Ipsilateral synchronous papillary and clear renal cell carcinoma:A case report and review of literature

BACKGROUND There is limited information on ipsilateral synchronous papillary renal cell carcinoma(PRCC)and clear cell renal cell carcinoma(CCRCC).Therefore,these rare tumors are often misdiagnosed preoperatively as a single tumor with intrarenal metastasis or some other diseases.Effective management and long-term overall survival might be affected because the prognosis of the two tumors differs.CASE SUMMARY We describe a case of ipsilateral synchronous PRCC and CCRCC with two histological variants in a 72-year-old man,whose mass was found incidentally,with no other chief complaints and vital signs were normal.Initial ultrasound revealed a hypoechoic lobular mass with a volume of 7.8 cm×4.8 cm×2.8 cm in the middle to lower pole of the left kidney.A subsequent contrast-enhanced computed tomography scan showed a single endophytic mass of 7.5 cm in diameter.The patient underwent laparoscopic left radical nephrectomy.A final diagnosis of ipsilateral synchronous PRCC and CCRCC was confirmed by pathological examination.There was no recurrence or metastasis after 25 mo follow-up.CONCLUSION We report a case of ipsilateral synchronous PRCC and CCRCC,and review related literature to estimate the prevalence of similar cases.The above descriptions may be expected to help understand the disease,and improve diagnosis in the future.

Low expression of fatty acid oxidation related gene ACADM indicates poor prognosis of renal clear cell carcinoma and is related to tumor immune infltration

This research aims to identify the key fatty acid beta-oxidation(FAO)genes that are altered in kidney renal clear cell carcinoma(KIRC)and to analyze the role of these genes in KIRC The Gene Expression Omnibus(GEO)and FAO datasets were used to identify these key genes.Wilcoxon rank sum test was used to assess the levels of acyl-CoA dehydrogenase medium chain(ACADM)between KIRC and non cancer samples.The logistic regression and Wilcoxon rank sum test were used to explore the association between ACADM and clinical features.The diagnostic performance of ACADM for KIRC was asessed using a diagnostic receiver operating ch aracteristic(ROC)curve.The co-expressed genes of ACADM were identifed in LinkedOmics database,and their function and pathway enrichment were analyzed.The correlation between ACADM expression level and immune infitration was analyzed by Gene Set Variation Analysis(GSVA)method Additionally,the proliferation,migration,and invasion abilities of KIRC cells were assessed after overexpressing ACADM.Following differential analysis and intersection,we identifed six hub genes,induding ACADM.We found that the expression level of ACADM was decreased in KIRC tissues and had a better diagnostic efect(AUC=0.916).Survival analysis suggested that patients with decreased ACADM expression had a worse prognosis.According to correlation analysis,a variety of dinical features were associated with the expression level of ACADML By analyzing the infiltration level of immune cells,we found that ACADM may be related to the enrichment of immune cells.Finally,ACADM overexpression inhibited proliferation,migration,and invasion of KIRC cells.In conclusion,our findings suggest that reduced ACADM expression in KIRC patients is indicative of poor prognosis.These results imply that ACADM may be a diagnostic and prognostic marker for individuals with KIRC,offering a reference for dinicians in diagnosis and treatment.

Network pharmacology and molecular docking analysis reveal insights into the molecular mechanism of Gualou Qumai Wan in clear cell renal cell carcinoma

Background:To initially clarify the potential therapeutic targets and pharmacological mechanism regarding Gualou Qumai Wan(GQW),a kind of traditional Chinese medicine(TCM),in clear cell renal cell carcinoma(ccRCC)by virtue of the network pharmacology analysis and molecular docking analysis.Methods:The screening of bioactive components and targets of GQW was based on the Traditional Chinese Medicine System Pharmacology(TCMSP)and the UniProt platform served for standardizing their targets.Online Mendelian Inheritance in Man(OMIM),PharmGkb,TTD,DrugBank and GeneCards databases were searched to collect the disease targets of ccRCC.Cytoscape assisted in constructing herb-compound-target(H-C-T)networks.The STRING database was searched for constructing the target protein-protein interaction(PPI)networks,while the R programming language served for analyzing GO functional terms and the KEGG pathways related to potential targets.Analyses of core genes related to survival and tumor microenvironment(TME)were conducted respectively based on the GEPIA2 database and TIMER 2.0 database.Human Protein Atlas(HPA)and The Cancer Genome Atlas(TCGA)helped to obtain core genes’protein expression as well as transcriptome expression level.Autodock Vina software validated the molecular docking regarding GQW components and pivotal targets.Results:The constructed H-C-T networks mainly had 33 compounds and 65 targets.A topological analysis of the PPI network identified that ESR1,AKT1,HIF1A,PTGS2,TP53 and VEGFA serve as core targets in the way GQW affects ccRCC.According to the GO and KEGG pathway enrichment analyses,the effects of GQW are mediated by genes related to hypoxia and oxidative stress as well as the Chemical carcinogenesis-receptor activation and PI3K-Akt signaling pathways.AKT1 shows a close relation to the recruitment of various immune cells and can remarkably affect disease prognosis according to reports.Molecular docking and molecular dynamics simulations showed that diosgenin has higher affinity with core targets.Conclusion:The study makes a comprehensive explanation of the biological activity,potential targets,as well as molecular mechanism regarding GQW against ccRCC,which promisingly assists in revealing the action mechanism of TCM formulae in disease treatment and the respective and scientific basis.

Solute carrier-related signature for assessing prognosis and immunity in patients with clear-cell renal cell carcinoma

Background:Clear-cell renal cell carcinoma(ccRCC)is the most common malignant kidney cancer.However,the tumor microenvironment and crosstalk involved in metabolic reprogramming in ccRCC are not well-understood.Methods:We used The Cancer Genome Atlas to obtain ccRCC transcriptome data and clinical information.The EMTAB-1980 cohort was used for external validation.The GENECARDS database contains the first 100 solute carrier(SLC)-related genes.The predictive value of SLC-related genes for ccRCC prognosis and treatment was assessed using univariate Cox regression analysis.An SLC-related predictive signature was developed through Lasso regression analysis and used to determine the risk profiles of patients with ccRCC.Patients in each cohort were separated into high-and low-risk groups based on their risk scores.The clinical importance of the signature was assessed through survival,immune microenvironment,drug sensitivity,and nomogram analyses using R software.Results:SLC25A23,SLC25A42,SLC5A1,SLC3A1,SLC25A37,SLC5A6,SLCO5A1,and SCP2 comprised the signatures of the eight SLCrelated genes.Patients with ccRCC were separated into high-and low-risk groups based on the risk value in the training and validation cohorts;the high-risk group had a significantly worse prognosis(p<0.001).The risk score was an independent predictive indicator of ccRCC in the two cohorts according to univariate and multivariate Cox regression(p<0.05).Analysis of the immune microenvironment showed that immune cell infiltration and immune checkpoint gene expression differed between the two groups(p<0.05).Drug sensitivity analysis showed that compared to the low-risk group,the high-risk group was more sensitive to sunitinib,nilotinib,JNK-inhibitor-VIII,dasatinib,bosutinib,and bortezomib(p<0.001).Survival analysis and receiver operating characteristic curves were validated using the E-MTAB-1980 cohort.Conclusions:SLC-related genes have predictive relevance in ccRCC and play roles in the immunological milieu.Our results provide insight into metabolic reprogramming in ccRCC and identify promising treatment targets for ccRCC.

Aryl hydrocarbon receptor nuclear translocator 2 as a prognostic biomarker and immunotherapeutic indicator for clear cell renal cell carcinoma

Background:In many cancer types,aryl hydrocarbon receptor nuclear translocator 2(ARNT2)has been found to be associated with tumor cell proliferation and prognosis.However,the role of ARNT2 in clear cell renal cell carcinoma(ccRCC)has not been completely elucidated.In this study,the potential role of ARNT2 in ccRCC development was characterized.Methods:A pan-cancer dataset(TCGA-TARGET-GTEx)was accessed from UCSC Xena Data Browser.ARNT2 expression in normal and tumor samples was compared.Univariate Cox regression was performed to evaluate the prognostic value of ARNT2.Single sample gene set enrichment analysis(ssGSEA)was used to estimate the enrichment of functional pathways and gene signatures.CIBERSORT and ESTIMATE methods evaluated the immune infiltration.The ARNT2 expression was determined in ccRCC tissue and cell lines using RT-qPCR and Western blot.Results:ARNT2 expression was significantly dysregulated in 23 out of 30 cancer types.Pan-cancer data revealed a strong correlation between ARNT2 expression and immune modulators,immune cell infiltration,and genomic alternations.In ccRCC patients,the low-ARNT2 expression group had higher immune infiltration,CD8 T cells,and programmed cell death ligand 1 expression,as well as higher enrichment score of immunotherapeutic predictors than those in the high-ARNT2 expression group.Low-ARNT2 expression group was more responsive to immunotherapy.Moreover,low ARNT2 expression was observed in ccRCC tissue and cell lines.Conclusions:Dysregulated ARNT2 expression is involved in cancer development and the modulation of the immune microenvironment.ARNT2 can be potentially used as a prognostic indicator and an immunotherapeutic indicator for ccRCC.

Iris metastasis from clear cell renal cell carcinoma: A case report

BACKGROUND Clear cell renal cell carcinoma(ccRCC)is a common type of tumor that can metastasize to any organs and sites.However,it is extremely rare for ccRCC to metastasize to the iris.Here,we describe a rare case of iris metastasis from ccRCC with a history of left nephrectomy in 2010.CASE SUMMARY A 62-year-old male was admitted to the hospital due to blurred vision and red eyes,and a mass was found on the iris in the right eye.B-scan ultrasonography revealed a well-bounded high-density lesion at the corner of the anterior chamber at the 3-4 o’clock position.Phacoemulsification with simultaneous intraocular lens implantation and iridocyclectomy was performed in the right eye.The lesion was confirmed to be metastatic ccRCC by histological and immunohistochemical analyses.The patient was still alive at 9 mo after surgical treatment.Ocular metastasis can be an initial sign with a poor prognosis.Timely detection and treatment may improve survival.Clinicians should pay attention to similar metastatic diseases to prevent misdiagnosis leading to missed treatment oppor-tunities.CONCLUSION This report of the characteristics and successful management of a rare case of iris metastasis from ccRCC highlights the importance of a comprehensive medical history,histopathology,immunohistochemistry,and clinical manifestation for successful disease diagnosis.

Pembrolizumab combined with axitinib in the treatment of skin metastasis of renal clear cell carcinoma to nasal ala:A case report

BACKGROUND Renal clear cell carcinoma(RCC)is a malignant tumor of the genitourinary system with a predilection for males.The most common metastatic sites are the lung,liver,lymph nodes,contralateral kidney or adrenal gland,however,skin metastasis has only been seen in 1.0%-3.3%of cases.The most common site of skin metastasis is the scalp,and metastasis to the nasal ala region is rare.CASE SUMMARY A 55-year-old man with clear cell carcinoma of the left kidney was treated with pembrolizumab and axitinib for half a year after surgery and was found to have a red mass on his right nasal ala for 3 mo.The skin lesion of the patient grew rapidly to the size of 2.0 cm×2.0 cm×1.2 cm after discontinuation of targeted drug therapy due to the coronavirus disease 2019 epidemic.The patient was finally diagnosed with skin metastasis of RCC in our hospital.The patient refused to undergo surgical resection and the tumor shrank rapidly after resuming target therapy for 2 wk.CONCLUSION It is rare for an RCC to metastasize to the skin of the nasal ala region.The tumor size change of this patient before and after treatment with targeted drugs shows the effectiveness of combination therapy for skin metastasis.

Correlation between Hypovitaminosis D Status and Hyperactivation of IL-6/STAT3 Signaling in Clear Cell Renal Cell Carcinoma

Objective:To analyze serum vitamin D levels in patients with clear cell renal cell carcinoma(ccRCC)by flow cytometry and to investigate the relationship between hypovitaminosis D status and hyperactivation of IL-6/STAT3 signaling in ccRCC.Methods:Eighty patients diagnosed with ccRCC by our oncology department from January 2019 to December 2021 were selected as study subjects,and the control subjects were selected from patients who were receiving health check-up from our hospital(matched according to case group:control group,1:2),with 160 healthy patients.All serum samples collected from the case-control subjects were allowed to stand for 1–2 hours,centrifuged at 3000 rpm for 10 minutes,and stored in a-80°C refrigerator,from which they were removed and thawed to measure 25-hydroxyvitamin D(25(OH)D)and interleukin 6(IL-6)levels.Results:The blood calcium level of patients in the cancer group was significantly lower than that of patients in the non-cancer group,and the difference was statistically significant(P<0.05).The IL-6 level of the cancer group was significantly higher than that of the non-cancer group.In high vitamin D state,the IL-6 level of the non-cancer group was higher than that of the cancer group,and the average concentration of IL-6 in both the cancer group and the non-cancer group was significantly higher in low vitamin D state compared with high vitamin D state(P<0.05);the correlation between hypovitaminosis D status and renal Ki-67 was found to be positive.Conclusion:The results showed that serum IL-6 levels were elevated in the cancer group and circulating serum 25(OH)D levels were negatively correlated with IL-6 levels.In addition,signal transducer and activator of transcription 3(STAT3)signaling in RCC tissues was activated in ccRCC patients and in those with low vitamin D status among the cancer group and was higher than that in those with high vitamin D status.These results suggest that hypovitaminosis D status in ccRCC patients is associated with activated IL-6/STAT3 signaling and the activation of tumor proliferation markers proliferating cell nuclear antigen(PCNA),cyclin D1,and Ki-67.

Epigenomics of clear cell renal cell carcinoma： mechanisms and potential use in molecular pathology

Clear cell renal cell carcinoma （ccRCC） is one frequent form of urologic malignancy with numerous genetic and epigenetic alterations. This review summarizes the recent major findings of epigenetic alterations including DNA methylation, histone modifications, microRNAs and recently identified long noncoding RNAs in the development and progression of ccRCC. These epigenetic profilings can provide a promising means of prognostication and early diagnosis for patients with ccRCCs. With the developed high- throughput technologies nowadays, the epigenetic analyses will have possible clinical applications in the molecular pathology of ccRCC.

Aberrant DNA methyltransferase 1 expression in clear cell renal cell carcinoma development and progression

Objective： To better understand the contribution of dysregulated DNA methyltransferase 1 （DNMT1） expression to the progression and biology of clear cell renal cell carcinoma （ccRCC）. Methods： We examined the differences in the expression of DNMT1 in 89 ecRCC and 22 normal tissue samples by immunohistochemistry. In addition, changes in cell viability, apoptosis, colony formation and invading ability of ccRCC cell lines （786-0 and Caki-1） were assessed after transfection with DNMT1 siRNA. Results： We found DNMT1 protein was significantly higher expressed in ccRCC than that of in no-tumor tissues （56.2% and 27.3%, respectively, P=0.018）. The expression of DNMT1 was strongly associated with ccRCC tumor size, tumor pathology stage, histological grading, lymph node metastasis, vascular invasion, recurrence and prognosis. Moreover, knockdown of DNMT1 expression significantly inhibited ccRCC cell viability, induced apoptosis, decreased colony formation and invading ability. Conclusions： Expression of DNMTI protein is increased in ccRCC tissues, and DNMT1 expression is associated with poor prognosis of patients. Experiments in vitro further showed DNMT1 played an essential role in proliferation and invasion of renal cancer cells. Moreover, targeting this enzyme could be a promising strategy for treating ccRCC, as evidenced by inhibited cell viability, increased apoptosis, decreased colony formation and invading ability.

Memory stem T cells generated by Wnt signaling from blood of human renal clear cell carcinoma patients

Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.

Correlation Between Hyaluronic Acid,Hyaluronic Acid Synthase And Human Renal Clear Cell Carcinoma

Objective：To study the correlation between hyaluronic acid（HA）,hyaluronic acid synthase（HAS） and human renal clear cell carcinoma（RCCC）.Methods：The expression of three HAS isoforms＇ gene and HA in 93 RCCC tissues,27 nephridial tissues by the side of RCCC from two hospitals were measured with Real-Time RT-PCR、Western Blot and immunohistochemical methods and analyzed.Results：All RCCC and adjacent normal tissues expressed three HASs＇ mRNA protein;at the mRNA level,both RCCC and adjacent normal tissues,expressed more HAS3 than HAS1 or HAS2,their differences were statistically significant（all P values 0.05）;but,at the protein level,all HAS isoforms presented the equivalent expression.Compared with the adjacent non-neoplastic kidney tissues,the expression of all HAS isoforms＇ mRNA in RCCC tissues were increased evidently and their differences were significant（all P values 0.0001）;but at the protein level,only the expression of HAS3 increased evidently（P=0.022）.In all adjacent normal tissues,more than 80% renal tubular cells strongly expressed HA,however,only the minority RCCC cases（16/93） presented weakly positive HA staining in few cancer nests（5%-30%）,the difference were significant（P0.0001）.In RCCC tissues subgrouped according to clinical stage,pathological grade,lymphatic metastasis or not and distant metastasis or not,the HASs＇ mRNA protein differential expression all had no statistical significance（all P values 0.05）.Conclusion：Different from other malignancy,HA and HASs（except for HAS3） may not play important roles in the biological progress of human RCCC.

Clival metastasis of renal clear cell carcinoma: Case report and literature review

The clivus is an atypical metastatic site for renal clear cell carcinoma(RCCC). Here we report a 54 year old man with acute cavernous sinus syndrome. Brain magnetic resonance imaging identified a clival-based lesion with associated bony erosion. The patient underwent endoscopic endonasal biopsy and partial resection of the clival mass. Because histologic examination of the resected specimen resulted in a diagnosis of RCCC, contrast-enhanced computed tomography scan of the abdomen was performed and showed an enhanced left renal mass. The patient subsequently underwent laparoscopic left radical nephrectomy and gamma knife was planned for the residual clival lesion. We also retrospectively reviewed available published reports on clival metastases, specifically those from RCCC, since 1990.

Pomegranate extract inhibits EMT in clear cell renal cell carcinoma in a NF-κB and JNK dependent manner

Objective:Clear cell renal cell carcinoma(ccRCC)is the most common subtype of renal cell carcinoma(RCC)and is characterized by biallelic inactivation of the von Hippel-Lindau(VHL)tumor suppressor gene.One effect of VHL inactivation is hypoxia inducible factor alpha(HIFa)-independent constitutive activation of nuclear factor kappa B(NF-κB)and c-jun N-terminal kinase(JNK).Both NF-κB and JNK drive ccRCC growth and epithelial to mesenchymal transition(EMT).The purpose of this study was to determine the biochemical effects of pomegranate juice extracts(PE)on RCC cell lines.Methods:The pre-clinical effects of PE on NF-κB,JNK,and the EMT phenotype were assayed,including its effect on proliferation,anchorage-independent growth,and invasion of pVHLdeficient RCCs.Results:PE inhibits the NF-κB and JNK pathways and consequently inhibits the EMT phenotype of pVHL-deficient ccRCCs.The effects of PE are concentration-dependent and affect not only biochemical markers of EMT(i.e.,cadherin expression)but also functional manifestations of EMT,such as invasion.These effects are manifested within days of exposure to PE when diluted 2000-fold.Highly dilute concentrations of PE(106 dilution),which do not impact these pathways in the short term,were found to have NF-κB and JNK inhibitory effects and ability to reverse the EMT phenotype following prolonged exposure.Conclusion:These findings suggest that PE may mediate inhibition growth of pVHL-deficient ccRCCs and raises the possibility of its use as a dietary adjunct to managing patients with active surveillance for small,localized,incidentally identified renal tumors so as to avoid more invasive procedures such as nephrectomy.

Characteristics of clear cell renal cell carcinoma metastases to the thyroid gland: A systematic review

BACKGROUND Thyroid gland is an uncommon site for metastases from clear cell renal cell carcinoma(CCRCC)and literature is scarce.Due to the variable and often long lag time before development of metastases in patients with CCRCC,thyroid nodules may be misdiagnosed initially as benign.This systematic review aims at a better understanding of the nature of these metastases.METHODS A bibliographic search was performed using PubMed(1990-2019),key words being“renal cell carcinoma,thyroid,kidney cancer,clear cell.”147 cases were analyzed.The patient’s characteristics assessed were:age,sex,stage,size of metastases,lag time,diagnostic modality,initial symptoms,treatment and outcome in last documented follow up.Binary logistic regression,Spearman’s rho and ANOVA were used to identify differences between the existing variables.RESULTS The mean age(±SD)was 64±(10)years in males and 64(±11)in females.The mean lag time to diagnosis of thyroid metastases was 8.7(±6.3)years.Gender distribution of the patients was 46.3%male,52.4%female.There was a weak correlation between lag time and size of metastases,not statistically significant.Size of metastases was significantly higher in symptomatic patients(6.06±3.51 cm)compared to those with painless mass(4.6±0.29 cm)and asymptomatic ones(3.93±1.99 cm)(P=0.03).Fine Needle Aspiration was diagnostic in 29.4%of cases,47.1%were non diagnostic.Most patients(80.3%)underwent thyroid surgery.At 1 year follow up,55.6%of patients operated were alive versus 35.3%who did not have surgery,though this was not statistically significant(P=0.1).CONCLUSION A larger size of thyroid metastasis was more likely to present with symptomatology.A high index of suspicion is warranted when evaluating thyroid nodules in CCRCC patients.There was no significant difference in outcome between patients who underwent surgery and those who did not.With the wider use of immune check-point inhibitors and tyrosine kinase inhibitors in metastatic CCRCC,surgery may eventually be reserved only for palliative purposes.

Clear cell papillary renal cell carcinoma: A case report and review of the literature

Clear cell papillary renal cell carcinoma(ccpRCC) was recently established as a distinct type of epithelial neoplasm by the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia. Here,we report a case of partial nephrectomy for a ccpRCC detected during the routine follow-up of a previously treated liposarcoma in a 70-year-old male patient. The patient was referred to the urology department for a right-sided renal mass(size: 2 cm)detected during routine annual imaging follow-up for a malignant right inguinal fibrous histocytoma and liposarcoma that had been diagnosed 6 and 4 years earlier,respectively,and treated with surgery and adjuvant radiation therapy.Following partial nephrectomy,the renal mass was pathologically diagnosed as ccpRCC,and immunohistochemistry revealed carbonic anhydrase 9(CA9)expression. No recurrences or metastases were detected on follow-up imaging for6 months. This is the first report of partial nephrectomy for incidentally discovered CA9-positive ccpRCC.

Netrin-1:the new tumor markers in renal clear cell carcinoma

Objective:To explore the expression of Netrin-1 protein in human renal clear cell carcinoma(RCCC) and the relationships between Netrin-1.pathology and prognosis.Methods:72 cases of RCCC admitted in our hospital from 2008 June to 2009 June and their adjacent tissues were selected for study.They included 30 cases in stage Ⅰ-Ⅱ.42 cases in stage Ⅲ-Ⅳ;9 cases in grade Ⅰ.9 cases in grade Ⅱ.40 cases in grade Ⅲ and 14 cases in grade Ⅳ.All cases were followed up for more than 5 years.Survival analysis lines were made by Kaplan—Meier method and the difference between groups was tested by the Log-rank test.The expression of Netrin-1 protein was detected by immunohistochemistry staining and its clinical significance was analyzed.Results:Renal clear cell carcinoma:51 cases in high expression of Netrin-1and 21 cases in low expression,normal tissues:12 cases in high expression of Netrin-1and 60 cases in low expression,the difference between the two groups is significant(x^2=42.921,P<0.01).The difference of the expression of Netrin-lin Fuhrman grade and AJCC clinical stage is significant(x^2=8.000.x^2=6.203:P<0.05).The 5-year survival rate in low protein expression group and in high protein expression group was 79% (17/21) and 62% (32/51).The survival curve had different trend,with no significant difference between groups(x^2=1.360.P=0.245).Conclusions:Netrin-1 protein plays an important role in the development of RCCC.It might be a new specific tumor marker of RCCC.and might become a new target in treatment of RCCC.

Link between dysregulated hypoxia signaling and aberrant methylation in clear cell renal cell carcinoma？

Dysregulated pseudo-hypoxia （through its effects on cell survival, angiogenesis, metabolism, invasion） and epigenetic dysregulation [through widespread suppression of tumor suppressor genes involved in cell cycle, apoptosis, adhesion, immune evasion, etc. （1）] are considered to be the two central driving pathogenic features in the progression of clear cell Renal Cell Carcinoma （ccRCC） （2,3）.

RNF43 is a novel tumor-suppressor and prognostic indicator in clear cell renal cell carcinoma

Identifying prognostic indicators of clear cell renal cell carcinoma(ccRCC)and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis.This study investigated the clinical significance and biological role of Ring finger protein 43(RNF43)in ccRCC.Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses.In vitro and in vivo experiments,RNA-seq,and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms.RNF43 expression was commonly decreased in ccRCC specimens,and low expression of RNF43 indicated a higher TNM stage,SSIGN score,and WHO/ISUP grade and short survival in patients with ccRCC.Additionally,RNF43 overexpression suppressed the proliferation,migration,and targeted drug resistance of ccRCC cells,while the knockdown of RNF43 enhanced these characteristics of ccRCC.RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP.By contrast,RNF43 overexpression showed the opposite effects.Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC.Additionally,restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC.Furthermore,combining the expression of RNF43 and YAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients.In summary,our study identified a novel tumor suppressor,RNF43,which is also a prognostic indicator and potential target for ccRCC.

Co-expression Network Analysis Identifies Fourteen Hub Genes Associated with Prognosis in Clear Cell Renal Cell Carcinoma

Summary:Renal cancer is a common genitourinary malignance,of which clear cell renal cell carcinoma(ccRCC)has high aggressiveness and leads to most cancer-related deaths.Identification of sensitive and reliable biomarkers for predicting tumorigenesis and progression has great significance in guiding the diagnosis and treatment of ccRCC.Here,we identified 2397 common difTerentially expressed genes(DEGs)using paired normal and tumor ccRCC tissues from GSE53757 and The Cancer Genome Atlas(TCGA).Then,we performed weighted gene co-expression network analysis and protein-protein interaction network analysis,17 candidate hub genes were identified.These candidate hub genes were further validated in GSE36895 and Oncomine database and 14 real hub genes were identified.All the hub genes were up-regulated and significantly positively correlated with pathological stage and histologic grade of ccRCC.Survival analysis showed that the higher expression level of each hub gene tended to predict a worse clinical outcome.ROC analysis showed that all the hub genes can accurately distinguish between tumor and normal samples,and between early stage and advanced stage ccRCC.Moreover,all the hub genes were positively associated with distant metastasis,lymph node infiltration,tumor recurrence and the expression of MKi67,suggesting these genes might promote tumor proliferation,invasion and metastasis.Furthermore,the functional annotation demonstrated that most genes were enriched in cell-cycle related biological function.In summary,our study identified 14 potential biomarkers for predicting tumorigenesis and progression,which might contribute to early diagnosis,prognosis prediction and therapeutic intervention.