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Wang K, Zhao H, Wang W, Zhu Y, Zhang X, Ma J, Tan H, Zhang Y, Lin C. Effect of upregulation of DD3 on early detection and prognosis in prostate cancer. Transl Androl Urol 2020; 9:1550-1558. [PMID: 32944517 PMCID: PMC7475679 DOI: 10.21037/tau-19-899] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background Expression of prostate cancer antigen 3 (PCA3 OR DD3) in the blood has been reported to be significantly higher in prostate cancer (PCa) than in benign prostate hyperplasia (BPH). To confirm whether DD3 expression is significantly different between PCa and BPH tissues, DD3 expression was tested in the blood both preoperatively and postoperatively and in the paired tissues of PCa patients. Methods Expression levels of DD3 mRNA in the blood of patients who did not undergo surgery (PCa, n=102; BPH, n=53), those underwent surgery (preoperative, n=35; postoperative, n=35), and in PCa tissue specimens (tumor, n=41; adjacent normal, n=21) were determined by real-time quantitative PCR. Sensitivity and specificity for DD3 in PCa patients were validated by receiver operating characteristic (ROC) curve analysis. Results Our data suggest that expression level of DD3 in blood samples was significantly higher in PCa patients than in BPH patients (P=0.005). Expression of DD3 mRNA was also significantly elevated in PCa tissues compared with adjacent normal tissues (P=0.013). The increase in DD3 expression in PCa patients was further validated using a dataset from The Cancer Genome Atlas (n=549). Postoperative DD3 expression decreased following surgical intervention (P<0.001). Moreover, low DD3 expression was associated with improved overall survival (OS). Using gene set enrichment analysis, DD3 expression was correlated with specific PCa target genes including carcinogenesis-related and cancer proliferation-related genes. Conclusions This study demonstrated that expression of DD3 was upregulated in blood and PCa tumor tissues and was associated with prognosis. The oncogenic role of DD3 was further validated in the TCGA database, indicating that DD3 is a potential therapeutic target for PCa. Furthermore, this study suggests that DD3 expression could be considered as a prognostic biomarker for PCa.
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Affiliation(s)
- Ke Wang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Huishan Zhao
- Reproductive Medicine Centre, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Wenting Wang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yingqian Zhu
- Department of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuebao Zhang
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jiajia Ma
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Haotian Tan
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yulian Zhang
- Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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2
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Tao L, Qiu J, Slavin S, Ou Z, Liu Z, Ge J, Zuo L, Guancial EA, Messing EM, Chang C, Yeh S. Recruited T cells promote the bladder cancer metastasis via up-regulation of the estrogen receptor β/IL-1/c-MET signals. Cancer Lett 2018; 430:215-223. [PMID: 29684419 DOI: 10.1016/j.canlet.2018.03.045] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 12/25/2022]
Abstract
Clinical data indicates that T cells can be recruited to bladder cancer (BCa), yet the impact of T cells on BCa progression remains unclear. In the present study, we found that T cells were recruited more to BCa tissues than to the surrounding normal bladder tissues. Results from an in vitro co-culture system also found that BCa recruited more CD4+ T cells than did normal bladder cells. The recruiting of T cells to BCa tissues may increase the proliferation and invasion of BCa cells. Mechanistic studies revealed that infiltrating T cells stimulate BCa estrogen receptor beta (ERβ) signaling and consequently increase the expression of MET proto-oncogene, receptor tyrosine kinase (c-MET), through either direct binding to its promoter or via modulation of IL-1 expression. Interruption of ERβ/c-MET or ERβ/IL-1/c-MET signaling via ERβ-shRNA, IL-1 antagonist, or the c-MET inhibitor, SU11274, could partially reverse the T cell-enhanced BCa cell invasion and proliferation. Finally, the mouse BCa model with xenografted BCa 5637 cells with T (HH) cells confirmed the results of in vitro co-culture studies showing that infiltrating T cells could promote BCa metastasis via modulation of the ERβ/c-MET or ERβ/IL-1/c-MET signaling pathways. These findings may provide a new therapeutic approach to better combat BCa progression via targeting these newly identified signaling pathways.
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Affiliation(s)
- Le Tao
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China; Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Jianxin Qiu
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China.
| | - Spencer Slavin
- Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Zhenyu Ou
- Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Zhihong Liu
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Jifu Ge
- Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai 200080, China
| | - Li Zuo
- Department of Urology, Changzhou No. 2 People's Hospital Affiliated to Nanjing Medical University, Changzhou 213003, China
| | - Elizabeth A Guancial
- Department of Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Edward M Messing
- Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Chawnshang Chang
- Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | - Shuyuan Yeh
- Departments of Urology and Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
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Datta D, Aftabuddin M, Gupta DK, Raha S, Sen P. Human Prostate Cancer Hallmarks Map. Sci Rep 2016; 6:30691. [PMID: 27476486 PMCID: PMC4967902 DOI: 10.1038/srep30691] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022] Open
Abstract
Human prostate cancer is a complex heterogeneous disease that mainly affects elder male population of the western world with a high rate of mortality. Acquisitions of diverse sets of hallmark capabilities along with an aberrant functioning of androgen receptor signaling are the central driving forces behind prostatic tumorigenesis and its transition into metastatic castration resistant disease. These hallmark capabilities arise due to an intense orchestration of several crucial factors, including deregulation of vital cell physiological processes, inactivation of tumor suppressive activity and disruption of prostate gland specific cellular homeostasis. The molecular complexity and redundancy of oncoproteins signaling in prostate cancer demands for concurrent inhibition of multiple hallmark associated pathways. By an extensive manual curation of the published biomedical literature, we have developed Human Prostate Cancer Hallmarks Map (HPCHM), an onco-functional atlas of human prostate cancer associated signaling and events. It explores molecular architecture of prostate cancer signaling at various levels, namely key protein components, molecular connectivity map, oncogenic signaling pathway map, pathway based functional connectivity map etc. Here, we briefly represent the systems level understanding of the molecular mechanisms associated with prostate tumorigenesis by considering each and individual molecular and cell biological events of this disease process.
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Affiliation(s)
- Dipamoy Datta
- Department of Biotechnology, Siksha Bhavana, Visva-Bharati, Santiniketan 731235, India
| | - Md Aftabuddin
- Maulana Abul Kalam Azad University of Technology, West Bengal, Salt Lake, Sector-I, Kolkata 700064, India
| | - Dinesh Kumar Gupta
- School of Studies in Neuroscience, Jiwaji University, Gwalior 474011, India
| | - Sanghamitra Raha
- Department of Biotechnology, Siksha Bhavana, Visva-Bharati, Santiniketan 731235, India
| | - Prosenjit Sen
- Biological Chemistry Division, Indian Association for the Cultivation of Science, Kolkata 700032, India
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Lin Q, Sun MZ, Guo C, Shi J, Chen X, Liu S. CRKL overexpression suppresses in vitro proliferation, invasion and migration of murine hepatocarcinoma Hca-P cells. Biomed Pharmacother 2014; 69:11-7. [PMID: 25661331 DOI: 10.1016/j.biopha.2014.10.025] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 10/18/2014] [Indexed: 12/17/2022] Open
Abstract
The signal adaptor CRK family protein play important roles in cancer cell progression, proliferation, migration and invasion. Previously, we showed that CRK was involved in lymphatic metastatic potential of murine hepatocarcinoma cells. In current work, as a member of CRK family, chicken tumour virus number 10 regulator of kinase-like protein (CRKL) was revealed to be associated with malignant behaviors of Hca-P, a murine HCC cell with lymph node metastatic (LNM) rate of ∼25%. CRKL overexpression in Hca-P by a constructed eukaryotic expression vector of pcDNA3.1/V5-HisB-CRKL significantly ameliorated its malignant biological properties. CCK-8 and soft agar colony formation assays indicated CRKL overexpression significantly inhibits the cell proliferation and colony formation abilities of Hca-P. Additionally, transwell assays indicated that the Hca-P cell migration and invasion capacities were apparently reduced following CRKL overexpression. As Hca-P is an ideal hepatocarcinoma cell model with low (initial) LNM potential, CRKL is shown to act as a potential suppressor and to provide new insight for both the malignant behaviors of hepatocarcinoma cells and lymphatic metastasis mechanism of hepatocarcinoma.
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Affiliation(s)
- Qiuyue Lin
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China; Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Ming-Zhong Sun
- Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Chunmei Guo
- Department of Biotechnology, Dalian Medical University, 116044 Dalian, PR China
| | - Ji Shi
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China
| | - Xin Chen
- Department of General Surgery of The Second Hospital, Dalian Medical University, 116021 Dalian, PR China
| | - Shuqing Liu
- Department of Biochemistry, Dalian Medical University, 116044 Dalian, PR China; Provincial Key Laboratory of Cell and Molecular Biology, Dalian Medical University, 116044 Dalian, PR China.
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5
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CRKL protein overexpression enhances cell proliferation and invasion in pancreatic cancer. Tumour Biol 2014; 36:1015-22. [PMID: 25318601 DOI: 10.1007/s13277-014-2706-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 10/01/2014] [Indexed: 10/24/2022] Open
Abstract
CRKL is an adapter protein which is overexpressed in many malignant tumors and plays crucial roles in tumor progression. However, expression pattern and biological roles of CRKL in pancreatic cancer have not been examined. In the present study, we found that CRKL expression in pancreatic cancer specimens was higher than that in normal pancreatic tissues. Colony formation assay and Matrigel invasion assay showed that the overexpression of CRKL in Bxpc3 and Capan2 cell lines with low endogenous expression increased cell proliferation and invasion. Flow cytometry showed that CRKL promoted cell proliferation by facilitating cell cycle. Further analysis of cell cycle- and invasion-related molecules showed that CRKL upregulated cyclin D1, cyclin A, matrix metalloproteinase 2 (MMP2) expression, and phosphorylated extracellular signal (ERK)-regulated kinase. In conclusion, our study demonstrated that CRKL was overexpressed in human pancreatic cancers and contributed to pancreatic cancer cell proliferation and invasion through ERK signaling.
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Hu S, Li L, Yeh S, Cui Y, Li X, Chang HC, Jin J, Chang C. Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling. Mol Oncol 2014; 9:44-57. [PMID: 25135278 DOI: 10.1016/j.molonc.2014.07.013] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 07/14/2014] [Accepted: 07/14/2014] [Indexed: 12/31/2022] Open
Abstract
Early clinical studies suggested infiltrating T cells might be associated with poor outcomes in prostate cancer (PCa) patients. The detailed mechanisms how T cells contribute to PCa progression, however, remained unclear. Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokines-CXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamide in PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion. Targeting these newly identified signals via FGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion. Results from in vivo mouse models also confirmed the in vitro cell lines in co-culture studies. Together, these results concluded that infiltrating CD4(+) T cells could promote PCa metastasis via modulation of FGF11→miRNA-541→AR→MMP9 signaling. Targeting these newly identified signals may provide us a new potential therapeutic approach to better battle PCa metastasis.
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Affiliation(s)
- Shuai Hu
- Department of Urology, Peking University First Hospital, Beijing, China; George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Lei Li
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Yun Cui
- Department of Urology, Peking University First Hospital, Beijing, China
| | - Xin Li
- Department of Urology, Peking University First Hospital, Beijing, China
| | - Hong-Chiang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
| | - Jie Jin
- Department of Urology, Peking University First Hospital, Beijing, China.
| | - Chawnshang Chang
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA; Sex Hormone Research Center, China Medical University/Hospital, Taichung, Taiwan.
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Grubisha MJ, DeFranco DB. Local endocrine, paracrine and redox signaling networks impact estrogen and androgen crosstalk in the prostate cancer microenvironment. Steroids 2013; 78:538-41. [PMID: 23380371 PMCID: PMC3644803 DOI: 10.1016/j.steroids.2013.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Revised: 01/10/2013] [Accepted: 01/18/2013] [Indexed: 12/16/2022]
Abstract
Androgen receptor (AR) signaling is essential for the initial development and progression of prostate cancer (PCa) as well as the growth and survival of castration-resistant tumors. However, AR action may be opposed by estrogen receptor beta (ERß) that responds to androgen metabolites produced in the prostate. The balance between the activity of these two receptors is not only influenced by the steroidogenic capacity of the prostatic microenvironment but also by its redox status and local paracrine signals such as transforming growth factor-beta (TGF-ß). In this review, we highlight the studies that revealed select roles for AR and ERß in distinct compartments of the prostate cancer microenvironment. We also discuss new work that identified stromal-epithelial crosstalk through TGF-ß1 signaling that drives the production of reactive oxygen species in stromal cells thereby selectively limiting the anti-tumor activity of ERß in cancer cells. Therefore, any new therapeutic approaches that seek to limit AR but enhance ERß activity in PCa, must take into account potential adaptive changes in the tumor microenvironment that utilize paracrine signals and altered redox balance to divert local androgen metabolites towards AR at the expense of ERß.
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Affiliation(s)
- Melanie J. Grubisha
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 3051 Fifth Avenue, Pittsburgh, PA 15260 USA
| | - Donald B. DeFranco
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 3051 Fifth Avenue, Pittsburgh, PA 15260 USA
- Corresponding Author: Donald B. DeFranco, tel: 412-624-4259, fax: 412-648-7029,
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HMGB1: A Promising Therapeutic Target for Prostate Cancer. Prostate Cancer 2013; 2013:157103. [PMID: 23766911 PMCID: PMC3666291 DOI: 10.1155/2013/157103] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Accepted: 04/15/2013] [Indexed: 12/16/2022] Open
Abstract
High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment.
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Lu Y, Feng F, Yang Y, Gao X, Cui J, Zhang C, Zhang F, Xu Z, Qv J, Wang C, Zeng Z, Zhu Y, Yang Y. LINE-1 ORF-1p functions as a novel androgen receptor co-activator and promotes the growth of human prostatic carcinoma cells. Cell Signal 2013; 25:479-89. [DOI: 10.1016/j.cellsig.2012.11.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Revised: 11/01/2012] [Accepted: 11/05/2012] [Indexed: 11/27/2022]
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10
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Ferreira LB, Palumbo A, de Mello KD, Sternberg C, Caetano MS, de Oliveira FL, Neves AF, Nasciutti LE, Goulart LR, Gimba ERP. PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling. BMC Cancer 2012; 12:507. [PMID: 23130941 PMCID: PMC3544699 DOI: 10.1186/1471-2407-12-507] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 10/19/2012] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND PCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling. METHODS LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. RESULTS LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. CONCLUSIONS Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new possibilities of using PCA3 knockdown as an additional therapeutic strategy for PCa control.
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Affiliation(s)
- Luciana Bueno Ferreira
- Instituto Nacional do Câncer/Programa de Carcinogênese Molecular and Programa de Pós Graduação Stricto Sensu em Oncologia, Rio de Janeiro, Brazil
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Teixeira GR, Fávaro WJ, Pinheiro PFF, Chuffa LGA, Amorim JPA, Mendes LO, Fioruci BA, Oba E, Martins OA, Martinez M, Martinez FE. Physical exercise on the rat ventral prostate: Steroid hormone receptors, apoptosis and cell proliferation. Scand J Med Sci Sports 2012; 22:e86-92. [DOI: 10.1111/j.1600-0838.2012.01501.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/04/2012] [Indexed: 11/28/2022]
Affiliation(s)
- G. R. Teixeira
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - W. J. Fávaro
- Department of Structural and Functional Biology; UNICAMP - Univ Estadual de Campinas; Campinas; SP; Brazil
| | - P. F. F. Pinheiro
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - L. G. A. Chuffa
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - J. P. A. Amorim
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - L. O. Mendes
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - B. A. Fioruci
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - E. Oba
- Department of Animal Reproduction and Veterinary Radiology; Faculty Veterinary Medicine and Zootechny; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - O. A. Martins
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
| | - M. Martinez
- Department of Morphology and Pathology; UFSCar - Univ Federal de São Carlos; São Carlos; SP; Brazil
| | - F. E. Martinez
- Department of Anatomy; Institute of Biosciences; UNESP - Univ Estadual Paulista; Botucatu; SP; Brazil
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Abstract
MicroRNAs (miRNAs) are an abundant class of noncoding RNAs that function to regulate post-transcriptional gene expression, predominantly by translational repression. In addition to their role in prostate cancer initiation and progression, recent evidence suggests that miRNAs might also participate in treatment response across a range of therapies including radiation treatment, chemotherapy and androgen suppression. The mechanism of this regulation is thought to be multifactorial and is currently poorly understood. To date, only a small number of studies have examined the functional role of miRNAs in response to prostate cancer treatment. Elucidating the role of miRNAs in treatment response following radiotherapy, chemotherapy and androgen suppression will provide new avenues of investigation for the development of novel therapies for the treatment of prostate cancer.
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13
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Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol 2011; 2:384-96. [PMID: 22171281 PMCID: PMC3235657 DOI: 10.5306/wjco.v2.i12.384] [Citation(s) in RCA: 92] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 11/08/2011] [Accepted: 11/15/2011] [Indexed: 02/06/2023] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine involved in prostate regulation and in prostate cancer (PC) development/progression. IL-6 acts as a paracrine and autocrine growth stimulator in benign and tumor prostate cells. The levels of IL-6 and respective receptors are increased during prostate carcinogenesis and tumor progression. Several studies reported that increased serum and plasma IL-6 and soluble interleukin-6 receptor levels are associated with aggressiveness of the disease and are associated with a poor prognosis in PC patients. In PC treatment, patients diagnosed with advanced stages are frequently submitted to hormonal castration, although most patients will eventually fail this therapy and die from recurrent castration-resistant prostate cancer (CRPC). Therefore, it is important to understand the mechanisms involved in CRPC. Several pathways have been proposed to be involved in CRPC development, and their understanding will improve the way to more effective therapies. In fact, the prostate is known to be dependent, not exclusively, on androgens, but also on growth factors and cytokines. The signaling pathway mediated by IL-6 may be an alternative pathway in the CRPC phenotype acquisition and cancer progression, under androgen deprivation conditions. The principal goal of this review is to evaluate the role of IL-6 pathway signaling in human PC development and progression and discuss the interaction of this pathway with the androgen recepto pathway. Furthermore, we intend to evaluate the inclusion of IL-6 and its receptor levels as a putative new class of tumor biomarkers.The IL-6/IL-6R signaling pathway may be included as a putative molecular marker for aggressiveness in PC and it may be able to maintain tumor growth through the AR pathway under androgen-deprivation conditions. The importance of the IL-6/IL-6R pathway in regulation of PC cells makes it a good candidate for targeted therapy.
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Affiliation(s)
- Andreia Azevedo
- Andreia Azevedo, Virginia Cunha, Ana Luisa Teixeira, Rui Medeiros, Molecular Oncology and Virology, Portuguese Institute of Oncology, 4200-072 Porto, Portugal
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14
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Reebye V, Frilling A, Hajitou A, Nicholls JP, Habib NA, Mintz PJ. A perspective on non-catalytic Src homology (SH) adaptor signalling proteins. Cell Signal 2011; 24:388-392. [PMID: 22024281 DOI: 10.1016/j.cellsig.2011.10.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 10/10/2011] [Indexed: 12/27/2022]
Abstract
Intracellular adaptor signalling proteins are members of a large family of mediators crucial for signal transduction pathways. Structurally, these molecules contain one Src Homology 2 (SH2) domain and one or more Src Homology 3 (SH3) domain(s); with either a catalytic subunit, or with other non-catalytic modular subunits. Cells depend on these regulatory signalling molecules to transmit information to the nucleus from both external and internal cues including growth factors, cytokines and steroids. Although there is a vast library of adaptor signalling proteins expressed ubiquitously in cells, the vital role these SH containing proteins play in regulating cellular signalling lacks the recognition they deserve. Their target selection method via the SH domains is simple yet highly effective. The SH3 domain(s) interact with proteins that contain proline-rich motifs, whereas the SH2 domain only binds to proteins containing phosphotyrosine residues. This unique characteristic physically enables proteins from a diverse range of networks to assemble for amplification of a signalling event. The biological consequence generated from these adaptor signalling proteins in a constantly changing microenvironment have profound regulatory effect on cell fate decision particularly when this is involved in the progression of a diseased state.
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Affiliation(s)
- Vikash Reebye
- Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, W12 0NN, UK
| | - Andrea Frilling
- Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, W12 0NN, UK
| | - Amin Hajitou
- Imperial College London, Faculty of Medicine, Division of Experimental Medicine, London, W12 0NN, UK
| | - Joanna P Nicholls
- Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, W12 0NN, UK
| | - Nagy A Habib
- Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, W12 0NN, UK
| | - Paul J Mintz
- Imperial College London, Faculty of Medicine, Department of Surgery and Cancer, London, W12 0NN, UK.
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