Search

Microphthalmia transcription factor (MiT) family translocation renal cell carcinoma (tRCC) is a rare type of kidney cancer, which is not well characterized. Here we show the comprehensive proteogenomic analysis of tRCC tumors and normal adjacent tissues to elucidate the molecular landscape of this disease. Our study reveals that defective DNA repair plays an important role in tRCC carcinogenesis and progression. Metabolic processes are markedly dysregulated at both the mRNA and protein levels. Proteomic and phosphoproteome data identify mTOR signaling pathway as a potential therapeutic target. Moreover, molecular subtyping and immune infiltration analysis characterize the inter-tumoral heterogeneity of tRCC. Multi-omic integration reveals the dysregulation of cellular processes affected by genomic alterations, including oxidative phosphorylation, autophagy, transcription factor activity, and proteasome function. This study represents a comprehensive proteogenomic analysis of tRCC, providing valuable insights into its biological mechanisms, disease diagnosis, and prognostication. more...

Epithelial-to-mesenchymal transition (EMT) is important in tumor invasiveness and metastasis. We aimed to determine prognostic value of six key EMT markers (CDH1, CDH2, SNAI1, SNAI2, VIM, TWIST1) in clear cell renal cell carcinoma (ccRCC). A total of 533 ccRCC patients with RNASeq data from The Cancer Genome Atlas (TCGA) cohort were included for analysis. Gene expression of these EMT markers was compared between tumor and normal tissues based on Oncomine database and TCGA cohort. Their correlations with progression-free survival (PFS) and overall survival (OS) were also examined in both TCGA cohort and FUSCC (Fudan University Shanghai Cancer Center) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Functional enrichment analyses were utilized to describe biologic function annotations and significantly involved hallmarks pathways of each gene. We found that Epithelial marker, CDH1 expression was lower, while mesenchymal markers (CDH2, SNAI1, VIM, TWIST1) expression was higher in ccRCC primary tumors. In the TCGA cohort, we found that patients with higher expression of VIM, TWIST1 or lower expression of CDH1 had worse prognosis. Further, in the FUSCC cohort, we confirmed the predictive ability of mesenchymal markers and epithelial marker expression in PFS and OS of ccRCC patients. After generating Cox regression models, EMT markers (CDH1, SNAI1, VIM, and TWIST1) were independent prognostic factors of both PFS and OS in ccRCC patients. Our preliminary EMT prediction model can facilitate further screening of EMT biomarkers and cast a better understanding of EMT gene function in ccRCC. more...

BACKGROUND This study aimed to evaluate the factors associated with a survival benefit for patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib, with and without cytoreductive nephrectomy (CN). MATERIAL AND METHODS This retrospective clinical study included 118 patients with mRCC who were treated with CN and sunitinib (CN-sunitinib) (N=70) and with sunitinib-alone (N=48). Categorical clinicopathological variables were compared with hypothesis tests using contingency tables and a chi-squared test. Independent indicators for progression-free survival (PFS) and overall survival (OS) were analyzed with univariate and multivariate Cox regression models. The Kaplan-Meier method and log-rank test were used to evaluate patient survival. RESULTS The median PFS and OS for the 118 patients were 8.38 and 15.48 months, respectively. There were no significant differences between the CN-sunitinib group and the sunitinib-alone group for either PFS (7.2 months vs. 11.6 months; P=0.525) or OS (16.7 months vs. 15.2 months; P=0.839). Stratification of patients based on clinicopathological characteristics showed that CN was significantly associated with reduced PFS and OS for patients with lymph node metastasis (PFS, P more...

Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy. more...

Background and objectives: Multi-gene signature can be used as prognostic indicator in many types of cancer, but the association with early-relapse in patients with stage I-III clear cell and papillary renal cell cancer (RCC) is unknown. We aim to establish a mRNAs signature for improving prediction of early-relapse in patients with stage I-III clear cell and papillary RCC. Methods: The data of 610 patients with stage I-III RCC from The Cancer Genome Atlas (TCGA) and 270 patients from Fudan University Shanghai Cancer Center (FUSCC) were extracted. Propensity score matching analysis, linear models for microarray data VOOM method, least absolute shrinkage and selection operation Cox regression modeling analysis was conducted in turn for selecting multi-mRNA signature. Survival differences were assessed by Kaplan-Meier estimate and compared using log-rank test. Multivariable Cox regression and time-dependent receiver operating characteristic curves were used to evaluate the association of mRNAs signature with relapse-free survival (RFS). Results: Seventeen mRNAs were identified to constitute the early-relapse signature. Among patients with stage I-III RCC, those with high-risk score calculated from 17 mRNAs signature showed shorter RFS than those with low-risk score, both in TCGA discovery and internal validation sets, and in FUSCC discovery and internal validation sets (all p < 0.05). In multivariable Cox regression analysis, the 17 mRNAs signature remained an independent prognostic factor both in TCGA discovery (HR 2.43, 95%CI 1.98-2.96) and internal validation sets (HR 1.66, 95%CI 1.19-2.30), and FUSCC discovery (HR 1.28, 95%CI 1.13-1.43) and internal validation sets (HR 1.65, 95%CI 1.11-2.48). Additionally, the 17 mRNAs signature achieved a higher accuracy for RFS estimation beyond clinical indicator. Conclusion: The 17 mRNAs signature could classify stage I-III RCC patients into low- or high-risk of early-relapse, and will help to guide interventions to optimize survival outcomes. more...

// Da-Long Cao 1, 2 , Ding-Wei Ye 1, 2 , Bo Dai 1, 2 , Hai-Liang Zhang 1, 2 , Yi-Jun Shen 1, 2 , Yao Zhu 1, 2 , Yi-Ping Zhu 1, 2 , Guo-Hai Shi 1, 2 , Chun-Guang Ma 1, 2 , Wen-Jun Xiao 1, 2 , Xiao-Jian Qin 1, 2 , Guo-Wen Lin 1, 2 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China Correspondence to: Ding-Wei Ye, e-mail: dwyeli@163.com Keywords: prostate cancer, susceptibility, polymorphism, glutathione S-transferases T1, glutathione S-transferases M1 Received: June 21, 2015 Accepted: September 14, 2015 Published: September 24, 2015 ABSTRACT Background: Genetic polymorphism was hypothesized to be reason of variation in prostate cancer incidence among different racial group. Based on that published data on the association of prostate cancer susceptibility with polymorphisms in genes encoding Glutathione S-transferases (GSTs) were inconclusive, the aim of this study was to more precisely address the role of GSTs polymorphisms (especially, GSTT1 and GSTM1 deletions) on prostate cancer risk in Asian descent. Methods: A meta-analysis including 8 articles with 711 cases and 1122 controls for GSTT1 and 1098 cases and 1588 controls for GSTM1 was performed. Results: Significantly increased prostate cancer risk was found among subjects carrying GSTM1 null genotype (odds ratio (OR) = 1.403; 95% confidence interval (CI) = 1.088 – 1.808) but not among subjects carrying GSTT1 deletion genotype (OR = 0.959; 95%CI = 0.709 – 1.297). When stratified by country, the null genotype of GSTT1 neither increased nor decreased prostate cancer risk significantly in China (OR = 1.355; 95%CI = 0.895 – 2.049), Japan (OR = 0.812; 95%CI = 0.545 – 1.211), and Korea (OR = 1.056; 95%CI = 0.727 – 1.534). While significant association of elevated prostate cancer risk with GSTM1 deletion were found in China (OR = 1.665; 95%CI = 1.324 – .094) and Korea (OR = 1.914; 95%CI = 1.311 – 2.793) but not in Japan (OR = 0.980; 95%CI = 0.726 – 1.321). Conclusion: In summary, this meta-analysis suggested that the null genotype of GSTM1 rather than GSTT1 may be involved in the etiology of prostate cancer in Asian population. more...

// Gui-Ming Zhang 1, 2 , Fang-Ning Wan 1, 2 , Xiao-Jian Qin 1 , Da-Long Cao 1 , Hai-Liang Zhang 1 , Yao Zhu 1 , Bo Dai 1 , Guo-Hai Shi 1 , Ding-Wei Ye 1 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Correspondence to: Guo-Hai Shi, e-mail: guohaishi@126.com Ding-Wei Ye, e-mail: yedingwei1963@126.com Keywords: TREK-1, prostate cancer, biochemical recurrence, cell proliferation, cell cycle Received: March 05, 2015 Accepted: April 13, 2015 Published: April 21, 2015 ABSTRACT Background: TREK-1 channels belong to the two-pore domain potassium channel superfamily and play an important role in central nervous system diseases. However, few studies have examined their role in carcinogenesis. Methods: In this study, we assessed the expression of TREK-1 in 100 prostate cancer (PCa) tissues using immunohistochemistry and further analyzed its clinicopathological significance. Next, cell proliferation and cell cycle analysis were carried out on human PCa PC-3 cell lines where TREK-1 was stably knockdown. Results: We found that compared with normal prostate tissues, PCa tissues showed overexpressed TREK-1 levels and TREK-1 levels were positively associated with Gleason score and T staging. High level of TREK-1 expression was related to shorter castration resistance free survival (CRFS). Furthermore, knockdown of TREK-1 significantly inhibited PCa cell proliferation in vitro and in vivo , and induced a G1/S cell cycle arrest. Conclusion: Our results suggest that TREK-1 might be a biomarker in CRFS judgment of PCa, as well as a potential therapeutic target. more...

BACKGROUND Multiplex urine-based assay emerged outperforms single biomarker (e.g., prostate-specific antigen, PSA) for predicting prostate cancer (CaP), whereas its combined mode has to be fully optimized. Our aim is to determine whether a strategy of combining gene-based, protein-based, metabolite-based with positive, negative makers in urine could optimize a multiplex model for detecting CaP. METHODS Using quantitative PCR, Western blot, and liquid chromatography-mass spectrometry, expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and urine PSA were evaluated in urine samples from 86 untreated patients with CaP and 45 patients with no evidence of malignancy. Multivariate logistic regression analysis was used to generate a final model and receiver-operating characteristic (ROC) analysis and special bootstrap software to assess diagnostic performance of tested variables. RESULTS The expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and a panel including these biomarkers were significant predictors of CaP both in patients with PSA 4–10 ng/ml and in all patients (all P more...

Micro (mi) RNAs are important regulators involved in various physical and pathological processes, including cancer. The miRNA-302 family has been documented as playing a critical role in carcinogenesis. In this study, we investigated the role of miRNA-302a in prostate cancer (PCa). MiRNA-302a expression was detected in 44 PCa tissues and 10 normal prostate tissues, and their clinicopathological significance was analyzed. Cell proliferation and cell cycle analysis were performed on PCa cells that stably expressed miRNA-302a. The target gene of miRNA-302a and the downstream pathway were further investigated. Compared with normal prostate tissues, miRNA-302a expression was downregulated in PCa tissues, and was even lower in PCa tissues with a Gleason score ≥8. Overexpression of miRNA-302a induced G1/S cell cycle arrest in PCa cells, and suppressed PCa cell proliferation both in vitro and in vivo. Furthermore, miRNA-302a inhibits AKT expression by directly binding to its 3΄ untranslated region, resulting in subsequent alterations of the AKT-GSK3β-cyclin D1 and AKT-p27Kip1 pathway. These results reveal miRNA-302a as a tumor suppressor in PCa, suggesting that miRNA-302a may be used as a potential target for therapeutic intervention in PCa. more...

The skeleton is the most common metastatic organ in patients with prostate cancer (PCa). Non-invasive biomarkers that can facilitate the detection and monitoring of bone metastases are highly desirable. We designed this study to assess the expression patterns of serum miR-141 in patients with bone-metastatic PCa. Serum samples were collected to measure the miR-141 level in 56 patients, including six with benign prostatic hyperplasia (BPH), 20 with localized PCa and 30 with bone-metastatic PCa (10 with hormone-naive PCa, 10 with hormone-sensitive PCa and 10 with hormone-refractory PCa). A bone scan was performed for each patient with PCa to assess the number of bone lesions. The quantification of serum miR-141 levels was assayed by specific TaqMan qRT-PCR. The results showed that serum miR-141 levels were elevated in patients with bone metastasis (P more...

To analyze the clinical and pathological informations of metastatic prostate cancer patients to find the predictive factors of the survival.To filter 364 cases of metastatic prostate cancer in the 940 cases of prostate cancer that were treated in Cancer Hospital Fudan University in Shanghai from March 1998 to June 2009, the cases had hormonal therapy and full clinical and pathological records. All the 364 cases were followed up and the clinical and pathological informations were analyzed, to find the predictive factors that related to the prognosis. Statistic software SPSS 15.0 was used for analysis. Cumulative survival was analyzed by the method of Kaplan-Meier. Cox regression was used for univariate and multivariate analysis. Log-rank method was used for the significance test.The last follow-up date was 30th June 2009 and the median follow-up time was 24 months. At the final follow-up, 240 cases were alive, 109 cases were dead and 15 cases were lost to follow up. The median survival time of metastatic prostate cancer was 64 months, and the one-year, two-year, three-year, four-year, five-year survival rate was 92%, 78%, 66%, 60%, 54%. The univariate analysis indicated that Gleason score (P = 0.033), clinical stage (P0.001), the effectiveness of hormonal therapy (P0.001), the prostate specific antigen (PSA) nadir during hormonal therapy (P0.001) and the time from the start of hormonal therapy to the PSA nadir (P = 0.002) were predictive factors for the survival time of metastatic prostate cancer. The multivariate analysis indicated that the PSA nadir during hormonal therapy (P0.001) and the time from the start of hormonal therapy to the PSA nadir (P0.001) were independent factors that predict the survival time of metastatic prostate cancer.The PSA nadir during hormonal therapy and the time from the start of hormonal therapy to the PSA nadir are independent factors that predict the survival time of metastatic prostate cancer. more...

Multiplex urine-based assay emerged outperforms single biomarker (e.g., prostate-specific antigen, PSA) for predicting prostate cancer (CaP), whereas its combined mode has to be fully optimized. Our aim is to determine whether a strategy of combining gene-based, protein-based, metabolite-based with positive, negative makers in urine could optimize a multiplex model for detecting CaP.Using quantitative PCR, Western blot, and liquid chromatography-mass spectrometry, expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and urine PSA were evaluated in urine samples from 86 untreated patients with CaP and 45 patients with no evidence of malignancy. Multivariate logistic regression analysis was used to generate a final model and receiver-operating characteristic (ROC) analysis and special bootstrap software to assess diagnostic performance of tested variables.The expression patterns of PCA3, TMPRSS2: ERG, Annexin A3, Sarcosine, and a panel including these biomarkers were significant predictors of CaP both in patients with PSA 4-10 ng/ml and in all patients (all P 0.05). Employing ROC analysis, the area under the curves of the panel in these both cohorts were 0.840 and 0.856, respectively, which outperform that of any single biomarker (PCA3: 0.733 and 0.739; TMPRSS2: ERG: 0.720 and 0.732; Annexin A3: 0.716 and 0.728; Sarcosine: 0.659 and 0.665, respectively).Compared with single biomarker, the multiplex model including PCA3, TMPRSS2: ERG, Annexin A3 and Sarcosine adds even more to the diagnostic performance for predicting CaP. Further validation experiments and optimization for the strategy of constructing this model are warranted. more...

More and more studies have revealed that the level of serum prostate specific antigen(PSA) has little value for early diagnosis of prostate cancer (PCa). For example, negative prostate biopsies are as high as 70%-80% for patients with serum PSA ranging between 4 ng/mL and 10 ng/mL. However, the negative results cannot exclude the existence of cancer. In the studies of the early diagnosis of PCa, investigators focused on seeking biomarkers that have higher sensitivity and specificity. Recently, PSA derivatives, HPC1, PCA3, TMPRSS2: ETS, GSTP1, AMACR, GOLPH2, EPCA, sarcosine, and the combination of multiple biomarkers are widely discussed. In this article, we have reviewed their recent development and the prospective value of the combination of multiple biomarkers, which may be helpful for the early diagnosis and the prognostic monitoring of patients with PCa. more...