Ren Jin - Academia.edu (original) (raw)

Papers by Ren Jin

Cancer research, 2004

Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with t... more Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with tumor progression and androgen-independent prostate cancer. However, the mechanisms by which NE cells influence prostate cancer growth and progression, especially after androgen ablation therapy, are poorly understood. To investigate the role of NE cells on prostate cancer growth, LNCaP xenograft tumors were implanted into nude mice. After the LNCaP tumors were established, the NE mouse prostate allograft (NE-10) was implanted on the opposite flank of these nude mice to test whether NE tumor-derived systemic factors can influence LNCaP growth. Mice bearing LNCaP tumors with or without NE allografts were castrated 2 weeks after NE tumor inoculation, and changes in LNCaP tumor growth rate and gene expression were investigated. After castration, LNCaP tumor growth decreased in mice bearing LNCaP tumors alone, and this was accompanied by a loss of nuclear androgen receptor (AR) localization. ...

Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regr... more Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. How- ever, the tumor will progress to an ''androgen-independent'' stage that results in renewed growth and spread of the cancer. Both nuclear factor-K B( NF -KB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is

Cancer Letters, 2004

We examined the functional role of clusterin in chemotherapy-induced apoptosis and tested whether... more We examined the functional role of clusterin in chemotherapy-induced apoptosis and tested whether anti-sense transfection targeted against clusterin enhances the chemosensitivity in human bladder cancer cells in vitro. Clusterin mRNA and protein expression of 253J cells, a human bladder carcinoma cell line, after treatment with cisplatin were measured by RT-PCR and Western blot analysis. Clusterin expression and cell growth were

Androgen Action in Prostate Cancer, 2009

... David J. DeGraff, Xiuping Yu, Qian Sun, Janni Mirosevich, Ren Jie Jin, Yongqing Wang, Aparna ... more ... David J. DeGraff, Xiuping Yu, Qian Sun, Janni Mirosevich, Ren Jie Jin, Yongqing Wang, Aparna Gupta, Srinivas Nandana, Thomas Case, Manik Paul, Hong-Ying Huang, Ellen Shapiro, Susan ... Reprinted with permission of John Wiley & Sons, Inc., Prostate 62:339–352, (2005) ...

Laboratory Investigation, 2006

Cell cultures representing different stages of prostatic carcinoma will be a useful tool allowing... more Cell cultures representing different stages of prostatic carcinoma will be a useful tool allowing a more complete understanding of the role of individual genes in tumorigenesis. We used the androgen-regulated probasin promoter linked to the neomycin phosphotransferase (Neo) gene, to generate the ARR 2 PBneo transgenic mouse model. Development was normal and all six ARR 2 PBneo transgenic founder lines expressed the Neo gene in a prostate-specific manner. Line C, which expressed high levels of neo, was crossbred to LPB-Tag 12T-7f transgenic mice (in which the SV40 large T antigen (Tag) was targeted to the prostate by the large probasin (LPB) promoter). Three bigenic males (carrying both Neo and Tag transgenes) were identified. Prostatic lesions developed in these mice in a predictable and heritable manner, indicating that Neo did not alter Tag-induced prostate tumor development and progression. Three separate NeoTag epithelial cell strains were established from three bigenic mice. G418 selection was used to obtain immortalized epithelial cells in culture. Selected cells expressed the Neo and Tag transgenes, cytokeratins 8 and 18, and were androgen responsive for growth. To determine if these NeoTag cells maintained a similar in vivo phenotype to the 12T-7f transgenic line, tissue recombinations were made with rat urogenital sinus mesenchyme (rUGM) and grafted under the renal capsule of male nude mouse hosts. In recombinants, the three NeoTag strains developed PIN lesions and/or more extensive adenocarcinoma than seen in the 12T-7f mouse. Androgen ablation demonstrated that the grafts were androgen responsive. NeoTag cells grafted without rUGM developed undifferentiated adenocarcinoma demonstrating that prostatic stroma dictates the glandular architecture seen in the well-differentiated adenocarcinoma.

Differentiation, 2008

Androgen receptor (AR) within prostatic mesenchymal cells, with the absence of AR in the epitheli... more Androgen receptor (AR) within prostatic mesenchymal cells, with the absence of AR in the epithelium, is still sufficient to induce prostate development. AR in the luminal epithelium is required to express the secretory markers associated with differentiation. Nkx3.1 is expressed in the epithelium in early prostatic embryonic development and expression is maintained in the adult. Induction of the mouse prostate gland by the embryonic mesenchymal cells results in the organization of a sparse basal layer below the luminal epithelium with rare neuroendocrine cells that are interdispersed within this basal layer. The human prostate shows similar glandular organization; however, the basal layer is continuous. The strong inductive nature of embryonic prostatic and bladder mesenchymal cells is demonstrated in grafts where embryonic stem (ES) cells are induced to differentiate and organize as a prostate and bladder, respectively. Further, the ES cells can be driven by the correct embryonic mesenchymal cells to form epithelium that differentiates into secretory prostate glands and differentiated bladders that produce uroplakin. This requires the ES cells to mature into endoderm that gives rise to differentiated epithelium. This process is control by transcription factors in both the inductive mesenchymal cells (AR) and the responding epithelium (FoxA1 and Nkx3.1) that allows for organ development and differentiation. In this review, we explore a molecular mechanism where the pattern of transcription factor expression controls cell determination, where the cell is assigned a developmental fate and subsequently cell differentiation, and where the assigned cell now emerges with it's own unique character.

Cancer Research, 2008

Typically, the initial response of a prostate cancer patient to androgen-ablation therapy is regr... more Typically, the initial response of a prostate cancer patient to androgen-ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" (AI) stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappa B (NF-κB) expression and neuroendocrine differentiation predicts poor prognosis but their precise contribution to prostate cancer progression is unknown. This report demonstrates that secretory proteins from neuroendocrine cells will activate the NF-κB pathway in LNCaP cells resulting in increased levels of active androgen receptor (AR). By blocking NF-κB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-κB signaling in vivo, by the absence of the IκBα inhibitor, prevents regression of the prostate after castration by sustaining high levels of nuclear AR, maintaining differentiated function and renewed proliferation of the epithelium. Furthermore, the NF-κB pathway was activated in the ARR 2 PB-myc-PAI (Hi-myc) mouse prostate by cross breeding into a IκBα +/ − haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-κB is sufficient to maintain AI growth of prostate and prostate cancer by regulating AR action. Thus, the NF-κB pathway may be a potential target for therapy against AI prostate cancer.

Cancer Gene Therapy, 2000

Angiogenesis is a critical event for solid tumor growth and metastasis. Within a given microenvir... more Angiogenesis is a critical event for solid tumor growth and metastasis. Within a given microenvironment, the angiogenic response is determined in part by the balance between angiogenesis inducers and inhibitors. The aim of this study was to establish a thrombospondin -1 ( TSP -1 ) ( an antiangiogenic gene ) expression vector, and to determine the feasibility for use of TSP -1 in prostate cancer gene therapy. The results of this study showed that pCR -TSP -1, the cloned TSP -1 expression plasmid vector, expressed the TSP -1 gene efficiently in DU145, a human prostate cancer cell line. pCR -TSP -1 did not exert any significant growth inhibitory activity on the tested cell line in vitro. However, TSP -1 overexpression inhibited the growth of DU -145 xenografts in Balb / c nude mice when directly transfected with pCR -TSP -1 in combination with a liposomal agent ( DOSPER ) . Histological analysis showed that there were extensive areas of necrosis in the TSP -1 overexpressing tumors, whereas no necrotic foci were observed in the control tumors. Furthermore, the microvessel density was lower in the TSP -1 overexpressing tumors compared to the control tumors. These results suggest that TSP -1 may be a potentially useful gene for prostate cancer gene therapy. Cancer Gene Therapy ( 2000 ) 7, 1537 ± 1542

Cancer and Metastasis Reviews, 2014

When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Pros... more When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for "prostate cancer mouse model" yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin promoter driving viral oncogenes such as Simian virus 40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and overexpression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question?

Cancer Research, 2008

p57 Kip2 has been considered a candidate tumor suppressor gene because of its location in the gen... more p57 Kip2 has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57 Kip2 in tumorigenesis and cancer progression. Here, we show that the expression of p57 Kip2 is significantly decreased in human prostate cancer, and the overexpression of p57 Kip2 in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57 Kip2 in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57 Kip2 knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57 Kip2 is an important gene in prostate cancer tumorigenesis, and the p57 Kip2 pathway may be a potential target for prostate cancer prevention and therapy.

Cancer research, 2004

Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with t... more Increases in neuroendocrine (NE) cells and their secretory products are closely correlated with tumor progression and androgen-independent prostate cancer. However, the mechanisms by which NE cells influence prostate cancer growth and progression, especially after androgen ablation therapy, are poorly understood. To investigate the role of NE cells on prostate cancer growth, LNCaP xenograft tumors were implanted into nude mice. After the LNCaP tumors were established, the NE mouse prostate allograft (NE-10) was implanted on the opposite flank of these nude mice to test whether NE tumor-derived systemic factors can influence LNCaP growth. Mice bearing LNCaP tumors with or without NE allografts were castrated 2 weeks after NE tumor inoculation, and changes in LNCaP tumor growth rate and gene expression were investigated. After castration, LNCaP tumor growth decreased in mice bearing LNCaP tumors alone, and this was accompanied by a loss of nuclear androgen receptor (AR) localization. ...

Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regr... more Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. How- ever, the tumor will progress to an ''androgen-independent'' stage that results in renewed growth and spread of the cancer. Both nuclear factor-K B( NF -KB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is

Cancer Letters, 2004

We examined the functional role of clusterin in chemotherapy-induced apoptosis and tested whether... more We examined the functional role of clusterin in chemotherapy-induced apoptosis and tested whether anti-sense transfection targeted against clusterin enhances the chemosensitivity in human bladder cancer cells in vitro. Clusterin mRNA and protein expression of 253J cells, a human bladder carcinoma cell line, after treatment with cisplatin were measured by RT-PCR and Western blot analysis. Clusterin expression and cell growth were

Androgen Action in Prostate Cancer, 2009

... David J. DeGraff, Xiuping Yu, Qian Sun, Janni Mirosevich, Ren Jie Jin, Yongqing Wang, Aparna ... more ... David J. DeGraff, Xiuping Yu, Qian Sun, Janni Mirosevich, Ren Jie Jin, Yongqing Wang, Aparna Gupta, Srinivas Nandana, Thomas Case, Manik Paul, Hong-Ying Huang, Ellen Shapiro, Susan ... Reprinted with permission of John Wiley & Sons, Inc., Prostate 62:339–352, (2005) ...

Laboratory Investigation, 2006

Cell cultures representing different stages of prostatic carcinoma will be a useful tool allowing... more Cell cultures representing different stages of prostatic carcinoma will be a useful tool allowing a more complete understanding of the role of individual genes in tumorigenesis. We used the androgen-regulated probasin promoter linked to the neomycin phosphotransferase (Neo) gene, to generate the ARR 2 PBneo transgenic mouse model. Development was normal and all six ARR 2 PBneo transgenic founder lines expressed the Neo gene in a prostate-specific manner. Line C, which expressed high levels of neo, was crossbred to LPB-Tag 12T-7f transgenic mice (in which the SV40 large T antigen (Tag) was targeted to the prostate by the large probasin (LPB) promoter). Three bigenic males (carrying both Neo and Tag transgenes) were identified. Prostatic lesions developed in these mice in a predictable and heritable manner, indicating that Neo did not alter Tag-induced prostate tumor development and progression. Three separate NeoTag epithelial cell strains were established from three bigenic mice. G418 selection was used to obtain immortalized epithelial cells in culture. Selected cells expressed the Neo and Tag transgenes, cytokeratins 8 and 18, and were androgen responsive for growth. To determine if these NeoTag cells maintained a similar in vivo phenotype to the 12T-7f transgenic line, tissue recombinations were made with rat urogenital sinus mesenchyme (rUGM) and grafted under the renal capsule of male nude mouse hosts. In recombinants, the three NeoTag strains developed PIN lesions and/or more extensive adenocarcinoma than seen in the 12T-7f mouse. Androgen ablation demonstrated that the grafts were androgen responsive. NeoTag cells grafted without rUGM developed undifferentiated adenocarcinoma demonstrating that prostatic stroma dictates the glandular architecture seen in the well-differentiated adenocarcinoma.

Differentiation, 2008

Androgen receptor (AR) within prostatic mesenchymal cells, with the absence of AR in the epitheli... more Androgen receptor (AR) within prostatic mesenchymal cells, with the absence of AR in the epithelium, is still sufficient to induce prostate development. AR in the luminal epithelium is required to express the secretory markers associated with differentiation. Nkx3.1 is expressed in the epithelium in early prostatic embryonic development and expression is maintained in the adult. Induction of the mouse prostate gland by the embryonic mesenchymal cells results in the organization of a sparse basal layer below the luminal epithelium with rare neuroendocrine cells that are interdispersed within this basal layer. The human prostate shows similar glandular organization; however, the basal layer is continuous. The strong inductive nature of embryonic prostatic and bladder mesenchymal cells is demonstrated in grafts where embryonic stem (ES) cells are induced to differentiate and organize as a prostate and bladder, respectively. Further, the ES cells can be driven by the correct embryonic mesenchymal cells to form epithelium that differentiates into secretory prostate glands and differentiated bladders that produce uroplakin. This requires the ES cells to mature into endoderm that gives rise to differentiated epithelium. This process is control by transcription factors in both the inductive mesenchymal cells (AR) and the responding epithelium (FoxA1 and Nkx3.1) that allows for organ development and differentiation. In this review, we explore a molecular mechanism where the pattern of transcription factor expression controls cell determination, where the cell is assigned a developmental fate and subsequently cell differentiation, and where the assigned cell now emerges with it's own unique character.

Cancer Research, 2008

Typically, the initial response of a prostate cancer patient to androgen-ablation therapy is regr... more Typically, the initial response of a prostate cancer patient to androgen-ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" (AI) stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappa B (NF-κB) expression and neuroendocrine differentiation predicts poor prognosis but their precise contribution to prostate cancer progression is unknown. This report demonstrates that secretory proteins from neuroendocrine cells will activate the NF-κB pathway in LNCaP cells resulting in increased levels of active androgen receptor (AR). By blocking NF-κB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-κB signaling in vivo, by the absence of the IκBα inhibitor, prevents regression of the prostate after castration by sustaining high levels of nuclear AR, maintaining differentiated function and renewed proliferation of the epithelium. Furthermore, the NF-κB pathway was activated in the ARR 2 PB-myc-PAI (Hi-myc) mouse prostate by cross breeding into a IκBα +/ − haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-κB is sufficient to maintain AI growth of prostate and prostate cancer by regulating AR action. Thus, the NF-κB pathway may be a potential target for therapy against AI prostate cancer.

Cancer Gene Therapy, 2000

Angiogenesis is a critical event for solid tumor growth and metastasis. Within a given microenvir... more Angiogenesis is a critical event for solid tumor growth and metastasis. Within a given microenvironment, the angiogenic response is determined in part by the balance between angiogenesis inducers and inhibitors. The aim of this study was to establish a thrombospondin -1 ( TSP -1 ) ( an antiangiogenic gene ) expression vector, and to determine the feasibility for use of TSP -1 in prostate cancer gene therapy. The results of this study showed that pCR -TSP -1, the cloned TSP -1 expression plasmid vector, expressed the TSP -1 gene efficiently in DU145, a human prostate cancer cell line. pCR -TSP -1 did not exert any significant growth inhibitory activity on the tested cell line in vitro. However, TSP -1 overexpression inhibited the growth of DU -145 xenografts in Balb / c nude mice when directly transfected with pCR -TSP -1 in combination with a liposomal agent ( DOSPER ) . Histological analysis showed that there were extensive areas of necrosis in the TSP -1 overexpressing tumors, whereas no necrotic foci were observed in the control tumors. Furthermore, the microvessel density was lower in the TSP -1 overexpressing tumors compared to the control tumors. These results suggest that TSP -1 may be a potentially useful gene for prostate cancer gene therapy. Cancer Gene Therapy ( 2000 ) 7, 1537 ± 1542

Cancer and Metastasis Reviews, 2014

When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Pros... more When the National Institutes of Health Mouse Models of Human Cancer Consortium initiated the Prostate Steering Committee 15 years ago, there were no genetically engineered mouse (GEM) models of prostate cancer (PCa). Today, a PubMed search for "prostate cancer mouse model" yields 3,200 publications and this list continues to grow. The first generation of GEM utilized the newly discovered and characterized probasin promoter driving viral oncogenes such as Simian virus 40 large T antigen to yield the LADY and TRAMP models. As the PCa research field has matured, the second generation of models has incorporated the single and multiple molecular changes observed in human disease, such as loss of PTEN and overexpression of Myc. Application of these models has revealed that mice are particularly resistant to developing invasive PCa, and once they achieve invasive disease, the PCa rarely resembles human disease. Nevertheless, these models and their application have provided vital information on human PCa progression. The aim of this review is to provide a brief primer on mouse and human prostate histology and pathology, provide descriptions of mouse models, as well as attempt to answer the age old question: Which GEM model of PCa is the best for my research question?

Cancer Research, 2008

p57 Kip2 has been considered a candidate tumor suppressor gene because of its location in the gen... more p57 Kip2 has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57 Kip2 in tumorigenesis and cancer progression. Here, we show that the expression of p57 Kip2 is significantly decreased in human prostate cancer, and the overexpression of p57 Kip2 in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57 Kip2 in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57 Kip2 knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57 Kip2 is an important gene in prostate cancer tumorigenesis, and the p57 Kip2 pathway may be a potential target for prostate cancer prevention and therapy.