Elevated ADH5 expression suggested better prognosis in kidney renal clear cell carcinoma (KIRC) and related to immunity through single-cell and bulk RNA-sequencing.

BACKGROUND: Despite the rapid advances in modern medical technology, kidney renal clear cell carcinoma (KIRC) remains a challenging clinical problem in urology. Researchers urgently search for useful markers to break through the therapeutic conundrum due to its high lethality. Therefore, the study explores the value of ADH5 on overall survival (OS) and the immunology of KIRC. METHODS: The gene expression matrix and clinical information on ADH5 in the TCGA database were validated using external databases and qRT-PCR. To confirm the correlation between ADH5 and KIRC prognosis, univariate/multivariate Cox regression analysis was used. We also explored the signaling pathways associated with ADH5 in KIRC and investigated its association with immunity. RESULTS: The mRNA and protein levels showed an apparent downregulation of ADH5 in KIRC. Correlation analysis revealed that ADH5 was directly related to histological grade, clinical stage, and TMN stage (p < 0.05). Univariate and multivariate Cox regression analysis identified ADH5 as an independent factor affecting the prognosis of KIRC. Enrichment analysis looked into five ADH5-related signaling pathways. The results showed no correlation between ADH5 and TMB, TNB, and MSI. From an immunological perspective, ADH5 was found to be associated with the tumor microenvironment, immune cell infiltration, and immune checkpoints. Lower ADH5 expression was associated with greater responsiveness to immunotherapy. Single-cell sequencing revealed that ADH5 is highly expressed in immune cells. CONCLUSION: ADH5 could be a promising prognostic biomarker and a potential therapeutic target for KIRC. Besides, it was found that KIRC patients with low ADH5 expression were more sensitive to immunotherapy.

Molecular subtypes based on metabolic genes are potential biomarkers for predicting prognosis and immune responses of clear cell renal cell carcinoma.

Due to the existence of tumor molecular heterogeneity, even patients having similar clinicopathological features could have vastly different survival rates. Hence, we aimed to explore novel metabolism-associated genes (MAGs) related molecular subtypes for clear cell renal cell carcinoma (ccRCC) and their immune landscapes for predicting prognosis and immune responses. Gene matrices and clinical information were downloaded from TCGA and ICGC datasets. Consensus clustering was conducted by the R "ConsensusClusterPlus" package. ccRCC patients were successfully divided into three clusters (MC1, MC2, and MC3) based on MAGs in both TCGA and ICGC datasets. Our established three MAGs were significantly associated with chemokine/chemokine receptor, IFN, CYT, angiogenesis, immune checkpoint molecules, tumor-infiltrating immune cells, oncogenic pathways, pan-cancer immune subtypes, and tumor microenvironment (TME) scores or expressions. Moreover, these three metabolic ccRCC subtypes could predict immunotherapeutic responses. We further constructed a characteristic index (LDAscore) in three metabolic ccRCC subtypes and identified LDAscore-related modules by WGCNA. After deep data mining, 10 hub genes were obtained and seven genes (ATRX, BPTF, DHX9, EP300, POLR2B, SIN3A, UBE3A) were finally validated by qRT-PCR. Our results successfully established a novel ccRCC subtype based on MAGs, providing novel insights into metabolism-related ccRCC tumor heterogeneity and facilitating individualized therapy for future work.

Development and External Validation of a Novel 12-Gene Signature for Prediction of Overall Survival in Muscle-Invasive Bladder Cancer.

Purpose: We aimed to develop and validate a novel gene signature from published data and improve the prediction of survival in muscle-invasive bladder cancer (MIBC). Methods: We searched the published gene signatures associated with the overall survival (OS) of MIBC and compiled all 274 genes to develop a novel gene signature. RNAseq data of TCGA (the Cancer Genome Atlas) bladder cohort were downloaded. All genes were included in a univariate Cox hazard ratio model. We then used a reduced multivariate Cox regression model, which included only genes achieving P < 0.05 in the univariate model. A total of 172 patients at Fudan University Shanghai Cancer Center (FUSCC) and 61 patients from GEO datasets were used as an external validation set. Results: A total of 327 patients in the TCGA cohort were enrolled. We identified 274 genes from eight published papers on the OS of MIBC. Using the TCGA database, we identified 12 genes that correlated with OS (P < 0.05 in both univariate and multivariate analyses). By integrating these genes with the RT-qPCR data in our validation dataset and GEO datasets, we confirmed that the power for predicting OS of the 12-gene panel (AUC of 0.741 and 0.727, respectively) was higher than just clinical data (including gender, age, T stage, grade, and N stage) alone in the TCGA and FUSCC cohort (AUC of 0.667 and 0.631, respectively). Additionally, upon combining the clinical data and 12-gene panel together, the AUC increased to 0.768, 0.757, and 0.88 in the TCGA, FUSCC and GSE13507 cohorts, respectively. Conclusions: Applying published gene signatures and TCGA data, we successfully built and externally validated a novel 12-gene signature for the survival of MIBC. BRIEF EXPLANATION: We systemically reviewed all published prognostic gene signatures of muscle-invasive bladder cancer (MIBC) and integrated the genes in the TCGA MIBC cohort. This new gene panel was validated in a newly established MIBC cohort in GEO and FUSCC. This method can help update the previous established panels in a new way.

MiR-455-5p Suppresses the Progression of Prostate Cancer by Targeting CCR5.

Accumulated evidence indicates that miR-455-5p functions as tumor suppressor in the progression of various cancers. However, the mechanism through which miR-455-5p influences the tumorigenesis of human prostate cancer (PCa) remains undetermined. In this study, reanalysis of data obtained from the Memorial Sloan Kettering Cancer Center showed that miR-455-5p can be used as biomarker for PCa diagnosis and predictor of poor prognosis. Functional assays indicated that miR-455-5p overexpression could suppress cellular proliferation, inhibit tumor growth, and trigger apoptosis by activating and cleaving caspase 3. We experimentally verified that miR-455-5p negatively regulated the C-C motif chemokine receptor 5 (CCR5). Overall, our data demonstrate that miR-455-5p suppressed PCa cellular proliferation and induced cell apoptosis by downregulating CCR5. Thus, miR-455-5p may be considered a new therapeutic strategy for PCa.

circLPAR1 is a novel biomarker of prognosis for muscle-invasive bladder cancer with invasion and metastasis by miR-762.

Circular RNAs (circRNAs) are a specific form of non-coding RNAs, that serve a pivotal role in the development of human diseases, including Alzheimer's disease and cancer; however, only a few are known with respect to cancer. The present study identified a novel circRNA, circ lysophosphatidic acid receptor 1 (LPAR1) (hsa_circ_0087960), derived from two exons 226 base pairs in length, in muscle-invasive bladder cancer (MIBC) tissues. circLPAR1 was identified to be lowly expressed in MIBC tissues in a cohort of 125 cases, and predicted a poor disease-specific survival time, compared with patients with high circLPAR1 expression (52.4 vs. 56.0 months; P=0.001) by univariate and multivariate Cox regression analyses. Matrigel and wound healing assays also demonstrated that the invasion of 5637 and T24 bladder cancer cells were significantly enhanced following the knockdown of circLPAR1 by small interfering RNA (si-circLPAR1-1 in T24 cell line, P=0.01; si-circLPAR1-2 in 5637 cell line, P=0.003; si-circLPAR1-2 in T24 cell line, P=0.002; si-circLPAR1-2 in 5637 cell line, P=0.006). The bioinformatics analysis indicated that circLPAR1 may harbor specific microRNAs (miRNAs) according to the miRNAs seed sequence matching. A luciferase reporter assay revealed that miR-762 can inhibit the activity of the transfected luciferase gene when inserted in a circLPAR1 wild-type fragment, and this inhibition could be alleviated when the luciferase gene was inserted in a circLPAR1 fragment with the mutated miR-762 target site. In conclusion, the circLPAR1 may function as a potential novel and stable biomarker for the prognosis of MIBC and may be associated with the invasion and metastasis by miR-762.

Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer.

Retinoic acid-related orphan receptor C (RORC) is a member of the nuclear orphan receptor family and performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various types of malignant tumors. Here we showed that expression of RORC is lost in tumor tissues of bladder cancer patients. Enhanced expression of RORC suppressed cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis in vitro and in vivo. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. PD-L1 directly interacted with integrin ß6 (ITGB6) and activated the ITGB6/FAK signaling pathway. RORC prevented the nuclear translocation of STAT3 via suppression of the PD-L1/ITGB6 signaling pathway, which further inhibited bladder cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis. These findings reveal that RORC regulates bladder cancer cell proliferation, glucose metabolism, and chemoresistance by participating in the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new understanding of PD-L1 signaling may guide the selection of therapeutic targets to prevent tumor recurrence. SIGNIFICANCE: These findings suggest that RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer provides several potential therapeutic targets to prevent tumor progression.

Tumor-associated Macrophage-derived Interleukin-23 Interlinks Kidney Cancer Glutamine Addiction with Immune Evasion.

BACKGROUND: Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities. OBJECTIVE: To seek a potential therapeutic target in glutamine-addicted ccRCC. DESIGN, SETTING, AND PARTICIPANTS: Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses. RESULTS AND LIMITATIONS: We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR]=2.04, cancer-specific survival [CSS] HR=2.95; all p<0.001) and Shanghai (OS HR=2.07, CSS HR=3.92; all p<0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor ß expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells. CONCLUSIONS: Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC. PATIENT SUMMARY: In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23-high patients had significantly poorer survival than IL-23-low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors.

Tumor stroma-infiltrating mast cells predict prognosis and adjuvant chemotherapeutic benefits in patients with muscle invasive bladder cancer.

Which subgroups patients with muscle-invasive bladder cancer (MIBC) could benefit most from adjuvant chemotherapy (ACT) is blurred. Here we tried to stratify MIBC patients with tumor infiltrating mast cells (TIMs), explore the prognostic and predictive value of TIMs, and provide possible cellular explanations. We selected 259 MIBC patients who underwent radical cystectomy from two independent clinical centers between 2002 and 2014. TIMs were evaluated and prognostic and predictive value was assessed. The CIBERSORT method, Gene Set Enrichment Analysis (GSEA) and differential gene expression analyses were performed to explore the possible cellular mechanisms. TIMs infiltration was distinct between stromal and epithelial area of MIBC specimens. Patients with higher stromal TIMs had a significant worse overall survival and recurrence free survival (HR = 2.228, 95%CI: 1.467-3.550; P = 0.001 and HR = 1.984, 95%CI: 1.105-3.374; P = 0.016). More importantly, pT2 patients with low stromal TIMs tended to have a lower risk of death and recurrence after ACT (HR = 0.233, 95%CI: 0.020-0.814; P = 0.033 and HR = 0.180, 95%CI: 0.022-0.722; P = 0.031). A negative correlativity between TIMs and CD8 + T cells was identified on TCGA-BLCA cohort. Immunohistochemistry results validated that high stromal TIMs were negatively correlated with CD8 + T cells (Spearman's rho = -0.215, P < 0.001). Differential gene expression suggested that low TIMs might represent a state of immune activation in MIBC. To conclude, high stromal TIMs infiltration was an independent unfavorable prognosticator for MIBC patients. Patients with low stromal TIMs might benefit the most from ACT, especially in pT2 stage.

B4GALT1 expression predicts prognosis and adjuvant chemotherapy benefits in muscle-invasive bladder cancer patients.

BACKGROUND: The expression alterations of B4GALT1 have been noted in some types of cancer and they are related to cancer cell proliferation, invasiveness, metastasis, and drug resistance. We aimed to establish the expression of B4GALT1 in bladder cancer and its connection to patient outcomes, as well as forecasting the advantages of adjuvant chemotherapy (ACT) in patients with muscle-invasive bladder cancer (MIBC). METHODS: There were 142 and 112 MIBC patients who were consecutively recruited and treated via radical cystectomy from 2008 to 2012 in Shanghai Zhongshan Hospital and Fudan University Shanghai Cancer Center (FUSCC), respectively. Tissue microarrays (TMAs) were constructed in triplicate from specimens that had been fixed in formalin and embedded in paraffin samples. Immunohistochemistry was conducted to evaluate B4GALT1 expression in tumor cores, the connection between B4GALT1 expression and patients' clinical characteristics, and clinical results. RESULTS: B4GALT1 expression was not connected to clinical prognosis markers, but it was linked to overall survival (OS) (P = 0.013 and P = 0.010, respectively) in the two groups. Moreover, the high levels of B4GALT1 expression were independent indicators of poor OS (P = 0.026 and P = 0.046, respectively). Inclusion of B4GALT1 in the prognostic model revealed a greater predictive accuracy than the primary models. In addition, no differences were observed between B4GALT1 expression (low vs. high) and CD8+ T cell infiltration density (number/cm2) within tumor cores, but there was a positive Pearson correlation between B4GALT1 expression and expression of inhibitory receptor ligands, such as PD-L1 and CTLA4. Most significantly, the advantage of ACT noted in pT3/4 or N+ bladder cancer patients with low B4GALT1 expression was greater than in patients with a high B4GALT1 expression. CONCLUSIONS: Our evaluation indicated that B4GALT1 may be a possible prognosticator of MIBC, and it may be a predictive marker for the choice of ACT in pT3/4 or N+ patients.

Author Correction: The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Identification and Validation of Stromal Immunotype Predict Survival and Benefit from Adjuvant Chemotherapy in Patients with Muscle-Invasive Bladder Cancer.

Purpose: This study aims to construct the stromal immunotype, which could improve the prediction of postsurgical survival and adjuvant platinum-based chemotherapy in muscle-invasive bladder cancer (MIBC).Experimental Design: A total of 118 patients with MIBC from Shanghai Cancer Center, 140 patients with MIBC from Zhongshan Hospital, and 287 patients with MIBC from TCGA cohort were included in the study. Immune cell infiltration was evaluated by IHC staining or CIBERSORT method. Five immune features were selected out of 22 immune features to construct immunotypes based on the LASSO Cox regression model.Results: Using the LASSO model, we classified patients with MIBC into stromal immunotype A subgroup (CTLhighNKhighTreglowMacrophagelowMClow) and stromal immunotype B subgroup (CTLlowNKlowTreghighMacrophagehighMChigh). Significant differences were found between immunotype A and immunotype B in the combined cohort with 5-year overall survival (OS, 76.0% vs. 44.0%; P < 0.001) and 5-year disease-free survival (DFS, 62.8% vs. 48.3%; P < 0.001). Stromal immunotype was revealed to be an independent prognostic indicator in multivariate analysis in all cohorts separately. Either OS or DFS was not improved by adjuvant chemotherapy (ACT) in pT2 stage patients or pT3+pT4 patients, but further analysis revealed that OS and disease-free was significantly improved by ACT in pT3+pT4 patients (P = 0.016 and P = 0.006, respectively). Finally, stromal immunotype A showed higher immune checkpoint molecules (PD-L1, PD-1, and CTLA-4) expression.Conclusions: The stromal immunotypes could effectively predict survival and recurrence of MIBC. Furthermore, the immunotypes might be a practical predictive tool to identify pT3+pT4 patients who would benefit from ACT. Clin Cancer Res; 24(13); 3069-78. ©2018 AACR.

Prognostic and Predictive Value of O6-methylguanine Methyltransferase for Chemotherapy in Patients with Muscle-Invasive Bladder Cancer.

PURPOSE: DNA repair genes are potential biomarkers for chemotherapy in muscle-invasive bladder cancer (MIBC). O6-methylguanine methyltransferase (MGMT) is involved in DNA repair and is found to affect the efficacy of platinum-based chemotherapy. However, the prognostic or predictive value of MGMT expression in chemotherapy for MIBC is unknown. MATERIALS AND METHODS: Immunohistochemical staining for MGMT was performed in paraffin-embedded tumor tissue of high-grade MIBC patients who underwent cystectomy in two independent cohorts [n = 74 for Fudan University Shanghai Cancer Center (FUSCC) cohort and n = 115 for Zhongshan Hospital (ZS) cohort]. MGMT messenger RNA (mRNA) analysis was conducted using patients' clinical and fragments per kilobase of exon model per million mapped fragments mRNA data from The Cancer Genome Atlas (TCGA) database (n = 245). RESULTS: In our cohorts, high MGMT expression was significantly correlated with shorter overall survival (OS) in patients with platinum-based adjuvant chemotherapy [hazard ratio (HR) 2.386, p = 0.048; HR 2.920, p = 0.007; HR 2.324, p = 0.004, respectively, in FUSCC, ZS, and combination sets], but not in patients without chemotherapy. These findings were corroborated by the TCGA set (HR 1.952 and 0.697 for patients with and without chemotherapy, respectively). The chemotherapy-MGMT interaction for OS was significant in both the surgery set (p = 0.045) and TCGA set (p = 0.034). CONCLUSIONS: We demonstrated that high MGMT expression is an independent poor prognostic factor in MIBC patients with platinum-based adjuvant chemotherapy, but not in patients without chemotherapy. MGMT expression may be a potential predictor for administration of adjuvant chemotherapy.

External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer.

Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC); however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS). We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%), 34 (30.9%), and 17 (15.5%) in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l-1), liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months) as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678-0.836). In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.

Expression of ARID1B Is Associated With Poor Outcomes and Predicts the Benefit from Adjuvant Chemotherapy in Bladder Urothelial Carcinoma.

Background ARID1B, which exists as a mutually exclusive isoform with ARID1A in the SWI/SNF chromatin remodeling complex, has been recently identified as a major mutant gene in a wide variety of cancers. The present study aimed to determine the association between ARID1B expression and outcomes, as well as the benefit from adjuvant chemotherapy in patients with bladder cancer. Methods Tissue microarrays of 143 consecutively recruited patients with bladder cancer from our center were created. Immunohistochemistry was performed to assess the expression of ARID1B and its association with outcomes. Clinicopathological factors were also evaluated. Results ARID1B expression was significantly associated with tumor size (P=0.015), T stage (P=0.027), lymph node status (P=0.030), TNM stage (P=0.040), overall survival (P<0.001), and progression-free survival (P=0.043). Furthermore, high expression of ARID1B was an independent indicator of poor OS (P=0.022). The prognostic model containing ARID1B showed a better predictive accuracy than the bench models. Most importantly, the benefit of adjuvant chemotherapy observed in patients with low ARID1B expression was superior to that observed in patients with high ARID1B expression. Conclusions Our study suggests that ARID1B can serve as a prognostic biomarker of bladder urothelial carcinoma. Additionally, ARID1B might be a predictive marker for selecting patients for adjuvant chemotherapy in the high-risk subgroup.

High CXC chemokine receptor 1 level represents an independent negative prognosticator in non-metastatic clear-cell renal cell carcinoma patients.

CXC chemokine receptor 1 (CXCR1) signaling has been shown as an essential molecular nexus regarding cancer cell proliferation, tumor inflammation, and angiogenesis in clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the prognostic significance of CXCR1 in patients with non-metastatic ccRCC. Data from 446 consecutive non-metastatic ccRCC patients, operated between 2003 and 2008 at a single institution, were evaluated retrospectively. The cohort was split into a training set (n = 223) and a validation set (n = 223). CXCR1 expression was assessed by immunohistochemistry staining and its association with clinicopathologic features and prognosis were evaluated. High CXCR1 epithelial expression presented prognostic value, and indicated poor overall survival (OS) (P = 0.010 and P = 0.015, respectively) and recurrence-free survival (P = 0.011 and P = 0.019, respectively) in the training and validation sets. The incorporation of CXCR1 into the T stage and SSIGN score would help to refine individual risk stratification. Multivariate analysis identified increased epithelial CXCR1 was statistically significantly associated with a poor outcome for OS (HR [95% CI] 1.808 [1.184-2.761]; P = 0.006) and RFS (HR [95% CI] 1.570 [1.076-2.290]; P = 0.019) in all non-metastatic ccRCC patients. Predictive nomograms were generated with identified independent prognosticators to assess patient overall survival and recurrence-free survival at 3, 5 and 10 y. Furthermore, high CXCR1 expression were correlated with elevated infiltrated neutrophils and enriched MMP family gene expression. To conclude, high CXCR1 level within epithelial area represented a potential independent negative prognostic factor regarding OS and RFS in non-metastatic ccRCC patients after nephrectomy.

High mucin 5AC expression predicts adverse postoperative recurrence and survival of patients with clear-cell renal cell carcinoma.

BACKGROUND: Mucin 5AC (MUC5AC), as a member of secreted/gel-forming mucin family, was frequently found to be abnormally expressed in inflammation or malignant diseases. However, the clinic pathologic features and prognostic values of MUC5AC in clear-cell renal cell carcinoma (ccRCC) have not been reported up to now. METHODS: MUC5AC expression was analyzed by immunohistochemistry on tissue microarrays. Kaplan-Meier survival curves, Univariate and Multivariate Cox analysis and newly-established nomogram model were performed to evaluate the prognostic value. RESULTS: MUC5AC expression was firstly found to be up-regulated in patients with ccRCC, positively associated with tumor size, pN stage, lymphovascular invasion, Fuhrman grade, rahbdoid differentiation, sarcomatoid features, tumor necrosis, ECOG-PS and recurrence. Furthermore, MUC5AC expression might be contributed to risk stratification of ccRCC patients with TNM stage III+IV or Fuhrman grade 3 or 4 for overall survival (OS) and recurrence-free survival (RFS) analysis, and it was demonstrated to be negatively correlated with OS and RFS of ccRCC patients. What's more, MUC5AC was identified as a potential independent adverse prognostic factor; prediction accuracy of MUC5AC-based new nomogram model was drastically improved for OS and RFS of ccRCC patients. CONCLUSION: MUC5AC is a promising independent adverse prognostic factor for ccRCC patients, it maybe conducive to postoperative risk stratification and guide treatment in the future.

The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII α1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients' survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.

Beta-1,4-galactosyltransferase II predicts poor prognosis of patients with non-metastatic clear-cell renal cell carcinoma.

Beta-1,4-galactosyltransferase II is found to be associated with the alterations of tumor-related glycosylation. However, the clinical significance of beta-1,4-galactosyltransferase II in non-metastatic clear-cell renal cell carcinoma has not been reported up to now. Herein, our researches suggested that the expression level of beta-1,4-galactosyltransferase II was first found to be positively associated with tumor size, Fuhrman grade, lymphovascular invasion, rhabdoid differentiation, tumor necrosis and poor overall survival and recurrence-free survival of patients with non-metastatic clear-cell renal cell carcinoma, both in training set and validation set. Moreover, beta-1,4-galactosyltransferase II expression was identified as an independent adverse prognosticator for overall survival and recurrence-free survival of patients with non-metastatic clear-cell renal cell carcinoma. Ultimately, prognostic accuracy of the nomogram integrating beta-1,4-galactosyltransferase II with other independent prognostic parameters was dramatically improved for overall survival and recurrence-free survival of patients with non-metastatic clear-cell renal cell carcinoma. Taken together, beta-1,4-galactosyltransferase II is a potential independent adverse prognostic factor for postoperative recurrence and survival, which could be developed as a useful biomarker for non-metastatic clear-cell renal cell carcinoma by a series of further independent and retrospective studies, so as to help the postsurgical management of clear-cell renal cell carcinoma patients.

Tumor Infiltrating Mast Cells (TIMs) Confers a Marked Survival Advantage in Nonmetastatic Clear-Cell Renal Cell Carcinoma.

PURPOSE: The role played by the innate immune system in determining the clinical outcome of clear-cell renal cell carcinoma (ccRCC) was still blurred. This study was designed to investigate the prognostic significance of tumor infiltrating mast cells (TIMs) in ccRCC. METHODS: The study retrospectively enrolled a training set (474 patients) and a validation set (188 patients) with nonmetastasis (pT1-4N0M0) ccRCC from two institutional medical centers of China. TIMs was evaluated by immunohistochemical staining of tryptase and its association with clinicopathologic features and prognosis were evaluated. RESULTS: In ccRCC tissues, TIMs ranged from 0 to 103 cells/mm2 and 0 to 113 cells/mm2 in the training set and validation set, respectively. TIMs was negatively correlated with tumor size (P < 0.001 and P < 0.001, respectively), pathological T stage (P = 0.005 and P = 0.007, respectively) and Fuhrman grade (P < 0.001 and P < 0.001, respectively). Patients with abundant TIMs infiltration showed significantly longer cancer-specific survival in the training cohort and the validation cohort (P < 0.001 and P < 0.001). Patients with abundant mast cell infiltration showed significantly longer overall survival in the TCGA cohort (P < 0.001). Moreover, multivariate analysis identified TIMs as an independent prognostic factor for cancer-specific survival (CSS) and relapse-free survival (RFS). Also, TIMs was significantly correlated with CSS and RFS of the mediate and high-risk patients in the training cohort and the validation cohort. CONCLUSIONS: TIMs density is a powerful independent prognostic factor for CSS and RFS in patients with nonmetastasis (pT1-4N0M0) ccRCC.