國立臺南大學教師基本資料

基本資料
姓名 丁慧如
系所 生物科技學系
職稱 助理教授
校內分機 7728
傳真
辦公室/研究室 ZC209-2
E-mail hting@mail.nutn.edu.tw
網址
專長/研究領域 cancer biology, toxicology
 

畢業學校國別主修學門學位修業期間
國立臺灣大學臺灣藥學學士1989/9~1993/6
國立臺灣大學臺灣毒理碩士1993/9~1995/6
University of RochesterUSAToxicologyPhD1997/08~2002/05

服務機關部門 / 系所職稱服務期間
University of RochesterUrologyPostdoc Fellow2002/5~2007/12
University of RochesterPathology and UrologyResearch Assistant Professor2008/1~2012/7
國立臺南大學生物科技學系助理教授2012/8~

著作
名稱Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. Chapter 12 Vitamin D and Prostate Cancer
年度2005
類別專書
摘要Nutritional factors have been hypothesized to be critical in the development of numerous cancers, and this holds true for prostate cancer. On the basis of geographic patterns of ultraviolet radiation throughout the contiguous United States, and on epidemiological data on prostate cancer incidence, the hypothesis was raised by Schwartz and colleagues that vitamin D deficiency may be a prostate cancer risk factor, and that increased exposure to sunlight may protect against clinical prostate cancer. In vitro studies have shown that ...
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名稱Vitamin D: Oxidative Stress, Immunity, and Aging
年度2012
類別專書
摘要The beneficial effects of vitamin D in several diseases, such as preventing bone loss, protecting neurons from degeneration, boosting immune response, preventing diabetes/diabetic toxicity, and acting as an anticancer agent, are well documented [1–6]. This encourages vitamin D supplementation in the general healthy population. Vitamin D maintains calcium homeostasis and participates in multiple cellular processes, such as differentiation, proliferation, and metabolism, through both nongenomic action and its ...
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名稱Differential induction of androgen receptor transactivation by different androgen receptor coactivators in human prostate cancer DU145 cells.
年度1999
類別期刊論文
摘要Recently identified androgen receptor (AR) coactivators were used in this study to determine whether the specificity of sex hormones and antiandrogens could be modulated at the coactivator level. We found that ARA70 is the best coactivator to confer the androgenic activity on 17beta-estradiol. Only ARA70 and ARA55 could increase significantly the androgenic activity of hydroxyflutamide, a widely used antiand rogen for the treatment of prostate cancer. None of the AR coactivators we tested could significantly confer androgenic activity on progesterone and glucocorticoid at their physiological concentrations (1-10nM). We also found that ARA70, ARA55, and ARA54, but not steroid receptor coactivator-1 (SRC-1) and Rb, could significantly enhance the delta5-androstenediol-mediated AR transactivation. Furthermore, in comparing the relative specificity of these coactivators to AR in DU145 cells, our results suggested that ARA70 has a relatively higher specificity and that SRC-1 can enhance almost equally well many other steroid receptors. Finally, our data demonstrated that AR itself and some select AR coactivators such as ARA70 or ARA54 could, respectively, interact with CBP and p300/CBP-associated factors that have histone acetyl-transferase activity for assisting chromatin remodeling. Together, our data suggest that the specificity of sex hormones and antiandrogens can be modulated by some selective AR coactivators. These findings may not only help us to better understand the specificity of the sex hormones and antiandrogens, but also facilitate the development of better antiandrogens to fight the androgen-related diseases, such as prostate cancer.
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名稱Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma.
年度1999
類別期刊論文
摘要In an effort to understand transcriptional regulation by the peroxisome proliferator-activated receptor gamma (PPARgamma), we have investigated its potential interaction with coregulators and have identified ARA70 as a ligand-enhanced coactivator. ARA70 was initially described as a coactivator for the androgen receptor (AR) and is expressed in a range of tissues including adipose tissue (Yeh, S., and Chang, C. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 5517-5521). Here we show that ARA70 and PPARgamma specifically interact by coimmunoprecipitation and in a mammalian two-hybrid assay. PPARgamma and ARA70 interact in the absence of the PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2, although the addition of exogenous ligand enhances this interaction. Similarly, in transient transfection of DU145 cells, cotransfection of PPARgamma and ARA70 induces transcription from reporter constructs driven by either three copies of an isolated PPAR response element or the natural promoter of the adipocyte fatty acid-binding protein 2 in the absence of exogenous 15-deoxy-Delta12,14-prostaglandin J2. However, this PPARgamma-ARA70 transactivation is enhanced by the addition of ligand. Thus, ARA70 can function as a ligand-enhanced coactivator of PPARgamma. Finally, we show that AR can squelch PPARgamma-ARA70 transactivation, which suggests that cross-talk may occur between PPARgamma- and AR-mediated responses in adipocytes.
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名稱Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells.
年度2000
類別期刊論文
摘要Although mutations of the breast cancer susceptibility gene 1 (BRCA1) may play important roles in breast and prostate cancers, the detailed mechanism linking the functions of BRCA1 to these two hormone-related tumors remains to be elucidated. Here, we report that BRCA1 interacts with androgen receptor (AR) and enhances AR target genes, such as p21((WAF1/CIP1)), that may result in the increase of androgen-induced cell death in prostate cancer cells. The BRCA1-enhanced AR transactivation can be further induced synergistically with AR coregulators, such as CBP, ARA55, and ARA70. Together, these data suggest that the BRCA1 may function as an AR coregulator and play positive roles in androgen-induced cell death in prostate cancer cells and other androgen/AR target organs.
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名稱Identification and characterization of androgen receptor associated coregulators in prostate cancer cells
年度2001
類別期刊論文
摘要The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily that mediates the effects of androgens on target tissues. Over the last decade, it has become apparent that NRs require accessory factors for optimal activation of target gene expression. Numerous NR coregulators have been identified, with diverse structures and potential mechanisms of coregulation, creating an increasingly complicated picture of NR action. Due to the expanding complexity of the coregulator field, this review will focus on the AR ligand-binding domain (LBD) and N-terminal interacting proteins identified by our lab. The LBD-interacting proteins ARA70, ARA55 and ARA54 were first characterized and ARA70 was found to have a relatively higher specificity for the AR in human prostate cancer DU145 cells. Characterization of the functional relationship between the AR and these coregulators indicated that ARA70 and ARA55 could enhance the androgenic effects of 17beta-estradiol (E2) and hydroxyflutamide (HF), an antiandrogen commonly used in the treatment of prostate cancer. ARA160, an AR N-terminal interacting protein also known as TATA element modulatory factor (TMF), was subsequently shown to cooperate with ARA70 in enhancing AR activity. Another AR N-terminal interacting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedys disease (X-linked spinal and bulbar muscular atrophy). More recently, our lab has identified ARA267, a SET domain containing protein, and supervillin, an F-actin binding protein, as AR coregulators. Collectively, the data from these studies indicate that these coregulators are necessary for optimal AR transactivation. Interruption of the interaction between AR and these proteins may serve as a new therapeutic target in the treatment of prostate cancer.
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名稱Supervillin associates with androgen receptor and modulates its transcriptional activity
年度2002
類別期刊論文
摘要Activation of androgen receptor (AR) via androgen in muscle cells has been closely linked to their growth and differentiation. Here, we report the cloning and characterization of supervillin (SV), a 205-kDa actin-binding protein, as an AR coregulator from the skeletal muscle cDNA library. Mammalian two-hybrid and glutathione S-transferase pull-down assays indicate a domain within SV (amino acids 594-1268) can interact with AR N terminus and DNA-binding domain-ligand-binding domain in a ligand-enhanced manner. Subcellular colocalization studies with fluorescence staining indicate SV can colocalize with AR in the presence of 5 alpha-dihydrotestosterone in COS-1 cells. The functional reporter assays showed full-length SV and the SV peptide (amino acids 831-1281) within the interaction domain can enhance AR transactivation. Furthermore, SV can enhance the endogenous AR target gene, p27(KIP1), expression in prostate PC-3(AR2) cells. SV preferentially enhanced AR rather than other tested nuclear receptors and could be induced by natural androgens better than other steroids. SV can also cooperate with other AR coregulators, such as ARA55 or ARA70, to enhance AR transactivation further. Unlike SRC-1 that can enhance the interaction between AR N terminus and AR C terminus, SV shows a mild suppressive effect on N-C interactions, suggesting SV may go through a different mechanism to enhance AR transactivation. Together, our data demonstrate that SV is an AR coregulator that can enhance AR transactivation in muscle and other cells.
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名稱Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.
年度2003
類別期刊論文
摘要The partial agonist effect of antiandrogens has been well documented, and such effect is amplified by derived mutant androgen receptors (ARs) in prostate cancer cells. Here we report the identification of gelsolin (GSN) as an AR-associated protein. Hydroxyflutamide (HF), as well as androgens, can promote the interaction between AR and GSN in a dose-dependent manner. GSN interacts with AR DNA-binding domain and ligand-binding domain via its COOH-terminal domain. Immunolocalization studies show that GSN interacts with AR during nuclear translocation. Functional analyses additionally demonstrate that GSN enhances AR activity in the presence of either androgen or HF. Two peptides representing partial regions of the AR DNA-binding domain and the ligand-binding domain can block the GSN-enhanced AR activity. The expression of GSN is enhanced in LNCaP cells, LNCaP xenografts, and human prostate tumors after androgen depletion. Increasing expression of GSN enhances the AR activity in the presence of HF. Together, these data suggest that the weak androgenic effect of HF may be amplified by increasing the amount of GSN after androgen ablation treatment. Therefore, blockage of the interaction between AR and GSN could become a potential therapeutic target for the treatment of prostate cancer.
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名稱The use of phage display technique for the isolation of androgen receptor interacting peptides with (F/W)XXL(F/W) and FXXLY new signature motifs.
年度2003
類別期刊論文
摘要Early studies suggested that the signature motif, LXXLL, within steroid hormone receptor p160 coregulators may play important roles for the mediation of receptor-coregulator interaction. Interestingly, several androgen receptor (AR) coregulators, such as ARA70 and ARA55, may not use such a unique motif to mediate their coregulator activity. Here we apply the phage display technique to identify some new signature motifs, (F/W)XXL(F/W) and FXXLY (where F is phenylalanine, W is tryptophan, L is leucine, Y is tyrosine, and X is any amino acid) that can influence the interaction between AR and AR coregulators. Sequence analyses found that several AR coregulators, such as ARA70, ARA55, ARA54, and FHL2, contain FXXL(F/Y) motifs. Both glutathione S-transferase pull-down assays and transient transfection reporter assays demonstrate that these AR coregulators may use the FXXL(F/Y) motif to interact with AR and exert their AR coregulator activity. Exchanging the amino acid of Phe, Trp, or Tyr in this newly identified signature motif cluster may influence these peptides to interact with AR. The motif-containing peptides, as well as ARA70 or ARA54, may require selective flanking sequences for the better interaction with AR. In addition to influencing the AR transactivation, these motifs in AR-interacting peptides/proteins were also able to influence the AR N-/C-terminal interaction. Together, our data suggest that AR interacting peptides and/or AR coregulators may utilize the (F/W)XXL(F/W) and FXXLY motifs to mediate their interaction with AR and exert their influences on the AR transactivation.
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名稱Androgen receptor regulates expression of skeletal muscle-specific proteins and muscle cell types.
年度2004
類別期刊論文
摘要C2C12 myoblasts expressing the androgen receptor (AR) were used to analyze the role of androgen-AR signaling pathway in skeletal muscle development. Marked up-regulation of AR expression was observed in differentiated myotubes. A nuclear run-on transcription assay demonstrated that transcription of the AR gene is increased during skeletal muscle cell differentiation. Regulation of skeletal muscle-specific protein expression by the androgen-AR signaling pathway was further analyzed using quadriceps skeletal muscle from wild-type (WT) and AR knock-out (ARKO) male mice. A histological analysis of quadriceps skeletal muscle indicates no morphological differences between ARKO and WT mice. However, the androgen-AR signaling pathway increases expression of slow-twitch-specific skeletal muscle proteins and downregulates fast-twitch-specific skeletal muscle proteins, resulting in an increase of slow-twitch muscle fiber type cells in quadriceps muscle.
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名稱Functional domain and motif analyses of androgen receptor coregulator ARA70 and its differential expression in prostate cancer
年度2004
類別期刊論文
摘要Androgen receptor (AR)-associated coregulator 70 (ARA70) was the first identified AR coregulator. However, its molecular mechanism and biological relevance to prostate cancer remain unclear. Here we show that ARA70 interacts with and promotes AR activity via the consensus FXXLF motif within the ARA70-N2 domain (amino acids 176-401). However, it does not promote AR activity via the classic LXXLL motif located at amino acids 92-96, although this classic LXXLL motif is important for ARA70 to interact with other receptors, such as PPARgamma. The molecular mechanisms by which ARA70 enhances AR transactivation involve the increase of AR expression, protein stability, and nuclear translocation. Furthermore, ARA70 protein is more frequently detected in prostate cancer specimens (91.74%) than in benign tissues (64.64%, p 0.0001). ARA70 expression is also increased in high-grade prostate cancer tissues as well as the hormone-refractory LNCaP xenografts and prostate cancer cell lines. Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer. Because ARA70-N2 containing the AR-interacting FXXLF motif without coactivation function can suppress HF-enhanced AR transactivation in the hormone-refractory LNCaP cells, using the ARA70-N2 inhibitory peptide at the hormone refractory stage to battle the HF withdrawal syndrome may become an alternative strategy to treat prostate cancer.
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名稱Actin monomer enhances supervillin-modulated androgen receptor transactivation
年度2004
類別期刊論文
摘要Actin-binding protein, supervillin, has been identified as an androgen receptor (AR) coregulator. Although actin has been suggested to participate in transcription regulation, the mechanism is not clear. Here we demonstrate signals involved in the cytoskeleton dynamic can modulate the coregulator function of supervillin. Three actin isoforms cooperate with supervillin in additive manner to further enhance AR transactivation. Latrunculin B toxin, an actin chelator, reduces the availability of monomer actin and attenuates supervillin function. Rac, the small G-protein kinase, is well studied in reorganization of cytoskeleton. The overexpression of constitutive-active Rac triggers the membrane ruffling site and reduces the coregulator activity of supervillin. Together, the availability of actin monomer affects supervillin-modulated AR transactivation.
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名稱Androgen signaling is required for the vitamin D-mediated growth inhibition in human prostate cancer cells.
年度2004
類別期刊論文
摘要Epidemiological data on prostate cancer incidence has suggested that vitamin D deficiency may be a risk factor for prostate cancer. The antiproliferative activity of 1alpha, 25-dihydroxyvitamin D3 (1,25-VD) and its analogues has been demonstrated in many prostate cancer models, yet the detailed mechanisms underlying this protective effect of vitamin D remain to be determined. Here, we demonstrate that two androgen receptor (AR)-positive prostate cancer cell lines, LNCaP and CWR22R, are more sensitive to the growth inhibitory effects of 1,25-VD compared to the AR-negative prostate cancer cell lines, PC-3 and DU 145. 1,25-VD treatment inhibited cyclin-dependent kinase 2 (cdk2) activity and induced G0/G1 arrest. Interestingly, we also found that 1,25-VD treatment induced the expression of AR, and that the onset of the G0/G1 arrest in LNCaP and CWR22R cells is correlated with the onset of increasing expression of AR. This implies that the antiproliferative actions of 1,25-VD in AR-positive prostate cancer might be mediated through AR. Furthermore, a reduction in 1,25-VD-mediated growth inhibition was observed when AR signaling was blocked by antiandrogens, AR RNA interference, or targeted disruption of AR. Taken together, our data suggest that the androgen/AR signaling plays an important role in the antiproliferative effects of 1,25-VD and restoration of androgen responsiveness by 1,25-VD might be beneficial for the treatment of hormone-refractory prostate cancer patients.
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名稱Androgen-receptor coregulators mediate the suppressive effect of androgen signals on vitamin D receptor activity.
年度2005
類別期刊論文
摘要Overexpression of androgen receptors (AR) in PC-3 cell, and treatment of 5alpha-dihydrotestosterone in LNCaP cells lead to the suppression of VDR transactivation. Competition for shared coregulators between AR and VDR is one possible mechanism to explain the suppressive effect of androgen-AR signals on VDR activity. Among the AR coregulators we tested, ARA54, ARA70, supervillin, and gelsolin were found to enhance VDR transactivation. Further characterization of the interaction between ARA54 or ARA70 and VDR demonstrated a direct interaction between VDR and ARA70, but no association between ARA54 and VDR. The LXXLL motif of ARA70 is essential for interaction with VDR and partially responsible for its function as a coactivator of VDR. The suppression of VDR transactivation by AR signal was restored by overexpression of ARA70, but not ARA54. Together, ARA70 and ARA54 modulate VDR transactivation, and the competition for ARA70 mediates the suppressive effect of androgen-AR on VDR transactivation.
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名稱Androgen receptor (AR) NH2- and COOH-terminal interactions result in the differential influences on the AR-mediated transactivation and cell growth.
年度2005
類別期刊論文
摘要Early reports showed that androgen receptor (AR) NH2- and COOH-terminal (N-C) interaction was important for full AR function. However, the influence of these interactions on the AR in vivo effects remains unclear. Here we tested some AR-associated peptides and coregulators to determine their influences on AR N-C interaction, AR transactivation, and AR coregulator function. The results showed that AR coactivators such as ARA70N, gelsolin, ARA54, and SRC-1 can enhance AR transactivation but showed differential influences on the N-C interaction. In contrast, AR corepressors ARA67 and Rad9 can suppress AR transactivation, with ARA67 enhancing and Rad9 suppressing AR N-C interaction. Furthermore, liganded AR C terminus-associated peptides can block AR N-C interaction, but only selective peptides can block AR transactivation and coregulator function. We found all the tested peptides can suppress prostate cancer LNCaP cell growth at different levels in the presence of 5alpha-dihydrotestosterone, but only the tested FXXLF-containing peptides, not FXXMF-containing peptides, can suppress prostate cancer CWR22R cell growth. Together, these results suggest that the effects of AR N-C interactions may not always correlate with similar effects on AR-mediated transactivation and/or AR-mediated cell growth. Therefore, drugs designed by targeting AR N-C interaction as a therapeutic intervention for prostate cancer treatment may face unpredictable in vivo effects.
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名稱Increased expression of corepressors in aggressive androgen-independent prostate cancer cells results in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness.
年度2007
類別期刊論文
摘要Vitamin D has antiproliferative activity in prostate cancer; however, resistance to vitamin D-mediated growth inhibition occurs. To investigate the mechanisms of vitamin D resistance, we screened two prostate cancer sublines of CWR22rv1, CWR22R-1, and CWR22R-2, with differential sensitivity to vitamin D. CWR22R-2 showed less response to the antiproliferative effect of vitamin D than CWR22R-1. The vitamin D receptor (VDR)-mediated transcriptional activity was also decreased in CWR22R-2. We further showed that the DNA-binding ability of VDR was decreased and the amount of NCoR in VDR response element was increased in CWR22R-2. Analysis of VDR-associated protein profiles found higher expression of the corepressors, NCoR1 and SMRT, in CWR22R-2 cells. Treatment with the histone deacetylase inhibitor, trichostatin A, increased vitamin D/VDR transcriptional activity and promoted the antiproliferative effect of vitamin D in CWR22R-2 cells. Targeted down-regulation of NCoR1 and SMRT by small interference RNA was able to restore CWR22R-2 response to vitamin D. Together, we showed that increased NCoR1 and SMRT expression in CWR22R-2 cells resulted in reduced VDR-mediated transcriptional activity and attenuated antiproliferative response to vitamin D. Our data suggest that the integrity of the vitamin D/VDR-mediated signaling pathway is crucial in predicting vitamin D responsiveness and thus provide a rational design to improve vitamin D-based treatment efficacy based on molecular profiles of patients.
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名稱Docetaxel-induced growth inhibition and apoptosis in androgen independent prostate cancer cells are enhanced by 1alpha,25-dihydroxyvitamin D3.
年度2007
類別期刊論文
摘要Pre-treatment with high-dose 1alpha,25-dihydroxyvitamin D(3) (1,25-VD) enhanced the antitumor activity of docetaxel in the androgen-independent prostate cancer cell line, PC-3. The effect manifested as an increasing population of apoptotic cells and amount of pro-apoptotic protein, Bax, under combined treatment compared with single treatment of either 1,25-VD or docetaxel alone. We further demonstrated that pre-treatment with 1,25-VD reduced the expression of multidrug resistance-associated protein-1 at both the mRNA and protein levels. This suggests pre-treatment with 1,25-VD can potentiate cytotoxicity of docetaxel in PC-3 due to 1,25-VD reducing multidrug resistance-associated protein-1 expression.
關鍵字Prostate cancer, Docetaxel, 1α,25-Vitamin D3, Growth inhibition, Multidrug resistance proteins
名稱Protective role of 1α, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells.
年度2008
類別期刊論文
摘要Overproduction of reactive oxygen species (ROS), through either endogenous or exogenous sources, could induce DNA damage, and accumulation of DNA damage might lead to multistep carcinogenesis. The antioxidative effects of vitamin D have been suggested by epidemiological and many in vitro and in vivo laboratory studies. While exploring the antioxidative effects of vitamin D in prostate cells, we found that the active form of vitamin D, 1 alpha, 25-dihydroxyvitamin D(3) (1,25-VD), can protect nonmalignant human prostate epithelial cell lines, BPH-1 and RWPE-1, but not malignant human prostate epithelial cells, CWR22R and DU 145, from oxidative stress-induced cell death. Glucose-6-phosphate dehydrogenase (G6PD), a key antioxidant enzyme, was dose- and time-dependently induced by 1,25-VD. Mechanistic studies using chromatin immunoprecipitation (ChIP) assay revealed that a direct repeat-3 (DR3) vitamin D response element located in the first intron of the G6PD genome can be bound by liganded vitamin D receptor, thereby regulating G6PD gene expression. Increasing G6PD activity and glutathione level by 1,25-VD can scavenge cellular ROS. Moreover, the protective effects of 1,25-VD were abolished by dehydroepiandrosterone, a noncompetitive inhibitor of G6PD activity. Together, our results showed that 1,25-VD can protect nonmalignant prostate cells from oxidative stress-induced cell death by elimination of ROS-induced cellular injuries through transcriptional activation of G6PD activity. The antioxidative effect of vitamin D strengthens its roles in cancer chemoprevention and adds to a growing list of beneficial effects of vitamin D against cancer.
關鍵字prostate cancer; vitamin D; G6PD; oxidative stress
名稱Actin associated proteins function as androgen receptor coregulators: an implication of androgen receptors roles in skeletal muscle.
年度2008
類別期刊論文
摘要This review of androgen receptor (AR) coregulators, which also function as actin-binding proteins, intends to establish the connection between actin cytoskeletal components and androgen signaling, especially in skeletal muscle. In cellular and animal models, androgen activated AR modulates myoblasts proliferation, promotes sexual dimorphic muscle development, and alters muscle fiber type. In the clinical setting, administration of anabolic androgens can decrease cachexia and speed wound healing. During myogenesis and regeneration of skeletal muscle in embryo and adult, the membrane of myoblasts fuse and the actin cytoskeleton is rearranged to form an alignment with myosin to form myotubes then ultimately the myofibrils. Contraction of skeletal muscle promotes the growth of myocytes by coordinating signals from the neuromuscular junction to intra-myofibrils through costameres, the functional structure comprised of signal proteins closely associated with actin filaments and involved in muscular dystrophy. Therefore, the discovery of actin-binding proteins functioning as AR coregulators implies that androgen signaling is tightly regulated during the process of the development and regeneration of skeletal muscle. The search for selective androgen receptor modulators (SARM) that act precisely in skeletal muscle instead of other tissues could target the engineering of a SARM-AR complex that selectively recruits these coregulators.
關鍵字Androgen receptor; Coregulators; Skeletal muscle; Actin-binding proteins; Supervillin; Gelsolin; Filamin; ARA55; Hic-5; Paxillin
名稱Down-regulation of NF-kappaB signals is involved in loss of 1alpha,25-dihydroxyvitamin D3 responsiveness.
年度2010
類別期刊論文
摘要Vitamin D anti-tumor effect is often found reduced in the late stages of cancer. To uncover vitamin D resistance mechanism, we established a vitamin D-resistant human prostate cancer LNCaP cell line, LNCaP-R, by chronic exposure of cells to 1,25-dihydroxyvitamin D3 (1,25-VD). The vitamin D receptor (VDR)-mediated transcriptional activitywasreduced in LNCaP-R, whereasVDRexpression level andDNAbinding capacity were similar compared to parental cells (LNCaP-P). The expressions of the key factors involved inVDRtransactivity, including CYP24A1 and VDR-associated proteins are all increased in LNCaPR cells, and yet treatment with ketoconazole, P450 enzymes inhibitor, as well as trichostatin A (TSA), a histone deacetylase inhibitor, did not sensitize LNCaP-R cells response to vitamin D, suggesting that neither a local 1,25-VD availability, nor VDR-associated proteins are responsible for the vitaminDresistance. Interestingly, nuclear factor-kappaB (NF-B) signaling, which is critical for 1,25-VD/VDR activity was found reduced in LNCaP-R cells, thereby treatment with NF-B activator, 12-O-tetradecanoylphorbol- 13-acetate (TPA), can sensitize LNCaP-R vitamin D response. Together, we conclude that NF-B signaling is critical for vitamin D sensitivity, and dysregulation of this pathway would result in vitamin D resistance and disease progression.
關鍵字Prostate cancer, Vitamin D-resistant, NF-kappa B
名稱Premature aging with impaired oxidative stress defense in mice lacking TR4.
年度2011
類別期刊論文
摘要Early studies suggest that TR4 nuclear receptor is a key transcriptional factor regulating various biological activities, including reproduction, cerebella development, and metabolism. Here we report that mice lacking TR4 (TR4(-/-)) exhibited increasing genome instability and defective oxidative stress defense, which are associated with premature aging phenotypes. At the cellular level, we observed rapid cellular growth arrest and less resistance to oxidative stress and DNA damage in TR4(-/-) mouse embryonic fibroblasts (MEFs) in vitro. Restoring TR4 or supplying the antioxidant N-acetyl-l-cysteine (NAC) to TR4(-/-) MEFs reduced the DNA damage and slowed down cellular growth arrest. Focused qPCR array revealed alteration of gene profiles in the DNA damage response (DDR) and anti-reactive oxygen species (ROS) pathways in TR4(-/-) MEFs, which further supports the hypothesis that the premature aging in TR4(-/-) mice might stem from oxidative DNA damage caused by increased oxidative stress or compromised genome integrity. Together, our finding identifies a novel role of TR4 in mediating the interplay between oxidative stress defense and aging.
關鍵字testicular nuclear receptor 4, senescence
名稱The roles of testicular nuclear receptor 4 (TR4) in male fertility-priapism and sexual behavior defects in TR4 knockout mice.
年度2011
類別期刊論文
摘要BACKGROUND: Successful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events. TR4 nuclear receptor is known to be involved in male fertility via controlling spermatogenesis, yet its roles in regulating other biological events related to reproduction have not been completely revealed. METHODS: Male TR4 knockout (TR4 -/-) and wild type mice were used for the sexual behavior and penile dysfunction studies. Mice were sacrificed for histological examination and corresponding genes profiles were analyzed by quantitative RT-PCR. Reporter gene assays were performed. RESULTS: We describe an unexpected finding of priapism in TR4 -/- mice. As a transcriptional factor, we demonstrated that TR4 transcriptionally modulates a key enzyme regulating penis erection and neuronal nitric oxide synthese NOS (nNOS). Thereby, elimination of TR4 results in nNOS reduction in both mRNA and protein levels, consequently may lead to erectile dysfunction. In addition, male TR4 -/- mice display defects in sexual and social behavior, with increased fear or anxiety, as well as reduced mounting, intromission, and ejaculation. Reduction of ER alpha, ER beta, and oxytocin in the hypothalamus may contribute to defects in sexual behavior and stress response. CONCLUSIONS: Together, these results provide in vivo evidence of important TR4 roles in penile physiology, as well as in male sexual behavior. In conjunction with previous finding, TR4 represents a key factor that controls male fertility via regulating behavior and internal physiological events.
關鍵字TR4, priapism, sexual behavior
名稱Testicular nuclear receptor 4 (TR4) regulates UV light-induced responses via Cockayne syndrome B protein-mediated transcription-coupled DNA repair.
年度2011
類別期刊論文
摘要UV irradiation is one of the major external insults to cells and can cause skin aging and cancer. In response to UV light-induced DNA damage, the nucleotide excision repair (NER) pathways are activated to remove DNA lesions. We report here that testicular nuclear receptor 4 (TR4), a member of the nuclear receptor family, modulates DNA repair specifically through the transcription-coupled (TC) NER pathway but not the global genomic NER pathway. The level of Cockayne syndrome B protein (CSB), a member of the TC-NER pathway, is 10-fold reduced in TR4-deficient mouse tissues, and TR4 directly regulates CSB at the transcriptional level. Moreover, restored CSB expression rescues UV hypersensitivity of TR4-deficient cells. Together, these results indicate that TR4 modulates UV sensitivity by promoting the TC-NER DNA repair pathway through transcriptional regulation of CSB. These results may lead to the development of new treatments for UV light-sensitive syndromes, skin cancer, and aging.
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名稱Suppression of prostate cancer cell rolling and adhesion to endothelium by 1alpha,25-dihydroxyvitamin D3.
年度2011
類別期刊論文
摘要Adhesion of circulating prostate cancer (PCa) cells to the microvascular endothelium is a critical step during cancer metastasis. To study PCa cell rolling and adhesion behavior, we developed a dynamic flow-based microtube system to mimic the microvascular environment. We found that PCa cell rolling capacity is mediated by E-selectin and can be enhanced by stromal cell-derived factor-1 under different wall shear stresses. Using this device, we tested if the chemopreventive agent, vitamin D, could interfere with PCa cell adhesion. We found that 1α,25-dihydroxyvitamin D(3) (1,25-VD), the bioactive form of vitamin D, reduced PCa cell rolling numbers and increased rolling velocities resulting in a significant decreased number of PCa cells adhering to the microtube. The inhibitory effects of 1,25-VD on PCa cell heterotypic adhesion were further confirmed using microvascular endothelial cells in a static condition. Furthermore, we demonstrated that 1,25-VD can increase E-cadherin expression in PCa cells and promote the homotypic cell-cell aggregation, which can then hinder PCa cell adhesion to the endothelium. Blocking E-cadherin with a neutralizing antibody can reverse 1,25-VD-mediated suppression of PCa cell adhesion to the endothelium. Taken together, our data revealed that 1,25-VD promoted PCa cell aggregation by increasing E-cadherin expression, thus interfering with circulating PCa cell adhesion to microvascular endothelial cells and potentially reducing their metastatic potential.
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名稱A Positive Feedback Signaling Loop between ATM and the Vitamin D Receptor Is Critical for Cancer Chemoprevention by Vitamin D
年度2012
類別期刊論文
摘要Both epidemiologic and laboratory studies have shown the chemopreventive effects of 1α,25-dihydroxyvitamin D(3) (1,25-VD) in tumorigenesis. However, understanding of the molecular mechanism by which 1,25-VD prevents tumorigenesis remains incomplete. In this study, we used an established mouse model of chemical carcinogenesis to investigate how 1,25-VD prevents malignant transformation. In this model, 1,25-VD promoted expression of the DNA repair genes RAD50 and ATM, both of which are critical for mediating the signaling responses to DNA damage. Correspondingly, 1,25-VD protected cells from genotoxic stress and growth inhibition by promoting double-strand break DNA repair. Depletion of the vitamin D receptor (VDR) reduced these genoprotective effects and drove malignant transformation that could not be prevented by 1,25-VD, defining an essential role for VDR in mediating the anticancer effects of 1,25-VD. Notably, genotoxic stress activated ATM and VDR through phosphorylation of VDR. Mutations in VDR at putative ATM phosphorylation sites impaired the ability of ATM to enhance VDR transactivation activity, diminishing 1,25-VD-mediated induction of ATM and RAD50 expression. Together, our findings identify a novel vitamin D-mediated chemopreventive mechanism involving a positive feedback loop between the DNA repair proteins ATM and VDR.
關鍵字vitamin D, chemoprevention, DNA repair, phosphorylation, transcription
名稱Deficiency in TR4 nuclear receptor abrogates Gadd45a expression and increases cytotoxicity induced by ionizing radiation.
年度2012
類別期刊論文
摘要The testicular receptor 4 (TR4) is a member of the nuclear receptor superfamily that controls various biological activities. A protective role of TR4 against oxidative stress has recently been discovered. We here examined the protective role of TR4 against ionizing radiation (IR) and found that small hairpin RNA mediated TR4 knockdown cells were highly sensitive to IR-induced cell death. IR exposure increased the expression of TR4 in scramble control small hairpin RNA expressing cells but not in TR4 knockdown cells. Examination of IR-responsive molecules found that the expression of Gadd45a, the growth arrest and DNA damage response gene, was dramatically decreased in Tr4 deficient (TR4KO) mice tissues and could not respond to IR stimulation in TR4KO mouse embryonic fibroblast cells. This TR4 regulation of GADD45A was at the transcriptional level. Promoter analysis identified four potential TR4 response elements located in intron 3 and exon 4 of the GADD45A gene. Reporter and chromatin immunoprecipitation (ChIP) assays provided evidence indicating that TR4 regulated the GADD45A expression through TR4 response elements located in intron 3 of the GADD45A gene. Together, we find that TR4 is essential in protecting cells from IR stress. Upon IR challenges, TR4 expression is increased, thereafter inducing GADD45A through transcriptional regulation. As GADD45A is directly involved in the DNA repair pathway, this suggests that TR4 senses genotoxic stress and up-regulates GADD45A expression to protect cells from IR-induced genotoxicity.
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名稱Identification of microRNA-98 as a therapeutic target inhibiting prostate cancer growth and a biomarker induced by vitamin D.
年度2013
類別期刊論文
摘要The anti-tumor effect of vitamin D has been well recognized but its translational application is hindered by side effects induced by supra-physiological concentration of vitamin D required for cancer treatment. Thus, exploring vitamin D tumor suppressive functional mechanism can facilitate improvement of its clinical application. We screened miRNA profiles in response to vitamin D and found that a tumor suppressive miRNA, miR-98, is transcriptionally induced by 1alpha,25-dihydroxyvitamin D3 (1,25-VD) in LNCaP. Mechanistic dissection revealed that 1,25-VD-induced miR-98 is mediated through both a direct mechanism, enhancing the VDR binding response element in the promoter region of miR-98, and an indirect mechanism, down-regulating LIN-28 expression. Knockdown of miR-98 led to a reduction of 1,25-VD anti-growth effect and overexpression of miR-98 suppressed the LNCaP cells growth via inducing G2/M arrest. And CCNJ, a protein controlling cell mitosis, is down-regulated by miR-98 via targeting 3-untranslated region of CCNJ. Interestingly, miR-98 levels in blood are increased upon 1,25-VD treatment in mice suggesting the biomarker potential of miR-98 in predicting 1,25-VD response. Together, the finding that growth inhibitive miR-98 is induced by 1,25-VD provides a potential therapeutic target for prostate cancer and a potential biomarker for 1,25-VD anti-tumor action.
關鍵字Cancer Prevention, MicroRNA, Prostate Cancer, Transcription Regulation, Vitamin D
名稱Bladder Cancer Exosomes Contain EDIL-3/Del1 and Facilitate Cancer Progression.
年度2014
類別期刊論文
摘要PURPOSE: High-grade bladder cancer (HGBC) is an extremely aggressive malignancy associated with high rates of morbidity and mortality. Understanding how exosomes may affect BC progression could reveal novel therapeutic targets. MATERIALS AND METHODS: Exosomes derived from human BC cell lines and urine of patients with HGBC were assessed for their ability to promote cancer progression in standard assays. Exosomes purified from the HGBC cell line TCC-SUP and nonmalignant urothelial cell line SV-HUC were submitted for mass spectrometry analysis and EGF-like repeats and discoidin I-like domains 3 (EDIL-3) was identified and selected for further analysis. Western blotting analysis was used to determine EDIL-3 levels in urinary exosomes from patients with HGBC. ShRNA gene knockdown and recombinant EDIL-3 were applied to study EDIL-3 function. RESULTS: We show exosomes isolated from HGBC cells and urine of patients with HGBC promote angiogenesis and migration of BC cells and endothelial cells. We silenced the expression of EDIL-3 and found that shEDIL-3 exosomes did not facilitate angiogenesis and urothelial and endothelial cell migration. Moreover, exosomes purified from the urine of patients with HGBC also contain significantly higher levels of EDIL-3 than exosomes from the urine of healthy controls. Importantly, we show that EDIL-3 activates epidermal growth factor receptor (EGFR) signaling and blockade of EGFR signaling abrogated this EDIL-3 induced bladder cell migration. CONCLUSION: Exosomes derived from the urine of BC patients contains bioactive molecules, such as EDIL-3 and identification of these components and their associated oncogenic pathways could lead to novel therapeutic targets and treatment strategies.
關鍵字EDIL-3 protein; disease progression; exosomes; human; urinary bladder; urinary bladder neoplasms
名稱Identification of a new androgen receptor (AR) co-regulator BUD31 and related peptides to suppress wild-type and mutated AR-mediated prostate cancer growth via peptide screening and X-ray structure analysis
年度2014
類別期刊論文
摘要Treatment with individual anti-androgens is associated with the development of hot-spot mutations in the androgen receptor (AR). Here, we found that anti-androgens-mt-ARs have similar binary structure to the 5alpha-dihydrotestosterone-wt-AR. Phage display revealed that these ARs bound to similar peptides, including BUD31, containing an Fxx(F/H/L/W/Y)Y motif cluster with Tyr in the +5 position. Structural analyses of the AR-LBD-BUD31 complex revealed formation of an extra hydrogen bond between the Tyr+5 residue of the peptide and the AR. Functional studies showed that BUD31-related peptides suppressed AR transactivation, interrupted AR N-C interaction, and suppressed AR-mediated cell growth. Combination of peptide screening and X-ray structure analysis may serve as a new strategy for developing anti-ARs that simultaneously suppress both wt and mutated AR function.
關鍵字Androgen receptor; Anti-androgen withdrawal syndrome; BUD31; Crystallography;FxxLF
名稱Chemopreventive effect of vitamin D
年度2009
類別研討會
摘要
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名稱CIRCULATING ROLLING PROSTATE CANCER CELLS POTENTIATE METASTASIS: A MICRO-CHANNEL MODEL
年度2010
類別研討會
摘要INTRODUCTION AND OBJECTIVES: Cancer metastasis is the most dangerous and life-threatening phase of the disease. Thus,identification of the pathways that control cancer metastasis could facilitate strategies for development of early detection and treatment of cancer before invasion and metastasis. Adhesion between prostate cancer (PCa) cells and endothelial cells is a critical event for PCa cells to metastasize to distant organs. The objective of this study is to isolate subpopulations of circulating PCa cells that possess higher rolling and adhesion capacity, then confirm their cellular metastasis behavior. Also, molecular networks that control PCa metastasis will be defined. METHODS: A dynamic flow-based fractionation of PCa cells into adhesion (rolling) and non-adhesion (floating) subpopulations was performed. The gene profiles between these two subpopulations were compared using cancer metastasis focus Q-PCR array. The cellular metastasis potential was further confirmed by invasion and migration assays as well as an orthotopic implantation nude mice model. RESULTS: This dynamic microchannel model can capture a small population of PCa cells that have higher metastatic characteristics during the circulation phase. This subpopulation of PCa cells: rolling cells, indeed display much more aggressive behaviors in both in vitro assays (invasion and migration) and in vivo orthotopic PCa implantation mouse models. Gene profile analysis further confirmed that 29/84 metastatic-promoting genes were up-regulated in this rolling PCa subpopulation. CONCLUSIONS: Using this flow-based dynamic system we were able to capture a small portion of circulating PCa cells that possess higher metastatic potential. This strategy provides a powerful way to capture and interrupt PCa adhesion to the blood vessel during circulation, which might eventually slow down PCa progression. Furthermore, this dynamic functional fractionation system could be further extended as a general approach for sorting of diverse cancer cell populations based on differences in functional adhesion properties.
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名稱CIRCULATING VITAMIN D3 AND INTRA-PROSTATIC CYP27B1 IN PROSTATE TUMORIGENESIS
年度2010
類別研討會
摘要INTRODUCTION AND OBJECTIVES: Epidemiological and preclinical studies suggest vitamin D3 is one of the nutrients effectively inhibiting prostate tumorigenesis. Unfortunately, the concern of systemic side effects from high doses of vitamin D3 limits its application in the general population. Defining the lowest amount of vitamin D3 uptake that can effectively prevent prostate tumorigenesis will establish a guideline for general healthy population. To translate the preventive effect of active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1,25-VD) to clinical application, it is necessary to determine the effective dosage of the circulating form of vitamin D3, 25-hydroxyvitamin D3 (25-VD) in preventing tumorigenesis. CYP27B1 is the key enzyme converting 25-VD to 1,25-VD; therefore, this autocrine synthesis of 1,25-VD by prostate cells is one profound biochemical mechanism for the vitamin D chemopreventive action. The objective of this proposal is to determine the effective concentration of 25-VD in mediating the chemopreventive effect and elucidate intra-prostate CYP27B1 level as a new biomarker to predict individualism for prostate cancer development and behavior. METHODS: The protein expression level of CYP27B1 was detected in several immortalized normal prostate cell lines. The transactivity of vitamin D receptor induced by different concentrations of 25-VD was measured by a reporter assay and Q-PCR which detects target gene expression. The effective concentration of 25-VD in preventing tumorigenesis was examined in carcinogen-induced prostate epithelial cell transformation models. The role of CYP27B1 in mediating the preventive effect of 25-VD was investigated by targeting knockdown of CYP27B1 using shRNA and human prostate tissue microarray (TMA). RESULTS: The equivalent concentration of 25-VD that induced the same level of VDR transactivity as 100 nM of 1,25-VD was between 250-350 nM in these cell lines. This equivalent concentration of 25-VD could effectively prevent tumorigenesis in the parental non-alignantprostate epithelial cell line, but not in the CYP27B1 knockdown cell line. Human prostate TMA detected CYP27B1 expresseion in normal prostate, but not in the prostate cancer. CONCLUSIONS: Here we defined the effective concentration of 25-VD and the role of CYP27B1 in preventing malignant-transformation of prostate epithelial cells. This study provides a guideline for future administration of vitamin D3 supplement and indicates that the individual variation of CYP27B1 expression level could contribute to the efficacy of vitamin D3 supplementation in preventing prostate cancer.
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名稱CAPTURE AND ANALYSIS OF PROSTATE CANCER STEM CELLS USING A MICROCIRCULATORY CHANNEL
年度2012
類別研討會
摘要Introduction and Objectives Recent studies show that cancer stem cells (CSCs) are the source of all the malignant cells in a primary tumor; they compose the reservoir of drug-resistant cells that are responsible for recurrence, and they give rise to metastases. Therefore, isolation and characterization of CSCs would facilitate the development strategy for not only personalized cancer treatment to eliminate the CSCs, but also for increasing the treatment potency and reducing the side effects of multiple drug use. The objective of this study is to target CSCs in the course of tumor metastasis, so we used a dynamic microcirculatory channel device to capture circulating CSCs. Their behaviors and controlled signals were also analyzed in vivo and in vitro. Methods We used selectin and SDF-1 coated micro-renathane tube to mimic pro-metastatic vascular endothelial cell surface to capture circulating CSC under constant flow (shear stress 1 dyne/cm2). Based on their adhesion ability, cells were sorted into: adhesion fraction which contains potential CSC cells (pCSC) population, and non-adhesion fraction which were ‘non-CSC’ cells. The expression of stem cell and EMT markers was examined by quantitative PCR. The cancer cells’ behaviors, especially colony formation ability in the 3-D sphere forming assay and anchorage independent growth, and their sensitivity to the chemoprevention drug were examined. The tumorigenicity of these pCSC populations and their metastatic potential were further tested by an in vivo orthotopic xenografted mouse model. Results Sorted pCSC cells express higher transcripts of stem cell and EMT markers like CD133, CD44, CK5, Nestin, Snail, and Twist. These pCSCs exhibited higher numbers and larger colonies when cultured in soft agar media, forming larger sphere stem cell like colonies in 3-D culture. They were more resistant to vitamin D’s anti-tumor effects. PCSCs also show higher static adhesion to human dermal microvascular endothelial cells (HMEC-1) and are more invasive by the metrigel coated invasion assay. Furthermore, in orthotopic implantation 6 out of 6 mice developed prostate cancer in primary sites as well as distant organs-lymph node and lung, when received pCSCs. Strikingly, none of mice that received non-CSCs grew any tumors within 3 months. Conclusions This flow based device provides a platform for isolating the most dangerous CSCs from human patients’ samples. It opens up a process for customized cancer treatment which can have more potent action and also reduce the disadvantage of multiple drug side effects.
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名稱Urothelial carcinoma exosomes contain Del1/EDIL-3 and facilitate bladder cancer progression
年度2013
類別研討會
摘要Small membrane-bound vesicles called exosomes are proving to be critical mediators of tumor progression. Here we show, for the first time, that exosomes isolated from the urine of patients with high-grade bladder cancer facilitate tumor progression and contain the matrix-associated glycoprotein EGF-like repeats and discoidin I-like domains (EDIL-3 aka Del1). EDIL-3 is a well-known tumor-associated angiogenic factor and increased expression of EDIL-3 has been shown in numerous tumors to correlate with poor prognosis. We demonstrate, that exosome-derived EDIL-3 is important for angiogenesis as well as urothelial and endothelial cell migration. Importantly, we show that recombinant (r)EDIL-3 is sufficient to promote migration of human urothelial carcinoma 5637 cells and blockade of either the epidermal growth factor receptor (EGFR) and/or the EGFR signal transduction propagating integrin beta 1 abrogated this effect. These data suggest a novel mechanism by which EDIL-3 may be involved in signal transduction pathways in cancer.
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名稱UROTHELIAL CARCINOMA EXOSOMES PROMOTE CANCER PROGRESSION
年度2013
類別研討會
摘要INTRODUCTION AND OBJECTIVES: Exosomes are 30-200nm membrane bound vesicles that contain biologically active mRNA, miRNA, and protein. These vesicles have been purified from cell culture supernatants as well as bodily fluids such as saliva, serum and urine. A growing body of literature has emerged in support of roles for exosomes in normal and pathological processes. Here we show that exosomes isolated from high grade muscle invasive (HGMI) urothelial cell lines as well as urinary exosomes from patients with HGMI disease facilitate angiogenesis, invasion and migration. METHODS: Mass spectrometry analysis of exosomes from high grade urothelial carcinoma (HGUC) cell lines was performed. To test angiogenesis, exosomes from HGUC cells were applied to endothelial cells in tube formation assays. Standard invasion and migration assays were done with HGUC exosomes. siRNA knockdown of a candidate protein in HGUC cell exosomes was achieved. To identify the candidate protein in patients with HGMI disease, western blots on urinary exosomes versus healthy controls were performed and immunohistochemistry (IHC) staining on cystectomy tissue was done. Urinary exosomes from patients with HGMI were used in angiogenesis, migration and invasion assays. RESULTS: Exosomes from HGUC cells contain proteins with roles in tumor progression. HGUC exosomes promote angiogenesis and facilitate migration of both endothelial cell lines and lower grade urothelial carcinoma cells. HGUC cell exosomes also facilitate invasion. A candidate protein identified by mass spectrometry with known roles in angiogenesis, migration and invasion was selected from further analysis. siRNA knockdown (KD) of this protein resulted in loss of migration capacity. Moreover, western blots of exosomes isolated from the urine of patients with HGMI disease shows this protein. IHC staining of tissue isolated at cystectomy also demonstrated this protein. Moreover, exosomes from the urine of patients with HGMI disease were capable of facilitating migration, angiogenesis and invasion. CONCLUSIONS: There is increasing interest in the pathological roles exosomes play. We show that HGUC exosomes have the capacity to facilitate events critical in the promotion of tumor progression. Moreover, we identified a protein in HGUC cell lines and the urinary exosomes of patients with HGMI disease that is involved in migration, invasion and angiogenesis. Clearly the appeal of investigating urinary derived exosomes lies in their tractability. We anticipate that the protein we have identified may ultimately serve as a marker for HGUC and as a potential target for intravesicle therapy.
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