein (BSP), that mimic that of osteoblasts. Elucidation of common proteins, presumably driven by the same promoters, expressed by both prostate cancer and bone stromal cells, could result in the development of novel preventive and therapeutic strategies for the treatment of prostate cancer skeletal metastasis. Agents developed using these strategies could have the potential advantage of interfering with growth and enhancing apoptosis in both prostate cancer and bone stromal compartments. The selective application of gene therapy strategy, driven by tissue-specific and tumor-restricted promoters for the safe delivery and expression of therapeutic genes in experimental models of prostate cancer metastasis, is discussed.

                Author and article information

                Pharmacogenomics J
                Pharmacogenomics J.
                The pharmacogenomics journal
                1 December 2011
                10 January 2012
                April 2013
                01 October 2013
                : 13
                : 2
                : 110-120
                [1 ]Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA
                [2 ]Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
                [3 ]Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
                [4 ]Department of Pathology and Urology, University of California San Francisco, San Francisco, California, USA
                Author notes
                [* ]Corresponding Author: Kathleen M. Giacomini, Ph.D., Professor, Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, 1550 4 th street, San Francisco, California 94158. Tel: 415-476-1936; Fax: 415-502-4322; kathy.giacomini@ 123456ucsf.edu

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funded by: National Institute of General Medical Sciences : NIGMS
                Award ID: U19 GM061390-11 || GM

                Pharmacology & Pharmaceutical medicine
                methylation and prostate cancer,polymorphism,slc22a3


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