TIMP1 shapes an immunosuppressive microenvironment by regulating anoikis to promote the progression of clear cell renal cell carcinoma.

BACKGROUND: The association between ccRCC and Anoikis remains to be thoroughly investigated. METHODS: Anoikis-related clusters were identified using NMF. To identify prognostic anoikis-related genes (ARGs) and establish an optimal prognostic model, univariate Cox and LASSO regression were employed. The E-MTAB-1980 cohort was utilized for external validation. Multiple algorithms were used to evaluate the immune properties of the model. GO, KEGG and GSVA analyses were employed to analyze biological pathway functions. qRT-PCR was employed to measure RNA levels of specific genes. Cell Counting Kit-8, wound healing, and Transwell chamber assays were performed to determine changes in the proliferative and metastatic abilities of A498 and 786-O cells. RESULTS: Based on the expression of 21 prognostic ARGs, we constructed anoikis-related clusters with different prognostic and immune characteristics. The cluster A1 showed a worse prognosis, higher infiltration of immunosuppressive cells and enrichment of several oncogenic pathways. We also calculated the Anoikis Index (AI). Patients in high AI group had a worse prognosis, higher infiltration of immunosuppressive cells and higher expression of immunosuppressive checkpoints. TIMP1 exerted a tumor-promoting role in ccRCC and was significantly associated with immunosuppressive cells and checkpoints. The downregulation of TIMP1 negatively regulated ccRCC cell proliferation and metastasis. CONCLUSIONS: ARGs played crucial roles in tumorigenesis and progression and were positively associated with a poor prognosis. AI had great accuracy in predicting the prognosis and immune characteristics of ccRCC patients. TIMP1 was significantly associated with clinicopathological variables and the immunosuppressive microenvironment, which could be exploited to design novel immunotherapies for ccRCC patients.

Incremental value of radiomics with machine learning to the existing prognostic models for predicting outcome in renal cell carcinoma.

Purpose: To systematically evaluate the potential of radiomics coupled with machine-learning algorithms to improve the predictive power for overall survival (OS) of renal cell carcinoma (RCC). Methods: A total of 689 RCC patients (281 in the training cohort, 225 in the validation cohort 1 and 183 in the validation cohort 2) who underwent preoperative contrast-enhanced CT and surgical treatment were recruited from three independent databases and one institution. 851 radiomics features were screened using machine-learning algorithm, including Random Forest and Lasso-COX Regression, to establish radiomics signature. The clinical and radiomics nomogram were built by multivariate COX regression. The models were further assessed by Time-dependent receiver operator characteristic, concordance index, calibration curve, clinical impact curve and decision curve analysis. Result: The radiomics signature comprised 11 prognosis-related features and was significantly correlated with OS in the training and two validation cohorts (Hazard Ratios: 2.718 (2.246,3.291)). Based on radiomics signature, WHOISUP, SSIGN, TNM Stage and clinical score, the radiomics nomogram has been developed. Compared with the existing prognostic models, the AUCs of 5 years OS prediction of the radiomics nomogram were superior to the TNM, WHOISUP and SSIGN model in the training cohort (0.841 vs 0.734, 0.707, 0.644) and validation cohort2 (0.917 vs 0.707, 0.773, 0.771). Stratification analysis suggested that the sensitivity of some drugs and pathways in cancer were observed different for RCC patients with high-and low-radiomics scores. Conclusion: This study showed the application of contrast-enhanced CT-based radiomics in RCC patients, creating novel radiomics nomogram that could be used to predict OS. Radiomics provided incremental prognostic value to the existing models and significantly improved the predictive power. The radiomics nomogram might be helpful for clinicians to evaluate the benefit of surgery or adjuvant therapy and make individualized therapeutic regimens for patients with renal cell carcinoma.

Exposure to bisphenol A alternatives bisphenol AF and fluorene-9-bisphenol induces gonadal injuries in male zebrafish.

Bisphenol A (BPA), present in many household products, can damage the male reproductive system. Accordingly, we summarized urine samples from 6921 human in National Health and Nutrition Examination Survey and found urinary BPA levels were inversely linked with blood testosterone in the children group. Currently, BPA replacements, such as fluorene-9-bisphenol (BHPF) and Bisphenol AF (BPAF), have been introduced to produce "BPA-free" products. Here we demonstrated that BPAF and BHPF could induce delayed gonadal migration and reduce the number of progenitors of germ cell lineage in zebrafish larvae. A close receptor analysis study reveals that BHPF and BPAF can strongly bind to androgen receptors, leading to the downregulation of meiosis-related genes and the overexpression of inflammatory markers. Furthermore, BPAF and BPHF can induce activation of the gonadal axis via negative feedback, leading to the hypersecretion of some upstream hormones and an increase in the expression of upstream hormone receptors. Our findings call for further research on the toxicological effects of BHPF and BPAF on human health and recommend that BPA replacements be investigated for anti-estrogenic action.

[Effects of regulation measure on soil and microbial biomass of moderately degraded alpine meadow in Qilian Mountain, China]. / 调控措施对祁连山中度退化高寒草甸土壤的影响.

We examined the effects of different regulation measures (spring rest grazing, spring rest grazing-cutting turf, spring rest grazing-cutting turf-fertilization, spring rest grazing-cutting turf-sowing, spring rest grazing-cutting turf-fertilization-sowing) on vegetation, soil physical and chemical properties, and soil microbial biomass in mode-rately degraded alpine meadow in Qilian Mountain. The results showed that all the regulation measures significantly increased plant coverage and aboveground and underground biomass of degraded alpine meadows. Plant species richness increased significantly under the two measures of spring rest grazing-cutting turf-fertilization and spring rest grazing-cutting turf-fertilization-sowing. The dominant species of spring rest grazing-cutting turf-sowing and spring rest grazing-cutting turf-fertilization-sowing was Poa pratensis cv. Qinghai. Soil pH and bulk density in moderately degraded alpine meadow (control) were significantly higher than those of all regulation measures. Soil water content, soil organic carbon, total nitrogen and total potassium, carbon-nitrogen ratio and nitrogen-phosphorus ratio of spring rest grazing-cutting turf-fertilization-sowing measures were the highest, which were 21.3%, 22.30 g·kg-1, 2.77 g·kg-1, 19.93 g·kg-1, 8.3 and 3.5, respectively. Soil microbial biomass nitrogen and phosphorus (104.98 and 40.74 mg·kg-1) of degraded meadows under spring rest grazing-cutting turf-fertilization-sowing measures were significantly higher than those of other measures, while soil microbial biomass carbon (240.72 mg·kg-1) of degraded meadows under spring rest grazing-cutting turf-fertilization measures was significantly higher than that of other measures. The results of radar map showed that the regulation measures affected the characteristics of degra-ded meadow vegetation (aboveground and underground biomass), soil physical and chemical properties (water content, organic carbon, total nitrogen, total phosphorus, and total potassium) and soil microbial biomass (carbon, nitrogen and phosphorus). Spring rest grazing-cutting turf-fertilization-sowing measures had the best performance in restoraing degraded meadows in the study area.

Predictive factors for successful sperm retrieval by microdissection testicular sperm extraction in men with nonobstructive azoospermia and a history of cryptorchidism.

This study aims to explore the factors influencing the success rate of the microdissection testicular sperm extraction (Micro-TESE) in patients with nonobstructive azoospermia (NOA) and cryptorchidism. Clinical data of 162 patients with cryptorchidism who underwent Micro-TESE due to infertility from December 2015 to May 2020 in the First Affiliated Hospital of Nanjing Medical University were analyzed retrospectively. In the univariate analysis, significant differences in the age of patient at the time of orchidopexy (median [interquartile range, IQR]: 7.0 [4.0-11.0] years vs 11.5 [9.0-14.5] years, P < 0.001), interval between orchidopexy and Micro-TESE (mean ± standard deviation: 17.5 ± 5.0 years vs 14.4 ± 4.4 years, P < 0.001), severity of cryptorchidism (unilateral [62.8%] vs bilateral [31.6%], P < 0.001; location of cryptorchidism, intra-abdominal [27.3%] vs inguinal [44.8%] vs suprascrotal [66.7%], P < 0.001), volume of the dominant testis (median [IQR]: 17.00 [15.00-19.00] ml vs 14.50 [11.75-16.25] ml, P < 0.001), and levels of follicle-stimulating hormone (FSH; P = 0.004) and testosterone (P = 0.006) were observed between the successful and failed sperm extraction groups. After conducting the multivariate analysis, four of these factors, including unilateral/bilateral cryptorchidism (P < 0.001), location of cryptorchidism (P = 0.032), age of orchidopexy (P < 0.001), and dominant testicular volume, were adopted in the clinical prediction model to evaluate preoperatively the success rate of Micro-TESE for patients with NOA and cryptorchidism. The likelihood of successful sperm retrieval by Micro-TESE in men with NOA and cryptorchidism increased in patients with mild forms of cryptorchidism.

[A case of complete androgen insensitivity syndrome with special family history and its genetic analysis].

OBJECTIVE: To report a case of complete androgen insensitivity syndrome with a special family history and its genetic analysis. METHODS: We studied the medical history, diagnosis and treatment of a case of complete androgen insensitivity syndrome, collected blood samples from the patient and his mother for whole exome sequencing, and analyzed the genetic etiology. RESULTS: The patient presented with "primary amenorrhea" and diagnosed with male pseudohermaphroditism, with the karyotype as 46, XY. Surgery confirmed undescended testes in the abdominal cavity. The androgen level was higher than normal. Whole exome sequencing of the patient and his mother found c.2678C>T (p.P893L) but no other abnormalities, which was considered as a suspected pathogenic mutation of complete androgen insensitivity syndrome. The patient had a "sister" with a similar medical history. CONCLUSION: c.2678C>T (p.P893L) is a suspected pathogenic mutation of complete androgen insensitivity syndrome, which usually cannot be detected until puberty, making it easy to delay the diagnosis.

TRIM37 orchestrates renal cell carcinoma progression via histone H2A ubiquitination-dependent manner.

BACKGROUND: Ubiquitylation modification is one of the multiple post-transcriptional process to regulate cellular physiology, including cell signaling, cycle regulation, DNA repair and transcriptional regulation. Members of TRIM family proteins could be defined as E3 ubiquitin ligases as they contain a RING-finger domain, and alterations of TRIM proteins are involved into a broad range of diverse disorders including cancer. TRIM37 is a novel discovered E3 ubiquitin ligase and acts as a oncoprotein in multiple human neoplasms, however its biological role in RCC still remains elusive. METHODS: RCC microarray chips and public datasets were screened to identify novel TRIMs member as TRIM37, which was dysregulated in RCC. Gain or loss of functional cancer cell models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Interactive network analyses were utilized to define intrinsic mechanism. RESULTS: We identified TRIM37 was upregulated in RCC tumors, and its aberrant function predicted aggressive neoplastic phenotypes, poorer survival endings. TRIM37 promoted RCC cells EMT and malignant progression via TGF-ß1 signaling activation, as a consequence of directly mediated by ubiquitinating-H2A modifications. CONCLUSIONS: Our findings identified a previously unappreciated role of TRIM37 in RCC progression and prognostic prediction. Importantly, we declared a novel ubiquitination-dependent link between TRIM ubiquitin ligases and TGF-ß1 signaling in regulating cancerous malignancies.

Identification of an independent immune-genes prognostic index for renal cell carcinoma.

BACKGROUND: Considerable evidence has indicated an association between the immune microenvironment and clinical outcome in ccRCC. The purpose of this study is to extensively figure out the influence of immune-related genes of tumors on the prognosis of patients with ccRCC. METHODS: Files containing 2498 immune-related genes were obtained from the Immunology Database and Analysis Portal (ImmPort), and the transcriptome data and clinical information relevant to patients with ccRCC were identified and downloaded from the TCGA data-base. Univariate and multivariate Cox regression analyses were used to screen out prognostic immune genes. The immune risk score model was established in light of the regression coefficient between survival and hub immune-related genes. We eventually set up a nomogram for the prediction of the overall survival for ccRCC. Kaplan-Meier (K-M) and ROC curve was used in evaluating the value of the predictive risk model. A P value of < 0.05 indicated statistically significant differences throughout data analysis. RESULTS: Via differential analysis, we found that 556 immune-related genes were expressed differentially between tumor and normal tissues (p < 0. 05). The analysis of univariate Cox regression exhibited that there was a statistical correlation between 43 immune genes and survival risk in patients with ccRCC (p < 0.05). Through Lasso-Cox regression analysis, we established an immune genetic risk scoring model based on 18 immune-related genes. The high-risk group showed a bad prognosis in K-M analysis. (p < 0.001). ROC curve showed that it was reliable of the immune risk score model to predict survival risk (5 year over survival, AUC = 0.802). The model indicated satisfactory AUC and survival correlation in the validation data set (5 year OS, Area Under Curve = 0.705, p < 0.05). From Multivariate regression analysis, the immune-risk score model plays an isolated role in the prediction of the prognosis of ccRCC. Under multivariate-Cox regression analysis, we set up a nomogram for comprehensive prediction of ccRCC patients' survival rate. At last, it was identified that 18 immune-related genes and risk scores were not only tremendously related to clinical prognosis but also contained in a variety of carcinogenic pathways. CONCLUSION: In general, tumor immune-related genes play essential roles in ccRCC development and progression. Our research established an unequal 18-immune gene risk index to predict the prognosis of ccRCC visually. This index was found to be an independent predictive factor for ccRCC.

Evaluation of post-adolescence exposure to bisphenol A on reproductive outcomes of male rodent models.

The effect of post-adolescence bisphenol A (BPA) exposure on the reproductive system is not well-defined. We therefore performed this meta-analysis to elucidate the associations between post-adolescence BPA exposure and reproductive-related outcomes. A search was performed on the PubMed, EMBASE, and Web of science databases to identify relevant literature. The standardized mean differences (SMDs) and the 95 % confidence intervals (CIs) were measured by fixed-effects or random-effects models. Publication bias was assessed using funnel plots and Egger's regression test. A total of 40 studies were included in the final analysis. The results showed that post-adolescence BPA exposure was negatively associated with reproductive-related organ weighty (Testis weight: SMD: -0.61; 95 % Cl: -0.85, -0.36; epididymis weight; SMD: -0.43; 95 % Cl: -0.69, -0.17; seminal vesicles weight; SMD: -0.77; 95 % Cl: -1.05, -0.49) and sperm parameters (Sperm motility: SMD: -1.44; 95 % Cl: -1.95, -0.93; epididymal sperm concentration: SMD: -2.26; 95 % Cl: -2.79, -1.72; and abnormal sperm morphology: SMD: 2.41; 95 % Cl: 1.41, 2.86). Moreover, BPA exposure decreased the level of testosterone (T) and superoxide dismutase (SOD), but increased the ratio of serum estradiol (E2) to T. This systematic review demonstrates that post-adolescence exposure to BPA may adversely affect reproductive functions in male rodents.

[Clinical characteristics and treatment strategies of prostatic mucinous adenocarcinoma: A report of 10 cases and literature review].

OBJECTIVE: To investigate the clinical characteristics and treatment strategies of prostatic mucinous adenocarcinoma (PMAC). METHODS: We retrospectively analyzed the clinical data on 10 cases of PMAC treated in the First Affiliated Hospital of Nanjing Medical University from January 2014 to June 2018. The patients were aged 51－79 (65 ± 14) years, with a medium PSA level of 89 (14.63－128.05) µg/L and Gleason scores of 3 + 3 in 1 case, 3 + 4 in 2, 4 + 3 in 1 and 8 in 6 cases preoperatively, 1 treated by robot-assisted radical prostatectomy and the other 9 by laparoscopic radical prostatectomy. We conducted pelvic cavity lymph node dissection for all the patients and analyzed their prognosis and survival. RESULTS: Operations were successfully completed in all the cases. Pathological examination revealed 2 cases of mucinous adenocarcinoma with signet ring cell carcinoma in the 10 PMAC patients, 2 at stage ≤T2b, 5 at stage ≥T2c, 3 positive at pelvic lymph node dissection and 5 positive at the incision margin. The patients were followed up for 6－48 (median 26) months. Four of the patients were found with biochemical recurrence within 2 years after operation and treated by androgen-deprivation therapy, radiotherapy and chemotherapy, which reduced the PSA level to <1.0 µg/ml in all the 4 cases. CONCLUSIONS: PMAC has a good prognosis. Radical surgery is recommended for moderate and low-risk PMAC and the patients with postoperative biochemical recurrence can benefit from comprehensive treatment of total androgen blockade.

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

Melanoma antigen-A11 (MAGE-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 MAGE-A11 in renal cell carcinoma (RCC) has not been established. Two intronic SNPs (rs6641352 and rs6540341) of MAGE-A11 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, P = 0.005 in the dominant model). However, there was no significant association between rs6540341 and RCC survival. Hence, rs6641352 in MAGE-A11 may contribute to the genetic susceptibility and prognosis for RCC and act as a biomarker for RCC occurrence and prognosis.

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

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 vitro. 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.

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

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.

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

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.

The metastasis suppressor CD82/KAI1 regulates cell migration and invasion via inhibiting TGF-ß 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-ß1/Smad pathway in RCC. Subsequently, upregulating protein level of TGF-ß1 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-ß1. 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-ß1/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-ß/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.

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

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.

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

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.

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

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.