Publications by authors named "Shifeng Su"

25 Publications

  • Page 1 of 1

Genetic variations in MAGE-A11 predict the risk and survival of renal cell cancer.

J Cancer 2019 27;10(20):4860-4865. Epub 2019 Aug 27.

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Melanoma antigen-A11 () is a low-abundance, primate-specific steroid receptor coregulator in normal tissues of the human reproductive tract, which plays an important role in tumorigenesis. Single-nucleotide polymorphisms (SNPs) have been shown to contribute to cancer risk and prognosis. However, the role of SNPs of in renal cell carcinoma (RCC) has not been established. Two intronic SNPs (rs6641352 and rs6540341) of have been screened to assess their associations with RCC risk and prognosis in a case control study. We found that rs6641352 was associated with RCC susceptibility in the dominant model (TC/CC vs. TT, adjusted odds ratio = 1.315, 95% confidence interval [CI] = 1.089-1.588) and with survival of RCC in the recessive model (CC vs. TT/TC, adjusted hazard ratio = 3.526, 95% CI = 1.072-11.595). For the SNP rs6540341, individuals with the T allele could have a critically increased risk of RCC (adjusted odds ratio = 1.301, 95% CI = 1.081-1.564, = 0.005 in the dominant model). However, there was no significant association between rs6540341 and RCC survival. Hence, rs6641352 in may contribute to the genetic susceptibility and prognosis for RCC and act as a biomarker for RCC occurrence and prognosis.
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http://dx.doi.org/10.7150/jca.32675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775520PMC
August 2019

MicroRNA-126 inhibits proliferation and metastasis in prostate cancer via regulation of ADAM9.

Oncol Lett 2018 Jun 18;15(6):9051-9060. Epub 2018 Apr 18.

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.

The aberrant expression of microRNAs (miRs) has been identified to serve a crucial role in tumor progression. The present study aimed to evaluate the role of miR-126 in human prostate cancer (PCa). Firstly, miR-126 expression in prostate cancer tissues and cell lines was analyzed. A luciferase reporter assay and a rescue assay were performed, which identified ADAM metalloproteinase domain 9 (ADAM9) as the target gene of miR-126. Subsequently, Kaplan-Meier and log-rank analyses were used to investigate the association between ADAM9 expression and PCa prognosis. The results revealed that miR-126 expression was significantly downregulated in PCa tissues and cell lines. miR-126 overexpression was demonstrated to reduce PCa cell proliferation and metastasis, and to reverse the epithelial-mesenchymal transition process . In addition, as the target gene of miR-126, the upregulation of ADAM9 reestablished cell functions, including cell proliferation, migration and invasion. Patients with high ADAM9 expression levels exhibited a shorter biochemical recurrence-free survival time. In summary, miR-126 serves a role in the proliferation and metastasis of PCa cells, indicating that miR-126 and ADAM9 may represent potential biomarkers in the progression of advanced PCa, in addition to therapeutic targets.
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http://dx.doi.org/10.3892/ol.2018.8528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958673PMC
June 2018

Clinicopathological and Prognostic Role of Long Noncoding RNA Linc00152 in Various Human Neoplasms: Evidence from Meta-Analysis.

Biomed Res Int 2017 23;2017:6010721. Epub 2017 Nov 23.

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Recent researches have demonstrated that long noncoding RNA linc00152 was aberrantly upregulated in multiple tumor types. High expression of linc00152 was associated with poor outcomes in cancer patients. Therefore, we conducted this meta-analysis to evaluate its potential value as a prognostic predictor in various human neoplasms. Eligible studies were searched through several electronic databases including PubMed, Embase, Web of Science, and the Cochrane Library. Eight original studies including 752 cancer patients were ultimately enrolled. Statistical analysis suggested that overexpression of linc00152 was significantly correlated with unfavorable overall survival (OS) (HR = 2.05, 95% CI: 1.59-2.64) and disease-free/progression-free survival (DFS/PFS) (HR = 3.52, 95% CI: 1.82-6.79) in cancer patients. In addition, a significant correlation was observed between aberrant linc000152 expression and lymph node metastasis (LNM) (OR = 2.49, 95% CI: 1.57-3.94) but not in vessel invasion (VI) (OR = 1.02, 95% CI: 0.54-1.93) and distant metastasis (DM) (OR = 0.600, 95% CI: 0.213-1.689). Our meta-analysis demonstrated that high linc00152 expression significantly predicted inferior OS and DFS/PFS in multiple neoplasms, as well as advanced LNM and VI. Linc00152 may serve as a potential indicator in predicting poor outcomes and metastases of diverse cancers.
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http://dx.doi.org/10.1155/2017/6010721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733223PMC
July 2018

Overexpression of CAPN2 promotes cell metastasis and proliferation via AKT/mTOR signaling in renal cell carcinoma.

Oncotarget 2017 Nov 26;8(58):97811-97821. Epub 2017 Oct 26.

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

The calpain 2 (CAPN2) is upregulated in various malignant carcinomas. Previous studies have reported that CAPN2 functioned as an oncogenic factor in human cancers. However, its clinical role and potential effects on cell metastasis and proliferation in renal cell carcinoma (RCC) remain unknown. In this study, we evaluated the mRNA and protein levels of CAPN2 in human RCC specimens, matched normal specimens, and RCC cell lines using quantitative Real-time PCR (RT-PCR) and western blot. Immunohistochemistry of 74 RCC tissues in a tissue microarrays (TMAs) and normal kidney tissues were performed. Kaplan-Meier survival curve analyses were conducted to measure the correlation between CAPN2 and tumor prognosis. Cell migration, invasion and proliferation were detected by transwell assays and Cell Counting Kit-8 (CCK-8) assays. CAPN2 exhibited a significant overexpression in human RCC tissues and cell lines compared with adjacent non-tumor tissues and normal human proximal tubule epithelial cell line HK-2. Strong staining of CAPN2 was associated with higher clinical stage and histological grade. In addition, sh-CAPN2 could significantly inhibit migration, invasion and proliferation of 769-P and CAKI-1 cells. Conversely, increased cell biological behaviors were observed in CAPN2-OV CAKI-2 cells. Moreover, the subsequent mechanism investigation suggested that CAPN2 promoted tumor progression by activating AKT/mTOR signaling, enhancing epithelial mesenchymal transition (EMT) and MMP9 levels. The present study indicates that CAPN2 may act as a prominent indicator for RCC progression and a novel therapeutic target for RCC patients.
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http://dx.doi.org/10.18632/oncotarget.22083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716693PMC
November 2017

The metastasis suppressor CD82/KAI1 regulates cell migration and invasion via inhibiting TGF-β 1/Smad signaling in renal cell carcinoma.

Oncotarget 2017 Aug 23;8(31):51559-51568. Epub 2017 May 23.

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

The tetraspanin KAI1/CD82 was identified as a tumor metastasis suppressor that downregulated in various malignant cell types. However, the function of CD82 and its underlying anti-metastasis role in renal cell carcinoma (RCC) is still unraveled. Here, we investigated the expression of CD82 in RCC and explored its regulatory mechanism in RCC cell lines. We found that CD82 was down-regulated in RCC tissues and cells and its expression was significantly associated with histological grade(p=0.041), tumour stage (p=0.036) and tumor size(p=0.020) by analyzing tissue microarrays. After upregulation of CD82 through lentivirus, reduced ability of migration and invasion in Caki-1 cells were detected. In contrast, gene silencing of CD82 by small interfering RNA promoted metastatic and invasive potential of 786-O cells. Furthermore, Western blot was performed to identify the influence of CD82 on MMP family and TGF-β1/Smad pathway in RCC. Subsequently, upregulating protein level of TGF-β1 with the overexpression of CD82 could rescue the malignant behaviors inhibited by CD82 which indicated that CD82 played its inhibitory role in RCC partially by attenuating the expression of TGF-β1. Taken together, CD82 played a prominent role in migration and invasion of RCC cells and it might exhibit its inhibitory role in RCC metastasis via block TGF-β1/Smad signaling pathway.
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http://dx.doi.org/10.18632/oncotarget.18086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584269PMC
August 2017

Prognostic role of matrix metalloproteinases in bladder carcinoma: a systematic review and meta-analysis.

Oncotarget 2017 May;8(19):32309-32321

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.

Recent studies have shown that matrix metalloproteinases (MMPs) might be a biomarker for predicting outcomes of bladder cancer. However, the prognostic value of overexpression of MMPs in bladder cancer is debatable and the studies are inconsistent. Therefore, this meta-analysis was performed to clarify the specific association and prognostic value of overexpression of MMPs in bladder carcinoma. Relevant studies were identified by searching PubMed, EMBASE, and the Web of Science. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for disease-specific survival (DSS), overall survival (OS), disease/recurrence-free survival (DFS/RFS), and progression/metastasis-free survival (PFS/MFS) were analyzed to determine the prognostic value of MMPs. In total, eighteen applicable studies were included in this meta-analysis. We found that high expression of MMPs significantly correlated with a poor DSS and OS (HR=1.66; 95% CI = 1.38-2.01 and HR= 1.67; 95%CI= 1.26-2.22). MMPs also predicted tumor progression and metastasis with a pooled HR of 3.03 (95% CI 1.98-4.64). However, high MMPs expression had no pivotal impact on DFS/RFS (HR= 1.21; 95% CI= 0.96-1.53). With the purpose of better understanding the prognostic role of MMPs in patients wirh bladder carcinoma, we carried out this systematic review and meta-analysis.
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http://dx.doi.org/10.18632/oncotarget.15907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458286PMC
May 2017

Silencing Trim59 inhibits invasion/migration and epithelial-to-mesenchymal transition via TGF-β/Smad2/3 signaling pathway in bladder cancer cells.

Onco Targets Ther 2017 9;10:1503-1512. Epub 2017 Mar 9.

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.

The evolutionarily conserved genes that encode the tripartite motif (TRIM) protein family are involved in various biological processes, including cellular immunity, inflammatory reaction, antiviral activity, and tumor progression. One member of this protein family, Trim59, has been reported as a novel biomarker for the occurrence and progression of multiple human carcinomas, such as lung cancer, gastric cancer, cervical cancer, and osteosarcoma. However, little is known about the relationship between Trim59 and bladder carcinogenesis. In this study, we examined the expression of Trim59 in bladder cancer (Bca) specimens and cell lines, and investigated its biological roles in Bca cell lines. We found that Trim59 was upregulated in Bca tissues and cell lines. In addition, using transwell chamber assays and the cell scratch test, we determined that knockdown of Trim59 significantly inhibited the epithelial-mesenchymal transition (EMT) and the processes of cell invasion and migration in Bca cell lines. Furthermore, we found that downregulated Trim59 expression could also inhibit cell proliferation and promote apoptosis. As a result, we demonstrated that the effects of Trim59-induced EMT and invasion/migration in Bca cells were achieved by the activation of the transforming growth factor beta/Smad2/3 signaling pathway. Our findings also revealed that Trim59 can present oncogenic activity, and may serve as a novel candidate target for bladder carcinoma treatment.
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http://dx.doi.org/10.2147/OTT.S130139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352237PMC
March 2017

Up-Regulation of Follistatin-Like 1 By the Androgen Receptor and Melanoma Antigen-A11 in Prostate Cancer.

Prostate 2017 04 14;77(5):505-516. Epub 2016 Dec 14.

Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina.

Background: High affinity androgen binding to the androgen receptor (AR) activates genes required for male sex differentiation and promotes the development and progression of prostate cancer. Human AR transcriptional activity involves interactions with coregulatory proteins that include primate-specific melanoma antigen-A11 (MAGE-A11), a coactivator that increases AR transcriptional activity during prostate cancer progression to castration-resistant/recurrent prostate cancer (CRPC).

Methods: Microarray analysis and quantitative RT-PCR were performed to identify androgen-regulated MAGE-A11-dependent genes in LAPC-4 prostate cancer cells after lentivirus shRNA knockdown of MAGE-A11. Chromatin immunoprecipitation was used to assess androgen-dependent AR recruitment, and immunocytochemistry to localize an androgen-dependent protein in prostate cancer cells and tissue and in the CWR22 human prostate cancer xenograft.

Results: Microarray analysis of androgen-treated LAPC-4 prostate cancer cells indicated follistatin-like 1 (FSTL1) is up-regulated by MAGE-A11. Androgen-dependent up-regulation of FSTL1 was inhibited in LAPC-4 cells by lentivirus shRNA knockdown of AR or MAGE-A11. Chromatin immunoprecipitation demonstrated AR recruitment to intron 10 of the FSTL1 gene that contains a classical consensus androgen response element. Increased levels of FSTL1 protein in LAPC-4 cells correlated with higher levels of MAGE-A11 relative to other prostate cancer cells. FSTL1 mRNA levels increased in CRPC and castration-recurrent CWR22 xenografts in association with predominantly nuclear FSTL1. Increased nuclear localization of FSTL1 in prostate cancer was suggested by predominantly cytoplasmic FSTL1 in benign prostate epithelial cells and predominantly nuclear FSTL1 in epithelial cells in CRPC tissue and the castration-recurrent CWR22 xenograft. AR expression studies showed nuclear colocalization of AR and endogenous FSTL1 in response to androgen.

Conclusion: AR and MAGE-A11 cooperate in the up-regulation of FSTL1 to promote growth and progression of CRPC. Prostate 77:505-516, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/pros.23288DOI Listing
April 2017

Abnormal Hypermethylation of the VDAC2 Promoter is a Potential Cause of Idiopathic Asthenospermia in Men.

Sci Rep 2016 11 28;6:37836. Epub 2016 Nov 28.

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

This study aimed to explore the association between the methylation status of the VDAC2 gene promoter region and idiopathic asthenospermia (IAS). Twenty-five IAS patients and 27 fertile normozoospermia (NZ) were involved. GC-2spd cells were treated with different concentrations of 5-aza-2'-deoxycytidine (5-Aza-CdR) for 24 h and 48 h. qRT-PCR was conducted to reveal whether or not VDAC2 expression was regulated by methylated modification. A dual-luciferase activity detection was used to verify VDAC2 promoter activity in GC-2spd cells. Bisulphite genomic sequence was used to analyse DNA methylation of the VDAC2 promoter. The results showed that VDAC2 expression was significantly increased after treated with 5-Aza-CdR. A strong activity of the promoter (-2000 bp to +1000 bp) was detected by dual-luciferase activity detection (P < 0.05). The bisulphite genomic sequencing and correlation analysis showed that sperm motility was positively associated with the methylation pattern of uncomplete methylation and mild hypermethylation, and negatively related to the percentage of moderate methylation. In conclusion, high methylation of the VDAC2 promoter CpGs could be positively correlated with low sperm motility. Abnormal methylation of VDAC2 promoter may be a potential cause to idiopathic asthenospermia.
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http://dx.doi.org/10.1038/srep37836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124954PMC
November 2016

Long noncoding RNA BX357664 regulates cell proliferation and epithelial-to-mesenchymal transition via inhibition of TGF-β1/p38/HSP27 signaling in renal cell carcinoma.

Oncotarget 2016 Dec;7(49):81410-81422

Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Antisense long noncoding RNAs (lncRNAs) are reported to play a regulating role in carcinogenesis of various human malignancies. However, the function of lncRNAs and their underlying mechanism in renal cell carcinoma (RCC) is still unknown. The aims of this study are to investigate the expression of lncRNA BX357664 in RCC and to explore its function in RCC cell lines. As a result, BX357664 was downregulated in RCC according to previous microarray analysis and qualitative real-time polymerase chain reaction. After the upregulation of BX357664, reduced migration, invasion, and proliferation capabilities in RCC cells were detected. Furthermore, Western blot analysis was conducted to identify the influence of BX357664 on epithelial-to-mesenchymal transition, matrix metalloproteinase 2, matrix metalloproteinase 9, and transforming growth factor-beta 1 (TGF-β1)/p38/HSP27 signaling pathway in RCC. Subsequently, upregulating the protein level of TGF-β1 in the presence of BX357664 could rescue the suppression of the malignant behavior mediated by BX357664, indicating that BX357664 attributed its inhibitory role to the suppression of TGF-β1. Therefore, we investigated a novel lncRNA BX357664, which might exhibit its inhibitory role in RCC metastasis and progression by blocking the TGF-β1/p38/HSP27 pathway.
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http://dx.doi.org/10.18632/oncotarget.12937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348402PMC
December 2016

Melanoma antigen-A11 regulates substrate-specificity of Skp2-mediated protein degradation.

Mol Cell Endocrinol 2017 01 6;439:1-9. Epub 2016 Oct 6.

Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Melanoma antigen-A11 (MAGE-A11) is a proto-oncogene involved in androgen receptor signaling and androgen-dependent cell growth. In this report we provide evidence that MAGE-A11 interacts with Skp2 (S phase kinase-associated protein), the substrate recognition protein of the Skp1-Cullin1-F-box E3 ubiquitin ligase, and with Skp2 binding protein, cyclin A. A similar cyclin A binding motif in MAGE-A11 and Skp2 was consistent with a competitive relationship between MAGE-A11 and Skp2 in binding cyclin A. Skp2 inhibited MAGE-A11 interaction with cyclin A. Differential effects of MAGE-A11 on Skp2-mediated protein degradation were also revealed. MAGE-A11 increased Skp2-mediated degradation of cyclin A and retinoblastoma-related protein p130. In contrast, MAGE-A11 decreased Skp2-mediated degradation of E2F1 and Skp2 self-ubiquitination. Stabilization of E2F1 by MAGE-A11 was associated with sequestration and inactivation of Skp2 through the formation of an E2F1-MAGE-A11-Skp2 complex. We conclude that direct interactions of MAGE-A11 with Skp2 and cyclin A regulate the substrate-specificity of Skp2-mediated protein degradation.
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http://dx.doi.org/10.1016/j.mce.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123923PMC
January 2017

Association between germline homeobox B13 (HOXB13) G84E allele and prostate cancer susceptibility: a meta-analysis and trial sequential analysis.

Oncotarget 2016 Oct;7(41):67101-67110

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Germline HOXB13 G84E mutation (rs138213197) has been described associated with prostate cancer (PCa) susceptibility but results of different studies are inconsistent. We conducted this meta-analysis to evaluate the specific role of this mutation. Relevant available studies were identified by searching the databases Pubmed, Embase and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the strength of the association. Subgroup analysis were performed to evaluate the specific role of rs138213197 in disease aggressiveness, diagnostic age and family history. Furthermore, trial sequential analysis (TSA) was conducted for the first time to estimate whether the evidence of the results is sufficient. Our results indicated that significant increased PCa susceptibility was associated with rs138213197 compared with non-carriers (OR = 3.38, 95% CI: 2.45-4.66). Besides, in subgroup analysis, HOXB13 G84E variant was obviously associated with early onset (OR = 2.90, 95% CI: 2.24-3.75), affected relatives (OR = 2.60, 95% CI 2.19-3.10) and highly aggressive disease (OR = 2.38, 95% CI 1.84-3.08). By TSA, the findings in the current study were based on sufficient evidence. Therefore, our results indicated that the G84E mutation in HOXB13 gene might increase susceptibility to PCa.
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http://dx.doi.org/10.18632/oncotarget.11937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341860PMC
October 2016

Prognostic Role of Secretory Clusterin in Multiple Human Malignant Neoplasms: A Meta-Analysis of 26 Immunohistochemistry Studies.

PLoS One 2016 17;11(8):e0161150. Epub 2016 Aug 17.

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing. 210029, China.

Secretory clusterin (sCLU) is a potential prognostic tumour biomarker, but results of different sCLU studies are inconsistent. We conducted this meta-analysis to evaluate the precise predictive value of sCLU. Qualified studies were identified by performing online searches in PubMed, EMBASE, and Web of Science. The selected articles were divided into three groups based on scoring method for clusterin detection. Pooled hazard ratios (HRs) with 95% confidence interval (CI) for patient survival and disease recurrence were calculated to determine the correlation between sCLU expression and cancer prognosis. Heterogeneity was assessed using I2 statistics, and specific heterogeneity in different groups was analysed. Elevated sCLU was significantly associated with recurrence-free survival in groups 1 and 3 (group 1: pooled HR = 1.35, 95% CI = 1.01 to 1.79; group 3: pooled HR = 1.80, 95% CI = 1.22 to 2.65). However, clusterin expression was not associated with overall survival in all three groups. Results showed that only the heterogeneity of group 2 was very strong (p = 0.013, I2 = 76.3%), in which the specimens were scored through sCLU staining intensity only. sCLU is a potential biomarker for tumour prognosis, and IHC methods can be more standardised if both intensity and staining proportion are considered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161150PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988765PMC
August 2017

Abnormal Expression of Sg I is Closely Related to Seminal Vesiculitis.

Urology 2016 Feb 27;88:227.e9-227.e14. Epub 2015 Oct 27.

Department of Urology and State Key Laboratory of Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Objective: To investigate firstly the relationship between semenogelin I (Sg I) expression and seminal vesiculitis. Seminal vesiculitis is one of the most common diseases in male urogenital system. However, the cause and the pathogenesis of seminal vesiculitis remain unknown. Sg I, mainly synthesized and secreted by seminal vesicle, is abundant in human seminal plasma and has antibacterial activity.

Materials And Methods: Tissue samples were collected from 15 normal cases and 28 patients with seminal vesiculitis. Reverse transcription-polymerase chain reaction was performed to detect the expression difference of Sg I messenger ribonucleic acid (RNA) between normal seminal vesicle tissues and seminal vesiculitis tissues. Immunohistochemistry was applied to detect the expression difference of Sg I protein between the 2 groups.

Results: Reverse transcription-polymerase chain reaction showed the expression of Sg I messenger RNA in seminal vesiculitis tissues to be significantly lower than in normal seminal vesicle tissues. In most cases with seminal vesiculitis (78.6%), the same result was observed upon immunohistochemical analysis at the protein level.

Conclusion: Abnormal expression of Sg I is closely related to seminal vesiculitis. Low expression of Sg I may play an important role in the occurrence and the development of seminal vesiculitis through weakening the antibacterial activity of seminal vesicle.
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http://dx.doi.org/10.1016/j.urology.2015.08.031DOI Listing
February 2016

Downregulation of tNASP inhibits proliferation through regulating cell cycle-related proteins and inactive ERK/MAPK signal pathway in renal cell carcinoma cells.

Tumour Biol 2015 Jul 12;36(7):5209-14. Epub 2015 Feb 12.

State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, China.

Nuclear auto-antigenic sperm protein (NASP), initially described as a highly auto-immunogenic testis and sperm-specific protein, is a histone chaperone that is proved to present in all dividing cells. NASP has two splice variants: testicular NASP (tNASP) and somatic form of NASP (sNASP). Only cancer, germ, transformed, and embryonic cells have a high level of expression of the tNASP. Up to now, little has been known about tNASP in renal cell carcinoma (RCC). In the present study, the molecular mechanism of tNASP in RCC was explored. The expression level of tNASP in 16 paired human RCC specimens was determined. Downregulation of tNASP by small interfering RNA (siRNA) was transfected in RCC cell lines. The effect of downregulation of tNASP by siRNA on cell colony formation and proliferation was examined by colony formation assay and CCK-8 assay, cell cycle was analyzed by flow cytometry, and the expression of cyclin D1 and P21 were detected by Western blotting. ERK/MAPK signaling was also analyzed. tNASP has a relative high expression level in human RCC tissues. Via upregulation of P21 and downregulation of cyclinD1, silence of tNASP can inhibit cell proliferation, which induces cell cycle arrest. Furthermore, ERK signaling pathway is confirmed to mediate the regulation of cell cycle-related proteins caused by silence of tNASP. Our research demonstrates that knockdown of tNASP effectively inhibits the proliferation and causes G1 phase arrest through ERK/MAPK signal pathway.
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http://dx.doi.org/10.1007/s13277-015-3177-9DOI Listing
July 2015

Seminal plasma protein in renal cell carcinoma: expression of semenogelin I is a predictor for cancer progression and prognosis.

Tumour Biol 2014 Sep 11;35(9):9095-100. Epub 2014 Jun 11.

State key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Guangzhou Road 300#, Nanjing, 210029, People's Republic of China.

The incidence of renal cell carcinoma (RCC) has been steadily rising each year. There are currently few recognized biomarkers for the diagnosis and prognosis of RCC. We investigated semenogelin I (Sg I) expression and its clinical significance in patients with RCC. The expression levels of Sg I and its protein were measured by qPCR and Western blotting, respectively. Immunohistochemistry was used to investigate the protein expression of Sg I in RCC and normal renal tissue from 53 patients. The Kaplan-Meier method and log-rank test were used to evaluate the data. By qRCR (p < 0.01) and Western blot, the level of Sg I expression in benign tissues was higher than that in RCC tissues. Expression of Sg I was observed in 30 (57 %) RCC cases, which was significantly lower than that observed in benign renal tissues from the same patients [Sg I positive in 53 (100 %) cases (p < 0.0001)] by immunohistochemistry. There was an inverse relation between Sg I expression and clinical stage (pT1-2 vs pT3-4, p < 0.0001). Patients with Sg I-negative tumor had a significantly higher risk of recurrence (Kaplan-Meier and log-rank tests, p < 0.0001). There was low Sg I expression in RCC. Sg I expression has potential value in predicting cancer progression and prognosis. These findings support the use of Sg I as a novel biomarker for RCC.
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http://dx.doi.org/10.1007/s13277-014-2184-6DOI Listing
September 2014

Is abnormal expression of semenogelin I involved with seminal vesiculitis?

Med Hypotheses 2014 Mar 14;82(3):338-40. Epub 2014 Jan 14.

State Key Laboratory of Reproductive Medicine and Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Seminal vesiculitis is the common disease of male urogenital system. However, the pathogenesis of seminal vesiculitis remains unclear. Semenogelin I (Sg I) is mainly synthesized and secreted by seminal vesicle and has antibacterial activity. We thus postulate that Sg I plays an important role during the occurrence and development of seminal vesiculitis. In the present study, we analyzed the expression of Sg I in normal seminal vesicle tissues and seminal vesiculitis tissues through immunohistochemistry. The results showed down-regulated expression of clusterin at protein level in seminal vesiculitis tissues compared with normal seminal vesicle tissues. Our preliminary data suggest that the abnormal expression of clusterin is closely related to seminal vesiculitis. Downregulation of Sg I expression may weaken the antibacterial activity of the seminal vesicle and then induce the occurrence of disease. This is the first study to focus on the relationship between Sg I and human seminal vesiculitis.
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http://dx.doi.org/10.1016/j.mehy.2013.12.022DOI Listing
March 2014

Correlation of epididymal protease inhibitor and fibronectin in human semen.

PLoS One 2013 16;8(12):e82600. Epub 2013 Dec 16.

State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Objective: Epididymal protease inhibitor (Eppin) was located on the surface of spermatozoa and modulates the liquefaction of human semen. Here, we identify the correlative protein partner of Eppin to explore the molecular mechanism of liquefaction of human semen.

Methods: (1) Human seminal vesicle proteins were transferred on the membrane by Western blotting and separated by 2-D electrophoresis and incubated in recombinant Eppin. The correlative protein was identified by Mass Spectrometry (MS) (2). Western blotting was used to determine the relation of rEppin and rFibronectin(Fn); (3) Co-localization in spermatozoa were detected using immunofluorescence; (4) Correalation of Eppin and Fn was proved by co-immunoprecipitation.

Results: Fn was identified as the binding partner of recombinant Eppin by MS. Recombinant of Eppin was made and demonstrated that the Eppin fragment binds the fn 607-1265 fragment. The Eppin-Fn complex presents on the sperm tail and particularly in the midpiece region of human ejaculated spermatozoa. Immunoprecipitation indicated that Eppin in the spermatozoa lysates was complexed with Fn.

Conclusions: Our study demonstrates that Eppin and Fn bind to each other in human semen and on human ejaculated spermatozoa. Eppin-Fn complex may involve in semen coagulation, liquefaction and the survival and preparation of spermatozoa for fertility in the female reproductive tract.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082600PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865146PMC
October 2014

The Cytochrome P4501A1 gene polymorphisms and idiopathic male infertility risk: a meta-analysis.

Gene 2014 Feb 6;535(2):93-6. Epub 2013 Dec 6.

State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China. Electronic address:

Studies of the relationship between male infertility and CYP1A1 polymorphisms are inconclusive. To drive a more precise estimation, we performed a meta-analysis based on 1060 cases and 1225 controls from 7 published case-control studies. PubMed and CNKI literature search were conducted to identify all eligible studies investigating such a relationship. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the additive model, dominant model, recessive model, and allele-frequency genetic model. In the overall analysis, the frequency of CYP1A12A genotype was significantly associated with susceptibility to idiopathic male infertility. Further stratified analysis by ethnicity showed notable association between the polymorphism and the risk of idiopathic male infertility in Asians. In conclusion, these results support that the CYP1A1 2A genotype polymorphism mainly contributes to idiopathic male infertility susceptibility in Asians but not in Caucasians.
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http://dx.doi.org/10.1016/j.gene.2013.11.011DOI Listing
February 2014

Association of the glutathione s-transferase m1, t1 polymorphisms with cancer: evidence from a meta-analysis.

PLoS One 2013 8;8(11):e78707. Epub 2013 Nov 8.

State Key Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Background: Glutathione S-transferases (GSTs) are a family of multifunctional enzymes that are involved in the metabolism of many xenobiotics, including a wide range of environmental carcinogens. While the null genotypes in GSTM1 and GSTT1 have been implicated in tumorigenesis, it remains inconsistent and inconclusive. Herein, we aimed to assess the possible associations of the GSTM1 and GSTT1 null genotype in cancer risks.

Methods: A meta-analysis based on 506 case-control studies was performed. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association.

Results: The null genotypes of GSTM1 and GSTT1 polymorphisms were associated with a significantly increased risk in cancer (for GSTM1: OR = 1.17; 95%CI = 1.14-1.21; for GSTT1: OR = 1.16; 95%CI = 1.11-1.21, respectively). When the analysis was performed based on their smoking history, the risk associated of GSTM1 null and GSTT1 null genotypes with cancer is further increased (for GSTM1: OR = 2.66; 95%CI = 2.19-3.24; for GSTT1: OR = 2.46; 95%CI = 1.83-3.32, respectively).

Conclusions: These findings indicate that GSTM1 and GSTT1 polymorphisms may play critical roles in the development of cancer, especially in smokers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078707PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826727PMC
March 2015

Proto-oncogene activity of melanoma antigen-A11 (MAGE-A11) regulates retinoblastoma-related p107 and E2F1 proteins.

J Biol Chem 2013 Aug 12;288(34):24809-24. Epub 2013 Jul 12.

Laboratories for Reproductive Biology, Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Melanoma antigen-A11 (MAGE-A11) is a low-abundance, primate-specific steroid receptor coregulator in normal tissues of the human reproductive tract that is expressed at higher levels in prostate cancer. Increased expression of MAGE-A11 enhances androgen receptor transcriptional activity and promotes prostate cancer cell growth. Further investigation into the mechanisms of MAGE-A11 function in prostate cancer demonstrated interactions with the retinoblastoma-related protein p107 and Rb tumor suppressor but no interaction with p130 of the Rb family. MAGE-A11 interaction with p107 was associated with transcriptional repression in cells with low MAGE-A11 and transcriptional activation in cells with higher MAGE-A11. Selective interaction of MAGE-A11 with retinoblastoma family members suggested the regulation of E2F transcription factors. MAGE-A11 stabilized p107 by inhibition of ubiquitination and linked p107 to hypophosphorylated E2F1 in association with the stabilization and activation of E2F1. The androgen receptor and MAGE-A11 modulated endogenous expression of the E2F1-regulated cyclin-dependent kinase inhibitor p27(Kip1). The ability of MAGE-A11 to increase E2F1 transcriptional activity was similar to the activity of adenovirus early oncoprotein E1A and depended on MAGE-A11 interactions with p107 and p300. The immunoreactivity of p107 and MAGE-A11 was greater in advanced prostate cancer than in benign prostate, and knockdown with small inhibitory RNA showed that p107 is a transcriptional activator in prostate cancer cells. These results suggest that MAGE-A11 is a proto-oncogene whose increased expression in prostate cancer reverses retinoblastoma-related protein p107 from a transcriptional repressor to a transcriptional activator of the androgen receptor and E2F1.
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http://dx.doi.org/10.1074/jbc.M113.468579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750176PMC
August 2013

Melanoma antigen-A11 (MAGE-A11) enhances transcriptional activity by linking androgen receptor dimers.

J Biol Chem 2013 Jan 21;288(3):1939-52. Epub 2012 Nov 21.

Laboratories for Reproductive Biology, Department of Pediatrics, University of North Carolina, Chapel Hill, NC 27599-7500, USA.

Prostate cancer growth and progression depend on androgen receptor (AR) signaling through transcriptional mechanisms that require interactions with coregulatory proteins, one of which is the primate-specific steroid receptor coregulator melanoma antigen-A11 (MAGE-A11). In this report, we provide evidence how increased expression of MAGE-A11 during prostate cancer progression enhances AR signaling and prostate cancer growth. MAGE-A11 protein levels were highest in castration-recurrent prostate cancer. The cyclic AMP-induced increase in androgen-dependent and androgen-independent AR transcriptional activity correlated with an increase in MAGE-A11 and was inhibited by silencing MAGE-A11 expression. MAGE-A11 mediated synergistic AR transcriptional activity in LAPC-4 prostate cancer cells. The ability of MAGE-A11 to rescue transcriptional activity of complementary inactive AR mutants and promote coimmunoprecipitation between unlike forms of AR suggests that MAGE-A11 links transcriptionally active AR dimers. A model for the AR·MAGE-A11 multidimeric complex is proposed in which one AR FXXLF motif of the AR dimer engages in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction, whereas the second FXXLF motif region of the AR dimer interacts with dimeric MAGE-A11. The AR·MAGE-A11 multidimeric complex accounts for the dual functions of the AR FXXLF motif in the androgen-dependent AR NH(2)- and carboxyl-terminal interaction and binding MAGE-A11 and for synergy between reported AR splice variants and full-length AR. We conclude that the increased expression of MAGE-A11 in castration-recurrent prostate cancer, which is enhanced by cyclic AMP signaling, increases AR-dependent growth of prostate cancer by MAGE-A11 forming a molecular bridge between transcriptionally active AR dimers.
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http://dx.doi.org/10.1074/jbc.M112.428409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548502PMC
January 2013

Primate-specific melanoma antigen-A11 regulates isoform-specific human progesterone receptor-B transactivation.

J Biol Chem 2012 Oct 13;287(41):34809-24. Epub 2012 Aug 13.

Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

Progesterone acting through the progesterone receptor (PR) and its coregulators prepares the human endometrium for receptivity to embryo implantation and maintains pregnancy. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE-11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Here we show that MAGE-11 is an isoform-specific coregulator responsible for the greater transcriptional activity of human PR-B relative to PR-A. PR was recruited to progesterone response regions of progesterone-regulated FK506-binding protein 5 (FKBP5) immunophilin and small Ras family G protein cell growth inhibitor RASD1 genes. Expression of MAGE-11 lentivirus shRNA in human endometrial Ishikawa cells expressing PR-B showed that MAGE-11 is required for isoform-specific PR-B up-regulation of FKBP5. In contrast, MAGE-11 was not required for progesterone up-regulation of RASD1 in endometrial cells expressing the PR-A/B heterodimer. Target gene specificity of PR-B depended on the synergistic actions of MAGE-11 and p300 mediated by the unique PR-B NH(2)-terminal (110)LLXXVLXXLL(119) motif that interacts with the MAGE-11 F-box region in a phosphorylation- and ubiquitinylation-dependent manner. A progesterone-dependent mechanism is proposed in which MAGE-11 and p300 increase PR-B up-regulation of the FKBP5 gene. MAGE-11 down-regulates PR-B, similar to the effects of progesterone, and interacts with FKBP5 to stabilize a complex with PR-B. We conclude that the coregulator function of MAGE-11 extends to isoform-specific regulation of PR-B during the cyclic development of the human endometrium.
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http://dx.doi.org/10.1074/jbc.M112.372797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464583PMC
October 2012

Gain in transcriptional activity by primate-specific coevolution of melanoma antigen-A11 and its interaction site in androgen receptor.

J Biol Chem 2011 Aug 5;286(34):29951-63. Epub 2011 Jul 5.

Laboratories for Reproductive Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7500, USA.

Male sex development and growth occur in response to high affinity androgen binding to the androgen receptor (AR). In contrast to complete amino acid sequence conservation in the AR DNA and ligand binding domains among mammals, a primate-specific difference in the AR NH(2)-terminal region that regulates the NH(2)- and carboxyl-terminal (N/C) interaction enables direct binding to melanoma antigen-A11 (MAGE-11), an AR coregulator that is also primate-specific. Human, mouse, and rat AR share the same NH(2)-terminal (23)FQNLF(27) sequence that mediates the androgen-dependent N/C interaction. However, the mouse and rat AR FXXLF motif is flanked by Ala(33) that evolved to Val(33) in primates. Human AR Val(33) was required to interact directly with MAGE-11 and for the inhibitory effect of the AR N/C interaction on activation function 2 that was relieved by MAGE-11. The functional importance of MAGE-11 was indicated by decreased human AR regulation of an androgen-dependent endogenous gene using lentivirus short hairpin RNAs and by the greater transcriptional strength of human compared with mouse AR. MAGE-11 increased progesterone and glucocorticoid receptor activity independently of binding an FXXLF motif by interacting with p300 and p160 coactivators. We conclude that the coevolution of the AR NH(2)-terminal sequence and MAGE-11 expression among primates provides increased regulatory control over activation domain dominance. Primate-specific expression of MAGE-11 results in greater steroid receptor transcriptional activity through direct interactions with the human AR FXXLF motif region and indirectly through steroid receptor-associated p300 and p160 coactivators.
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http://dx.doi.org/10.1074/jbc.M111.244715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191036PMC
August 2011

Characterization of lactoferrin receptor on human spermatozoa.

Reprod Biomed Online 2011 Feb 15;22(2):155-61. Epub 2010 Oct 15.

Laboratory of Reproductive Medicine, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Lactoferrin (LF) is abundant in human seminal plasma and on sperm surfaces. However, lactoferrin receptor (LFR) on human spermatozoa has not yet been reported. To study the expression, localization and characteristics of LFR on human spermatozoa, different experimental approaches were applied: LFR gene was amplified from a human testis cDNA library and recombinant LFR (rLFR) protein was produced in the expression vector Escherichia coli BL21 (DE3); human sperm membrane proteins were extracted and analysed via Western blot; the binding of LF to LFR was investigated by Far-Western blot, immunoprecipitation and autoradiography analysis and the localization of LFR on sperm surfaces was detected using immunofluorescence. LFR gene was amplified from a human testis cDNA library and the molecular weight of rLFR was 34kDa. The native LFR on human spermatozoa was a 136-kDa tetramer which was anchored to the sperm head and mid-piece through glycophosphatidylinositol. LF could bind to LFR competitively in vitro. As far as is known, this study has elucidated for the first time that LFR was expressed at the testis level, was anchored to the sperm membrane by glycophosphatidylinositol during spermatogenesis. LFR may play important roles through binding to and mediating LF.
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http://dx.doi.org/10.1016/j.rbmo.2010.10.003DOI Listing
February 2011