| 1. |
- Bechis, Seth K, et al.
(författare)
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Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2 : Implications for Personalized Therapy of Benign Prostatic Hyperplasia.
- 2015
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 194:4
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: In men with symptomatic benign prostatic hyperplasia 5α-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5α-reductase inhibitors. We have found that a third of adult prostate samples do not express 5α-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5α-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5α-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen.MATERIALS AND METHODS: Prostate samples from men undergoing transurethral prostate resection were used. We determined 5α-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling.RESULTS: Body mass index and age significantly correlated with methylation of the 5α-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5α-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01).CONCLUSIONS: Increasing age and body mass index correlate with increased 5α-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.
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| 2. |
- Bechis, Seth K, et al.
(författare)
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Personalized medicine for the management of benign prostatic hyperplasia.
- 2014
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 192:1
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Benign prostatic hyperplasia affects more than 50% of men by age 60 years, and is the cause of millions of dollars in health care expenditure for the treatment of lower urinary tract symptoms and urinary obstruction. Despite the widespread use of medical therapy, there is no universal therapy that treats all men with symptomatic benign prostatic hyperplasia. At least 30% of patients do not respond to medical management and a subset require surgery. Significant advances have been made in understanding the natural history and development of the prostate, such as elucidating the role of the enzyme 5α-reductase type 2, and advances in genomics and biomarker discovery offer the potential for a more targeted approach to therapy. We review the current understanding of benign prostatic hyperplasia progression as well as the key genes and signaling pathways implicated in the process such as 5α-reductase. We also explore the potential of biomarker screening and gene specific therapies as tools to risk stratify patients with benign prostatic hyperplasia and identify those with symptomatic or medically resistant forms.MATERIALS AND METHODS: A PubMed® literature search of current and past peer reviewed literature on prostate development, lower urinary tract symptoms, benign prostatic hyperplasia pathogenesis, targeted therapy, biomarkers, epigenetics, 5α-reductase type 2 and personalized medicine was performed. An additional Google Scholar™ search was conducted to broaden the scope of the review. Relevant reviews and original research articles were examined, as were their cited references, and a synopsis of original data was generated with the goal of informing the practicing urologist of these advances and their implications.RESULTS: Benign prostatic hyperplasia is associated with a state of hyperplasia of the stromal and epithelial compartments, with 5α-reductase type 2 and androgen signaling having key roles in the development and maintenance of the prostate. Chronic inflammation, multiple growth factor and hormonal signaling pathways, and medical comorbidities have complex roles in prostate tissue homeostasis as well as its evolution into the clinical state of benign prostatic hyperplasia. Resistance to medical therapy with finasteride may occur through silencing of the 5α-reductase type 2 gene by DNA methylation, leading to a state in which 30% of adult prostates do not express 5α-reductase type 2. Novel biomarkers such as single nucleotide polymorphisms may be used to risk stratify patients with symptomatic benign prostatic hyperplasia and identify those at risk for progression or failure of medical therapy. Several inhibitors of the androgen receptor and other signaling pathways have recently been identified which appear to attenuate benign prostatic hyperplasia progression and may offer alternative targets for medical therapy.CONCLUSIONS: Progressive worsening of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia is the result of multiple pathways including androgen receptor signaling, proinflammatory cytokines and growth factor signals. New techniques in genomics, proteomics and epigenetics have led to the discovery of aberrant signaling pathways, novel biomarkers, DNA methylation signatures and potential gene specific targets. As personalized medicine continues to develop, the ability to risk stratify patients with symptomatic benign prostatic hyperplasia, identify those at higher risk for progression, and seek alternative therapies for those in whom conventional options are likely to fail will become the standard of targeted therapy.
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| 3. |
- Ge, Rongbin
(författare)
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Development of nonviral gene delivery and of anti-gene reagents
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although significant progress has been made in the basic science and applications of various non-viral gene delivery systems, the majority of non-viral approaches are still much less efficient than viral vectors, especially for in vivo gene delivery, Therefore, non-viral gene delivery must be developed in order to increase the efficiency of in vivo delivery. Moreover, a novel anti-gene reagent was developed for sequence-specific gene silencing. Peptide Nucleic Acid (PNA), a mimic of oligonucleotide with a neutral pseudopeptide backbone consisting of repeating N- (2-amino-ethyl)-glycine units, can invade double-stranded DNA to generate a stable single-strand D-loop. Locked Nucleic Acid (LNA) are synthetic analogs of nucleic acids, which contain a bridging methylene carbon between the 2’ and 4’ positions of the ribose ring. Over the years, a variety of chemically modified small molecules have been developed. Among them, PNA and LNA have shown great promise for a number of applications. In order to further develop a technology for linking functional entities to non-viral vectors, the Bioplex technology, we investigated how hybridization of PNA to supercoiled plasmids would be affected by the binding of multiple PNA-peptides to DNA strands. Cooperative effects were found at a distance of up to three bases. With a peptide present at the end of one of the PNA, steric hindrance occurred, reducing the increase in binding rate when the distance between the two sites was less than two bases. In addition, we found enhanced kinetics when PNA binding to overlapping sites on opposite DNA strands were added, without the use of further chemically modified bases in the PNAs (I). We also generated a novel, sequence-specific anti-gene molecule “Zorro LNA”, in which a 14- mer LNA binds to the coding strand, while a 16-mer connected LNA binds to the template strand. Our data suggest that the “Zorro LNA” induced effective and specific strand invasion into DNA duplexes and potent inhibition of gene transcription, also in mammalian cells. This offers a novel type of anti-gene drug, which is easy to synthesize (II). We also found that the Zorro LNA construct efficiently inhibited pol III-dependent transcription in a cellular context, including in vivo in a mouse model. Thus, this new form of gene silencer could potentially serve as a versatile regulator of pol III-dependent transcription, including various forms of shRNAs (III). Finally, In order to further evaluate the in vivo activity of Zorro LNA and trace its long-term effect in inhibiting gene expression, we inserted two adjacent Zorro LNA-binding sites flanked by loxP sites within the transcribed region of a reporter gene. As previously observed, after Zorro LNA was hybridized to the plasmid, it significantly induced gene silencing in the mammalian cells. Both in transfected cells and in mouse model the silencing effect was lost when Cre-recombinase expressing plasmids were subsequently transfected. This suggests that binding of Zorro LNA is stable over a period of days.
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| 4. |
- Ge, Rongbin, et al.
(författare)
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DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate.
- 2015
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 185:3
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Tidskriftsartikel (refereegranskat)abstract
- 5-α Reductase type 2 (SRD5A2) is a critical enzyme for prostatic development and growth. Inhibition of SRD5A2 by finasteride is used commonly for the management of urinary obstruction caused by benign prostatic hyperplasia. Contrary to common belief, we have found that expression of SRD5A2 is variable and absent in one third of benign adult prostates. In human samples, absent SRD5A2 expression is associated with hypermethylation of the SRD5A2 promoter, and in vitro SRD5A2 promoter activity is suppressed by methylation. We show that methylation of SRD5A2 is regulated by DNA methyltransferase 1, and inflammatory mediators such as tumor necrosis factor α, NF-κB, and IL-6 regulate DNA methyltransferase 1 expression and thereby affect SRD5A2 promoter methylation and gene expression. Furthermore, we show that increasing age in mice and humans is associated with increased methylation of the SRD5A2 promoter and concomitantly decreased protein expression. Artificial induction of inflammation in prostate primary epithelial cells leads to hypermethylation of the SRD5A2 promoter and silencing of SRD5A2, whereas inhibition with tumor necrosis factor α inhibitor reactivates SRD5A2 expression. Therefore, expression of SRD5A2 is not static and ubiquitous in benign adult prostate tissues. Methylation and expression of SRD5A2 may be used as a gene signature to tailor therapies for more effective treatment of prostatic diseases.
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| 5. |
- Ge, Rongbin, et al.
(författare)
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Metformin represses cancer cells via alternate pathways in N-cadherin expressing vs. N-cadherin deficient cells.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:30
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Tidskriftsartikel (refereegranskat)abstract
- Metformin has emerged as a potential anticancer agent. Here, we demonstrate that metformin plays an anti-tumor role via repressing N-cadherin, independent of AMPK, in wild-type N-cadherin cancer cells. Ectopic-expression of N-cadherin develops metformin-resistant cancer cells, while suppression of N-cadherin sensitizes cancer to metformin. Manipulation of AMPK expression does not alter sensitivity of cancer to metformin. We show that NF-kappaB is a downstream molecule of N-cadherin and metformin regulates NF-kappaB signaling via suppressing N-cadherin. Moreover, we also suggest that TWIST1 is an upstream molecule of N-cadherin/NF-kappaB signaling and manipulation of TWIST1 expression changes the sensitivity of cancer cells to metformin. In contrast to the cells that express N-cadherin, in N-cadherin deficient cells, metformin plays an anti-tumor role via activation of AMPK. Ectopic expression of N-cadherin makes cancer more resistant to metformin. Therefore, we suggest that metformin's anti-cancer therapeutic effect is mediated through different molecular mechanism in wild-type vs. deficient N-cadherin cancer cells. At last, we selected 49 out of 984 patients' samples with prostatic cancer after radical prostatectomy (selection criteria: Gleason score ≥ 7 and all patients taking metformin) and showed levels of N-cadherin, p65 and AMPK could predict post-surgical recurrence in prostate cancer after treatment of metformin.
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