Shifeng Su

Association of the Glutathione S-Transferase M1, T1 Polymorphisms with Cancer: Evidence from a Meta-Analysis

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.

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

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.

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

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.

Characterization of lactoferrin receptor on human spermatozoa

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.

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

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.

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

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.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.

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

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.

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

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.

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

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.

MP07-14 CO-INCUBATION OF HUMAN SPERMATOZOA WITH ANTI-VDAC ANTIBODY REDUCED SPERM MOTILITY

Background: Voltage-dependent anion channel (VDAC), a channel protein, exists in the outer mitochondrial membrane of somatic cells and is involved in multiple physiological and pathophysiological processes. Up until now, little has been known about VDAC in male germ cells. In the present study, the relationship between VDAC and human sperm motility was explored. Methods: Highly motile human spermatozoa were incubated in vitro with antiVDAC antibody. Total sperm motility, straight line velocity (VSL), curvilinear velocity (VCL), and average path velocity (VAP) were recorded. Intracellular free calcium concentration ([Ca 2+ ] i ), pH value (pHi), and ATP content were determined. Results: Co-incubation with anti-VDAC antibody reduced VSL, VCL, and VAP of spermatozoa. Co-incubation further reduced [Ca 2+ ] i . Anti-VDAC antibody did not significantly alter total sperm motility, pHi and intracellular ATP content. Conclusion: The data suggest that co-incubation with anti-VDAC antibody reduces sperm motility through inhibition of Ca 2+ transmembrane flow. In this way, VDAC participates in the modulation of human sperm motility through mediating Ca 2+ transmembrane transport and exchange.