Publications by authors named "Yanqing Gong"

81 Publications

Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40.

Nat Commun 2021 06 8;12(1):3424. Epub 2021 Jun 8.

Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA.

Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
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http://dx.doi.org/10.1038/s41467-021-23832-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187342PMC
June 2021

Upregulation of ATP Binding Cassette Subfamily C Member 5 facilitates Prostate Cancer progression and Enzalutamide resistance via the CDK1-mediated AR Ser81 Phosphorylation Pathway.

Int J Biol Sci 2021 12;17(7):1613-1628. Epub 2021 Apr 12.

Institute of Urology, Peking University. Department of Urology, Peking University First Hospital. National Urological Cancer Center of China, Beijing, China.

The treatment of advanced prostate cancer, castration-resistant prostate cancer, remains challenging. The mechanisms of action of ATP binding cassette subfamily C member 5 (ABCC5) in prostate cancer and its relationship with drug resistance are still unclear. Expression and prognostic analyses of ABCC5 were performed through bioinformatic methods and immunohistochemistry analyses in multiple public databases as well as in our own prostate cancer cohort. The biological function of ABCC5 in prostate cancer cells was evaluated by and cell proliferation and migration and invasion assays. The regulation of CDK1 by ABCC5 was determined via RT-qPCR, western blots, and immunofluorescence. ABCC5 was significantly overexpressed in prostate cancer and positively associated with unfavorable clinicopathological features and prognosis. Upregulation of ABCC5 could enhance the cell proliferation, migration, and invasion of prostate cancer and . Mechanistically, ABCC5 exerts a protumor effect by binding to and inhibiting the protein degradation of CDK1, which promotes the phosphorylation of AR at Ser81 by CDK1 and activates the transcriptional activity of AR on target genes. Moreover, the addition of a CDK1 inhibitor or knockdown of CDK1 significantly improved the efficacy of enzalutamide on prostate cancer cells. The ABCC5-CDK1-AR regulatory pathway could be a potential therapeutic target for advanced prostate cancer, especially castration-resistant prostate cancer (CRPC), to enhance the therapeutic effect of enzalutamide.
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http://dx.doi.org/10.7150/ijbs.59559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120459PMC
April 2021

Prognostic Models for Patients With Gleason Score 9 Prostate Cancer: A Population-Based Study.

Front Oncol 2021 26;11:633312. Epub 2021 Apr 26.

Department of Urology, Peking University First Hospital, Beijing, China.

Gleason score (GS) system is one of the most widely used histological grading methods for prostate cancer (PCa) all over the world. GS can be obtained by adding the primary Gleason pattern (GP) and secondary GP. Different proportions of GP 4 and GP 5 in prostate specimens can both lead to GS 9. In this study, we explored whether GP 5 + 4 or GP 4 + 5 was associated with different prognoses among patients with GS 9 PCa. A retrospective population-based study was conducted on 10,124 subjects diagnosed with GS 9 PCa between 2004 and 2009 from the Surveillance, Epidemiology, and End Results program. A 1:1 propensity-score matching (PSM) was performed to balance the baseline characteristics between the GP 4 + 5 and 5 + 4 groups and to compare the prognoses between the two groups. Cox regression analysis and Fine-Gray competing risk regression models were adopted to screen the covariates significantly associated with all-cause mortality (ACM) and cancer-specific mortality (CAM). GP 5 + 4 was associated with higher risks of ACM and CSM before or after PSM than GP 4 + 5. In the original cohort, there were eight independent predictors for ACM, which were age at diagnosis, race, AJCC NM stage, PSA levels, treatments, GP, and marital status, confirmed by the Cox analysis; and nine independent predictors for CSM, which were age at diagnosis, race, AJCC TNM stage, PSA levels, treatments, GP, and marital status, confirmed by the competing-risk model. GP 5 + 4 was associated with a poorer overall survival and cancer-specific survival compared with GP 4 + 5.
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http://dx.doi.org/10.3389/fonc.2021.633312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107690PMC
April 2021

Noninvasive evaluation of tumor immune microenvironment in patients with clear cell renal cell carcinoma using metabolic parameter from preoperative 2-[F]FDG PET/CT.

Eur J Nucl Med Mol Imaging 2021 May 12. Epub 2021 May 12.

Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.

Purpose: Nowadays, it is necessary to explore effective biomarkers associated with tumor immune microenvironment (TIME) noninvasively. Here, we investigated whether the metabolic parameter from preoperative 2-[F]FDG PET/CT could provide information related to TIME in patients with clear cell renal cell carcinoma (ccRCC).

Methods: Ninety patients with newly diagnosed ccRCC who underwent 2-[F]FDG PET/CT prior to surgery were retrospectively reviewed. The immunological features included tumor-infiltrating lymphocytes (TILs) density, programmed death-ligand 1 (PD-L1) expression, and tumor immune microenvironment types (TIMTs). TIMTs were classified as TIMT I (positive PD-L1 and high TILs), TIMT II (negative PD-L1 and low TILs), TIMT III (positive PD-L1 and low TILs), and TIMT IV (negative PD-L1 and high TILs). The relationship between maximum standardized uptake value (SUVmax) in the primary lesion from 2-[F]FDG PET/CT and immunological features was analyzed. Cox proportional hazards analyses were performed to identify the prognostic factors for disease-free survival (DFS) after nephrectomy.

Results: Tumors with high TILs infiltration showed remarkable correlation with elevated SUVmax and aggressive clinicopathological characteristics, such as high World Health Organization/International Society of Urological Pathology (WHO/ISUP) grade. PD-L1 expression on tumor cells was positively associated with WHO/ISUP grade and negatively correlated with body mass index (BMI). However, no correlation was observed between SUVmax and PD-L1 expression, regardless of its spatial tissue distribution. SUVmax of TIMT I and IV was higher than that of TIMT II, but there was remarkable difference merely between TIMT II and IV. In multivariate analysis, SUVmax (P = 0.022, HR 3.120, 95% CI 1.175-8.284) and WHO/ISUP grade (P = 0.046, HR 2.613, 95% CI 1.017-6.710) were the significant prognostic factors for DFS. Six cases (16.2%) with normal SUVmax showed disease progression, while 25 cases (71.4%) with elevated SUVmax experienced disease progression. Conversely, the immunological features held no prognostic value.

Conclusions: Our findings demonstrated that 2-[F]FDG PET/CT could provide metabolic information of TIME for ccRCC patients and develop image-guided therapeutic strategies accordingly. Patients with elevated preoperative SUVmax should be seriously considered, and perioperative immunotherapy might be beneficial for them.
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http://dx.doi.org/10.1007/s00259-021-05399-9DOI Listing
May 2021

Association between vasectomy and risk of prostate cancer: a meta-analysis.

Prostate Cancer Prostatic Dis 2021 Apr 29. Epub 2021 Apr 29.

Department of Urology, Peking University First Hospital, The Institute of Urology, Peking University, National Urological Cancer Center, Beijing Key Laboratory of Urogenital Diseases (Male) Molecular Diagnosis and Treatment Center, Beijing, 100034, China.

Background: The debate over the association between vasectomy and prostate cancer has been lasted about 40 years and there is no sign of stopping. In the present study, we aimed to evaluate whether vasectomy is associated with prostate cancer based on the most comprehensive and up-to-date evidence available.

Methods: The PubMed, Cochrane Library, and EMBASE databases were systematically searched inception to March 14, 2021 without year or language restriction. Multivariable adjusted risk ratios (RRs) were used to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale.

Results: A total of 58 studies involving 16,989,237 participants fulfilled inclusion criteria. There was significant association of vasectomy with risk of any prostate cancer (risk ratio, 1.18, 95% CI, 1.07-1.31). Association between vasectomy and advanced prostate cancer (risk ratio, 1.06, 95% CI, 1.01-1.12), low-grade prostate cancer (risk ratio, 1.06, 95% CI, 1.02-1.10), and intermediate-grade prostate cancer (risk ratio, 1.12, 95% CI, 1.03-1.22) were significant. There was no significant association between vasectomy and prostate cancer-specific mortality (risk ratio, 1.01, 95% CI, 0.93-1.10).

Conclusions: This study found that vasectomy was associated with the risk of any prostate cancer and advanced prostate cancer. From the current evidence, patients should be fully informed of the risk of prostate cancer before vasectomy.
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http://dx.doi.org/10.1038/s41391-021-00368-7DOI Listing
April 2021

Identification and validation of the clinical roles of the VHL-related LncRNAs in clear cell renal cell carcinoma.

J Cancer 2021 5;12(9):2702-2714. Epub 2021 Mar 5.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

Accumulating evidence suggests that lncRNAs (long non-coding RNAs) function as oncogenes or tumor suppressor genes in ccRCC (clear cell renal cell carcinoma). Although VHL (Von Hippel-Lindau) gene inactivation is by far the most common carcinogenic driving event in ccRCC, the roles of VHL-related lncRNAs in ccRCC remain unknown. In this study, using RNA-seq and clinical data in TCGA-KIRC (the Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma), we identified VHL-related lncRNAs through WGCNA (Weighted Gene Co-expression Network Analysis), correlation analysis and catRAPID algorithm, and explored their clinical characteristics in ccRCC. Results showed that 10 lncRNAs (AC112220.2, AL391121.1, USP46-AS1, AL450326.1, MID1IP1-AS1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2) were identified as VHL-related lncRNAs, and they were down-regulated in ccRCC tissues. Survival analysis results indicated that high expression groups of AC112220.2, AL391121.1, USP46-AS1, AL450326.1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2 had significantly longer OS (Overall Survival) than their respective low expression groups. Meanwhile high AC112220.2, USP46-AS1, AL450326.1, SUCLG2-AS1, FGD5-AS1, AC018647.2 and AC015922.2 expression groups had remarkably longer DFS (Disease Free Survival) than their respective low expression groups. Besides, FGD5-AS1 and AL391121.1 expression were decreased in VHL mutant tissues compared with VHL non-mutant tissues. Moreover, high expression group of FGD5-AS1 had significantly longer OS and DFS than their respective low expression groups in VHL mutant ccRCC. In addition, we found that DNA hypermethylation may also play an important role in decreased FGD5-AS1 expression. Furthermore, we validated the expression of FGD5-AS1 in VHL mutant and non-mutant ccRCC tissues and cell lines. In conclusion, our results demonstrated that lncRNA FGD5-AS1 was significantly associated with VHL and can serve as a novel biomarker of ccRCC.
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http://dx.doi.org/10.7150/jca.55113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040721PMC
March 2021

Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1.

J Exp Clin Cancer Res 2021 Mar 10;40(1):92. Epub 2021 Mar 10.

Department of Urology, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, 100034, China.

Background: Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear.

Methods: Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level.

Results: ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression.

Conclusions: This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.
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http://dx.doi.org/10.1186/s13046-021-01889-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945252PMC
March 2021

Enhanced Detection of Genitourinary Cancers Using Fragmentation and Copy Number Profiles Obtained from Urinary Cell-Free DNA.

Clin Chem 2021 Jan;67(2):394-403

Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing China.

Background: Recent studies have reported that examining the fragmentation profiles (FP) of plasma cell-free DNA (cfDNA) further improves the clinical sensitivity of tumor detection. We hypothesized that considering the differences of the FP of urinary cfDNA would increase the clinical sensitivity of genitourinary (GU) cancer detection.

Methods: 177 patients with GU cancer and 94 individuals without tumors were enrolled in the discovery cohort. An independent validation dataset comprising 30 patients without tumors and 66 patients with GU cancer was also collected. We constructed an ensemble classifier, GUIDER, to detect and localize GU cancers using fragmentation and copy number profiles obtained from shallow whole-genome sequencing of urinary cfDNA.

Results: Urinary cfDNA of patients with GU cancer had a higher proportion of long fragments (209-280 bp) and a lower proportion of short fragments (140-208 bp) compared to controls. The overall mean classification accuracy of the FP was 74.62%-85.39% for different algorithms, and integration of the FP and copy number alteration (CNA) features further enhanced the classification of samples from patients with GU cancer. The mean diagnostic accuracy was further improved by the ensemble classifier GUIDER, which integrated the FP and CNA profiles and resulted in a higher mean accuracy (87.52%) compared to the analysis performed without FP features (74.62%). GUIDER performed well in an independent validation dataset.

Conclusions: The lengthening and shortening of urinary cfDNA within specific size ranges were identified in patients with GU cancer. Integration of the FP should further enhance the ability to use urinary cfDNA as a molecular diagnostic tool.
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http://dx.doi.org/10.1093/clinchem/hvaa283DOI Listing
January 2021

Cell-cycle arrest and senescence in TP53-wild type renal carcinoma by enhancer RNA-P53-bound enhancer regions 2 (p53BER2) in a p53-dependent pathway.

Cell Death Dis 2021 01 5;12(1). Epub 2021 Jan 5.

Department of Urology, Peking University First Hospital, Beijing, People's Republic of China.

TP53 is a classic tumor suppressor, but its role in kidney cancer remains unclear. In our study, we tried to explain the role of p53 in kidney cancer through the p53-related enhancer RNA pathway. Functional experiments were used to explore whether P53-bound enhancer regions 2 (p53BER2) has a role in the cell cycle and senescence response of TP53-wild type (WT) renal cancer cells in vitro or vivo. RNA-sequencing was used to identify the potential target of p53BER2. The results showed that the expression level of P53BER2 was downregulated in renal cancer tissues and cell lines, further dual-luciferase experiments and APR-256-reactivated experiments showed p53BER2 expresses in a p53-dependent way. Moreover, knockdown p53BER2 could reverse nutlin-3-induced cytotoxic effect in TP53-WT cell lines. Further exploration showed the downregulation of p53BER2 could reverse nutlin-3-induced G1-arrest and senescence in TP53-WT cell lines. What is more, the knockdown of p53BER2 showed resistance to nutlin-3 treatment in vivo. Additionally, we found BRCA2 could be regulated by p53BER2 in vitro and vivo; further experiment showed p53BER2 could induce cell-cycle arrest and DNA repair by mediating BRCA2. In summary, the p53-associated enhancer RNA-p53BER2 mediates the cell cycle and senescence of p53 in TP53-WT renal cancer cells.
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http://dx.doi.org/10.1038/s41419-020-03229-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791070PMC
January 2021

ACE2 Correlated With Immune Infiltration Serves As A Novel Prognostic Biomarker In Clear Cell Renal Cell Carcinoma: Implication For COVID-19.

Int J Biol Sci 2021 1;17(1):20-31. Epub 2021 Jan 1.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global infection, and is seriously threatening human life, especially cancer patients. Thus, we sought to determine the clinical roles of ACE2 (the cell entry receptor of SARS-CoV-2) in ccRCC (clear cell renal cell carcinoma). TCGA, GEO and TIP datasets, and immunohistochemistry and western blot results were used to determine the prognostic and clinicopathological characteristics of ACE2. ACE2 expression was down-regulated in ccRCC tissues and cell lines. The multivariate Cox regression analysis results indicated that increased ACE2 expression was independent predictor of longer OS (HR: 0.8259, 95%CI: 0.7734-0.8819, P<0.0001) and RFS (HR: 0.8023, 95%CI: 0.7375-0.8729, P<0.0001) in ccRCC patients. Lower ACE2 expression was also associated with advanced tumor stage, higher histological grade and pathological stage, and metastasis. Besides, ACE2 expression was significantly positively and negatively correlated with CD4 Naïve infiltration and CD4 Memory infiltration, respectively. Moreover, higher CD4 Naïve and lower CD4 Memory infiltration levels were associated with better pathological features and longer OS and RFS. Furthermore, high ACE2 expression group in decreased CD4 Naïve, enriched CD4 Naïve and enriched CD4 memory cohort had favorable prognosis. These findings identified that AEC2 was significantly reduced in ccRCC, and decreased ACE2 was related to worse pathological features and poor prognosis. Low ACE2 expression in ccRCC may partially affect the prognosis due to altered immune cells infiltration levels.
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http://dx.doi.org/10.7150/ijbs.51969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757050PMC
January 2021

P4HB: A novel diagnostic and prognostic biomarker for bladder carcinoma.

Oncol Lett 2021 Feb 6;21(2):95. Epub 2020 Dec 6.

Department of Urology, Peking University First Hospital, Xicheng, Beijing 100034, P.R. China.

Prolyl 4-hydroxylase, beta polypeptide (P4HB) protein is an endoplasmic reticulum (ER) molecular chaperone protein and has been reported to be overexpressed in multiple tumor types. However, the role of P4HB in bladder cancer (BLCA) has not yet been elucidated. The aim of the present study was to investigate the prognostic value of P4HB and the association between clinicopathological characteristics and P4HB in BLCA. P4HB expression levels were assessed through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and validated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis in BLCA tissues and cells. A total of 69 pairs of tumor and normal samples were used to analyze the expression of P4HB via immunohistochemical staining. A co-expression network and functional enrichment analyses were conducted to investigate the biological function of P4HB in BLCA. The protein-protein interaction (PPI) network was constructed by Search Tool for the Retrieval of Interacting Genes. The results showed that P4HB was highly expressed in BLCA cells and tissues. The area under the curve value for P4HB expression to discriminate between tumor and normal tissues was up to 0.888 (95% CI: 0.801-0.975; P<0.001) and 0.881 (95% CI: 0.825-0.937; P<0.001) in TCGA database and our database, respectively. Furthermore, the expression level of P4HB was an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) by univariate and multivariate analyses. Kaplan-Meier survival analysis demonstrated that high P4HB expression was associated with low OS and RFS. Pathway enrichment analysis suggested that P4HB was involved in protein processing in the endoplasmic reticulum (ER), including N-glycan modification and protein metabolic processes responding to ER stress. PPI analysis revealed that the potential targets of P4HB were mainly involved in posttranslational protein modification and response to ER stress. In conclusion, the expression level of P4HB aid in identifying patients with early-stage BLCA and predicting the prognosis of BLCA. Therefore, P4HB may be a novel diagnostic and prognostic biomarker for BLCA.
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http://dx.doi.org/10.3892/ol.2020.12356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751343PMC
February 2021

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population.

Front Genet 2020 10;11:532588. Epub 2020 Dec 10.

Department of Urology, Peking University First Hospital, Beijing, China.

Purpose: Von Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It's unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype.

Methods: We enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks.

Results: Patients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors ( = 0.638, 95%CI 0.461-0.883, = 0.007), CHB ( = 0.596, 95%CI 0.409-0.868, = 0.007) or PCT ( = 0.595, 95%CI 0.368-0.961, = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB ( = 0.652, 95%CI 0.476-0.893, = 0.008) and PCT ( = 0.605, 95%CI 0.398-0.918, = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort ( = 577), PHEO was an independent protective factor for CHB ( = 0.001) and survival ( = 0.005). RA and CHB failed to predict the age-related risk of each other.

Conclusion: The mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.
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http://dx.doi.org/10.3389/fgene.2020.532588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762453PMC
December 2020

Let-7d inhibits intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-13 and IL-10.

Cancer Immunol Immunother 2021 Jun 25;70(6):1619-1634. Epub 2020 Nov 25.

Department of Urology, Peking University First Hospital and the Institute of Urology, Peking University, Beijing, 100034, People's Republic of China.

The microRNA let-7d has been reported to be a tumor suppressor in renal cell carcinoma (RCC). Tumor-associated macrophages (TAM) are M2-polarized macrophages that can enhance tumor growth and angiogenesis in many human cancers. However, the role of let-7d in TAM-associated RCC progression remains elusive. First, we observed a strongly inverse correlation between let-7d expression and microvessel density in RCC tissues. Furthermore, the proliferation, migration, and tube formation of HUVECs were significantly inhibited by conditioned medium from a coculture system of the phorbol myristate acetate pretreated human THP-1 macrophages and let-7d-overexpressing RCC cells. Moreover, the proportion of M2 macrophages was significantly lower in the group that was cocultured with let-7d-overexpressing RCC cells. Subcutaneous xenografts formed by the injection of let-7d-overexpressing RCC cells together with THP-1 cells resulted in a significant decrease in the M2 macrophage ratio and microvessel density compared with those formed by the injection of control RCC cells with THP-1 cells. In silico and experimental analysis revealed interleukin-10 (IL-10) and IL-13 as let-7d target genes. Importantly, the addition of IL-10 and IL-13 counteracted the inhibitory effects of the conditioned medium from the coculture system with let-7d-overexpressing RCC cells in vitro. Additionally, overexpression of IL-10 and IL-13 reversed the effects of let-7d on macrophage M2 polarization and tumor angiogenesis in vivo. Finally, the expression of IL-10 and IL-13 were inversely correlated with the expression of let-7d in RCC clinical specimens. These results suggest that let-7d may inhibit intratumoral macrophage M2 polarization and subsequent tumor angiogenesis by targeting IL-10 and IL-13.
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http://dx.doi.org/10.1007/s00262-020-02791-6DOI Listing
June 2021

Identification of immune-related LncRNA for predicting prognosis and immunotherapeutic response in bladder cancer.

Aging (Albany NY) 2020 11 18;12(22):23306-23325. Epub 2020 Nov 18.

Department of Urology, Peking University First Hospital, Beijing, China.

Long noncoding RNAs (lncRNAs) have multiple functions in the cancer immunity response and the tumor microenvironment. To investigate the immune-related lncRNA (IRlncRNA) signature for predicting prognosis and immunotherapeutic response in bladder cancer (BLCA), we extracted BLCA data from The Cancer Genome Atlas (TCGA) database. Finally, a total of 405 cases were enrolled and 8 prognostic IRlncRNAs (, , , were identified in the training set. Risk scores were calculated to divide patients into high-risk and low-risk groups, and the high-risk patients tended to have a poor overall survival (OS). Multivariate Cox regression analysis confirmed that the IRlncRNA signature could be an independent prognostic factor. The results were subsequently confirmed in the validating set. Additionally, this 8-IRlncRNA classifier was related to recurrence free survival (RFS) of BLCA. Functional characterization revealed this signature mediated immune-related phenotype. This signature was also associated with immune cell infiltration (i.e., macrophages M0, M2, Tregs, CD8 T cells, and neutrophils) and immune checkpoint inhibitors (ICIs) immunotherapy-related biomarkers [mismatch repair (MMR) genes, tumor mutation burden (TMB) and immune checkpoint genes]. The present study highlighted the value of the 8-IRlncRNA signature as a predictor of prognosis and immunotherapeutic response in BLCA.
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http://dx.doi.org/10.18632/aging.104115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746369PMC
November 2020

CLDN10 associated with immune infiltration is a novel prognostic biomarker for clear cell renal cell carcinoma.

Epigenomics 2021 Jan 18;13(1):31-45. Epub 2020 Nov 18.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

To identify the clinical roles of CLDN10 in clear cell renal cell carcinoma (ccRCC). Using data from TCGA-KIRC, GEO DataSets and laboratory experiments to determine the prognostic and clinicopathological characteristics of CLDN10. CLDN10 expression was remarkably reduced in ccRCC. Downregulated CLDN10 was related to metastasis and poor prognosis. Multivariate Cox analysis determined that elevated CLDN10 expression was independently correlated with longer OS and DFS. Moreover, CLDN10 expression was negatively associated with the methylation levels of cg10305311 and cg16275739. CLDN10 expression was also associated with naive CD4 and memory T-cell and dendritic cell infiltration. Immune-related CLDN10 is an independent prognostic biomarker of ccRCC. DNA hypermethylation plays an important role in decreased CLDN10 expression.
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http://dx.doi.org/10.2217/epi-2020-0256DOI Listing
January 2021

Identification of the Six-RNA-Binding Protein Signature for Prognosis Prediction in Bladder Cancer.

Front Genet 2020 28;11:992. Epub 2020 Aug 28.

Department of Urology, Peking University First Hospital, Beijing, China.

RNA-binding proteins (RBPs) are a kind of gene regulatory factor that presents a significant biological effect in the initiation and development of various tumors, including bladder cancer (BLCA). However, the RBP-based prognosis signature for BLCA has not been investigated. In this study, we attempted to develop an RBP-based classifier to predict overall survival (OS) for BLCA based on transcriptome analysis. We extracted data of BLCA patients from The Cancer Genome Atlas database (TCGA) and UCSC Xena. Finally, a total of 398 cases without missing clinical data were enrolled and six RBPs (, , , , , and ) associated with OS of BLCA were identified through univariate and multivariate Cox regression analysis. Online analyses and immunohistochemistry validated the prognostic value and expression of six RBPs. Risk scores were calculated to divide patients into high-risk and low-risk level, and patients in the high-risk group tended to have a poor prognosis. In addition, the receiver operating characteristic (ROC) curve analysis was performed to assess the prognostic value of RBPs, and the area under the curve (AUC) values were 0.711 and 0.706, respectively, in the training set and validating set. The findings were further validated in an external validation set. Subsequently, the 6-RBP-based signature and pathological stage were used to construct the nomogram to predict the 3- and 5-years OS of BLCA patients. Also, this 6-RBP-based signature was highly related to recurrence-free survival of BLCA. Weighted co-expression network analysis (WGCNA) combined with functional enrichment analysis contributed to study the potential pathways of six RBPs, including keratinocyte differentiation, RHO GTPases activate PNKs, epithelial tube morphogenesis, establishment or maintenance of cell polarity, and so on. In summary, the 6-RBP-based signature holds the potentiality to serve as a novel prognostic predictor of OS for BLCA.
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http://dx.doi.org/10.3389/fgene.2020.00992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493641PMC
August 2020

Plasminogen regulates mesenchymal stem cell-mediated tissue repair after ischemia through Cyr61 activation.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

Division of Translational Medicine and Human Genetics, Department of Medicine, and.

Stem cell transplantation has emerged as a promising strategy in regenerative medicine. However, the poor survival and persistence of the transplanted cells, including mesenchymal stem cells (MSCs), in the hostile ischemic microenvironments represents a major therapeutic barrier. Here we report that plasminogen (Plg) stimulated MSC functions and promoted MSC survival during tissue repair after ischemia. Genetic Plg ablation abolished MSC survival, migration, and proliferation in mouse ischemic limbs, and abrogated MSC-mediated blood reperfusion, neovascularization, and tissue repair after ischemia, suggesting a critical role for Plg in MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identified that Plg cleaved and activated cysteine-rich protein 61 (Cyr61), an ECM-associated growth factor, to stimulate MSC survival and migration. Overexpression with truncated Cyr61 in MSCs rescued blood reperfusion after hind limb ischemia in Plg-deficient mice. Finally, Plg-mediated Cyr61 cleavage promoted endothelial cell migration and neovascularization in vitro and in vivo. Our study reveals that Plg promotes MSC survival, persistence, and paracrine effects and improves postischemic neovascularization and tissue repair through Cyr61 cleavage and activation. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases.
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http://dx.doi.org/10.1172/jci.insight.131376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455064PMC
August 2020

Comprehensive analysis of m6A regulators prognostic value in prostate cancer.

Aging (Albany NY) 2020 07 25;12(14):14863-14884. Epub 2020 Jul 25.

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center of China, Beijing, China.

Background: N6-methyladenosine (m6A) is the most prevalent RNA modification. While the role of m6A in prostate cancer remains unknown. We aim to measure the effects of m6A methylation regulatory genes during the development and progression of prostate cancer.

Methods: We collected transcriptome information and gene-level alteration data from The Cancer Genome Atlas datasets. The log-rank test and Cox regression model were used to examine the prognosis value of m6A methylation regulatory genes of prostate cancer.

Results: We discovered that most of m6A methylation regulators were highly expressed in aggressive prostate cancer. Univariable and multivariable Cox regression results showed that the expression of Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), Heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) and N6-adenosine-methyltransferase non-catalytic subunit (METTL14) and copy number variant of AlkB Homolog 5 (ALKBH5) were considerably associated with a recurrence-free survival of prostate cancer. Furthermore, a high level of m6A methylation in mRNA promotes the progression of prostate cancer via regulating subcellular protein localization.

Conclusion: Patients with a high level of mRNA methylation resulted from overexpression of reader proteins and methyltransferase complexes had poor survival benefits through influencing protein subcellular location in prostate cancer.
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http://dx.doi.org/10.18632/aging.103549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425456PMC
July 2020

Stereotactic radiosurgery for central nervous system hemangioblastoma in von Hippel-Lindau disease: A systematic review and meta-analysis.

Clin Neurol Neurosurg 2020 08 15;195:105912. Epub 2020 May 15.

Department of Urology, Peking University First Hospital, Beijing, China; Institute of Urology, Peking University, Beijing, China; National Urological Cancer Center, Beijing, China. Electronic address:

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder marked by multiorgan tumors, such as central nervous system benign hemangioblastomas (CHB). Stereotactic radiosurgery (SRS) has also been used to treat CHB for a long time. The purpose of this meta-analysis is to provide a long-term outcome of SRS for VHL-associated CHB by reviewing published studies. We completed a Pubmed/Embase/SCOPUS/Cochrane Library literature search to get eligible studies published from January 1990 to December 2019 about using SRS to treat VHL-associated CHB. 15 studies met eligibility for qualitative systematic review, of which nine studies were ultimately eligible for quantity meta-analysis of 5-year tumor control rates (TCR), representing 170 subjects with a total of 660 lesions. Gamma Knife was the most published SRS method for VHL-associated CHB. The pooled 5-year TCR across the nine studies was 0.919 (95 %CI: 0.881-0.957). The pooled 5-year TCR for only intracranial lesions across eight studies was 0.917 (95 %CI: 0.876-0.957). Individual patient data were extracted from 9 studies, representing 298 lesions of 70 subjects. Sex, tumor volume, radiosurgery methods, marginal doses, maximum doses, the number of tumors for radiosurgery, age at the time of radiosurgery, tumor locations were not proven to be associated with tumor progression. SRS offered a satisfactory 5-year tumor control of CHB for VHL patients. Despite the paucity of randomized control trials, SRS is recommended to patients with limited surgical alternatives. However, the long-term outcomes and underlying factors associated with tumor progression remain to be investigated.
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http://dx.doi.org/10.1016/j.clineuro.2020.105912DOI Listing
August 2020

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Theranostics 2020 4;10(10):4323-4333. Epub 2020 Mar 4.

Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.

: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. : We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. : Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. : The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.
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http://dx.doi.org/10.7150/thno.43251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150494PMC
February 2021

Single cell transcriptomics identifies a unique adipose lineage cell population that regulates bone marrow environment.

Elife 2020 04 14;9. Epub 2020 Apr 14.

Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.
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http://dx.doi.org/10.7554/eLife.54695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220380PMC
April 2020

Discovery and validation of the prognostic value of the lncRNAs encoding snoRNAs in patients with clear cell renal cell carcinoma.

Aging (Albany NY) 2020 03 3;12(5):4424-4444. Epub 2020 Mar 3.

Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.

Some lncRNAs can encode small nucleolar RNAs (snoRNAs), called small nucleolar RNA host genes (SNHGs), which have exerted certain predictive values for the prognosis of some cancer patients. In this study, using RNA-seq and survival data in TCGA-KIRC, we examined the expression profile of 20 SNHGs and explored their prognostic values in ccRCC. Results showed that SNHG1, GAS5, SNHG3-8, SNHG11, SNHG12, SNHG15-17, SNHG20, SNHG22 and SNHG25 were significantly upregulated in ccRCC tissues compared with adjacent normal tissues. After adjustment for confounding factors, the multivariate analysis confirmed that increased SNHG3 expression was independently associated with shorter OS, while increased SNHG15 expression was an independent predictor of shorter RFS. Using the methylation data, the methylation status of 2 CpG sites (cg07807470 and cg15161854) and 2 CpG sites (cg00953154 and cg16459265) were negatively correlated with SNHG3 and SNHG15 expression, respectively. Moreover, low methylation levels of the 4 CpG sites were significantly associated with shorter OS. Furthermore, we validated the expression patterns, methylation status and prognostic value of SNHG3 and SNHG15 using clinical ccRCC samples. Taken together, SNHG3 and SNHG15 might be valuable prognostic markers in ccRCC, and DNA hypomethylation might play an important role in elevated SNHG3 and SNHG15 transcription in ccRCC.
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http://dx.doi.org/10.18632/aging.102894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093172PMC
March 2020

Wnt-mediated endothelial transformation into mesenchymal stem cell-like cells induces chemoresistance in glioblastoma.

Sci Transl Med 2020 02;12(532)

Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces β-catenin phosphorylation at Ser and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of β-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/β-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.
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http://dx.doi.org/10.1126/scitranslmed.aay7522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261487PMC
February 2020

Long non-coding RNA SOX2OT promotes the stemness phenotype of bladder cancer cells by modulating SOX2.

Mol Cancer 2020 02 4;19(1):25. Epub 2020 Feb 4.

Department of Urology, Peking University First Hospital, The Institute of Urology, Peking University, National Urological Cancer Center, No. 8 Xishiku street, Beijing, 100034, China.

Background: Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are potential biomarkers and key regulators of tumour development and progression. SOX2 overlapping transcript (SOX2OT) is a novel lncRNA that acts as a potential biomarker and is involved in the development of cancer and cancer stem cells. However, the clinical significance and molecular mechanism of SOX2OT in bladder cancer are still unknown.

Methods: The expression level of SOX2OT was determined by RT-qPCR in a total of 106 patients with urothelial bladder cancer and in different bladder cancer cell (BCC) lines. Bladder cancer stem cells (BCSCs) were isolated from BCCs using flow cytometry based on the stem cell markers CD44 and ALDH1. Loss-of-function experiments were performed to investigate the biological roles of SOX2OT in the stemness phenotype of BCSCs. Comprehensive transcriptional analysis, RNA FISH, dual-luciferase reporter assays and western blots were performed to explore the molecular mechanisms underlying the functions of SOX2OT.

Results: SOX2OT was highly expressed in bladder cancer, and increased SOX2OT expression was positively correlated with a high histological grade, advanced TNM stage and poor prognosis. Further experiments demonstrated that knockdown of SOX2OT inhibited the stemness phenotype of BCSCs. Moreover, inhibition of SOX2OT delayed xenograft tumour growth and decreased metastases in vivo. Mechanistically, we found that SOX2OT was mainly distributed in the cytoplasm and positively regulated SOX2 expression by sponging miR-200c. Furthermore, SOX2 overexpression reversed the SOX2OT silencing-induced inhibition of the BCSC stemness phenotype.

Conclusion: This study is the first to demonstrate that SOX2OT plays an important regulatory role in BCSCs and that SOX2OT may serve as a potential diagnostic biomarker and therapeutic target in bladder cancer.
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http://dx.doi.org/10.1186/s12943-020-1143-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998848PMC
February 2020

MTDH promotes metastasis of clear cell renal cell carcinoma by activating SND1-mediated ERK signaling and epithelial-mesenchymal transition.

Aging (Albany NY) 2020 01 24;12(2):1465-1487. Epub 2020 Jan 24.

Department of Urology, Peking University First Hospital, Beijing 100034, China.

Background: Metastasis is the principal cause of renal cell carcinoma-associated mortality. Metadherin (MTDH) was identified as a vital metastasis driver involved in the metastatic progression of various types of tumors, suggesting that MTDH is a prognostic metastatic biomarker and potential therapeutic target. The role and mechanism of MTDH in the metastatic progression of ccRCC have not yet been adequately explored.

Results: MTDH was remarkably elevated in ccRCC tissues, especially in metastatic ccRCC tissues, compared with normal kidney tissues and correlated with advanced clinicopathological features and poor prognosis. MTDH activated ERK signaling and EMT, thus promoting the migration and invasion of ccRCC cells. The interaction between MTDH and SND1 at the protein level was confirmed using immunoprecipitation and immunofluorescence. Based on the analysis of datasets from GEO and TCGA, SND1 was remarkably increased in ccRCC, especially in metastatic ccRCC, and associated with advanced clinicopathological features and poor prognosis. Knockdown of SND1 mainly abolished the migration and invasion of ccRCC cells by blocking MTDH-mediated ERK and EMT signaling activation.

Conclusion: These results revealed that MTDH may be a prognostic metastatic biomarker of ccRCC that promotes ccRCC metastasis by activating SND1-mediated the ERK and EMT signaling pathways. MTDH may serve as an anti-tumor therapeutic target that can be applied for the clinical treatment of metastatic ccRCC.

Methods: MTDH/SND1 mRNA expression in clear cell renal cell carcinoma (ccRCC) was comprehensively estimated by analysis of GEO-ccRCC and TCGA-KIRC datasets with R software and packages. MTDH protein expression was assessed in a total of 111 ccRCC patients from Peking University First Hospital by immunohistochemistry (IHC). In vitro migration and invasion assays were carried out, and an in vivo metastatic mouse model was developed to investigate the biological functions of MTDH in ccRCC cells. Correlation analysis, immunoprecipitation, western blotting and immunofluorescence were applied to explore the molecular mechanisms of MTDH in ccRCC.
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http://dx.doi.org/10.18632/aging.102694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053596PMC
January 2020

Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing.

Clin Chem 2020 01;66(1):188-198

Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Background: Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity.

Methods: We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients.

Results: Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients.

Conclusions: Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.
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http://dx.doi.org/10.1373/clinchem.2019.309633DOI Listing
January 2020

The Efficacy and Safety of Tyrosine Kinase Inhibitors for Von Hippel-Lindau Disease: A Retrospective Study of 32 Patients.

Front Oncol 2019 1;9:1122. Epub 2019 Nov 1.

Department of Urology, Peking University First Hospital, Beijing, China.

Von Hippel-Lindau (VHL) disease is an autosomal-dominant hereditary cancer syndrome. Currently, studies on tyrosine kinase inhibitor (TKI) therapy for VHL disease are scarce. In this study, we retrospectively evaluated the efficacy and safety of four TKIs in patients with VHL disease. Patients diagnosed with VHL disease who were receiving TKIs were recruited. Patients were treated with sunitinib ( = 12), sorafenib ( = 11), axitinib ( = 6), or pazopanib ( = 3). The therapeutic response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. From July 2009 to September 2018, 32 patients with VHL disease were eligible and included in this study. The median duration of TKI therapy was 22 months (IQR 8.5-44.75), and the median follow-up period was 31.5 months (IQR 13.5-63.5). According to the RECIST, 9 (28%) of 32 patients showed a partial response, 15 (47%) achieved stable disease, and eight exhibited continued disease progression. A partial response was observed in 11 (31%) of 36 renal cell carcinomas, 4 (27%) of 15 pancreatic lesions, and 1 (20%) of five central nervous system (CNS) hemangioblastomas. The average tumor size decreased significantly for renal cell carcinomas ( = 0.0001), renal cysts ( = 0.027), and pancreatic lesions ( = 0.003) after TKI therapy. Common side effects included hand-foot skin reactions, diarrhea, alopecia, thrombocytopenia, and fatigue. Partial alleviation of VHL disease-related tumors can be achieved by TKI therapies in some patients, providing an alternative treatment strategy, and the side effects of TKIs are acceptable. Larger prospective studies are warranted to further evaluate the efficacy and safety of TKIs in patients with VHL disease.
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http://dx.doi.org/10.3389/fonc.2019.01122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839035PMC
November 2019

Prognostic value of long non-coding RNA signatures in bladder cancer.

Aging (Albany NY) 2019 08 20;11(16):6237-6251. Epub 2019 Aug 20.

Department of Urology, Peking University First Hospital, Beijing 100034, China.

Bladder cancer (BLCA) is a devastating cancer whose early diagnosis can ensure better prognosis. Aim of this study was to evaluate the potential utility of lncRNAs in constructing lncRNA-based classifiers of BLCA prognosis and recurrence. Based on the data concerning BLCA retrieved from TCGA, lncRNA-based classifiers for OS and RFS were built using the least absolute shrinkage and selection operation (LASSO) Cox regression model in the training cohorts. More specifically, a 14-lncRNA-based classifier for OS and a 12-lncRNA-based classifier for RFS were constructed using the LASSO Cox regression. According to the prediction value, patients were divided into high/low-risk groups based on the cut-off of the median risk-score. The log-rank test showed significant differences in OS and RFS between low- and high-risk groups in the training, validation and whole cohorts. In the time-dependent ROC curve analysis, the AUCs for OS in the first, third, and fifth year were 0.734, 0.78, and 0.78 respectively, whereas the prediction capability of the 14-lncRNA classifier was superior to a previously published lncRNA classifier. As for the RFS, the AUCs in the first, third, and fifth year were 0.755, 0.715, and 0.740 respectively. In summary, the two-lncRNA-based classifiers could serve as novel and independent prognostic factors for OS and RFS individually.
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http://dx.doi.org/10.18632/aging.102185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738399PMC
August 2019

TGF-β-induced transgelin promotes bladder cancer metastasis by regulating epithelial-mesenchymal transition and invadopodia formation.

EBioMedicine 2019 Sep 13;47:208-220. Epub 2019 Aug 13.

Department of Urology, Peking University First Hospital, Beijing 100034, China; Institute of Urology, Peking University, Beijing 100034, China; National Urological Cancer Center, Beijing 100034, China; Beijing Key Laboratory of Urogenital Diseases (male) Molecular Diagnosis and Treatment Center, Beijing 100034, China. Electronic address:

Background: Metastatic bladder cancer (BLCA) is a lethal disease with an unmet need for study. Transgelin (TAGLN) is an actin-binding protein that affects the dynamics of the actin cytoskeleton indicating its robust potential as a metastasis initiator. Here, we sought to explore the expression pattern of TAGLN and elucidate its specific functioning and mechanisms in BLCA.

Methods: A comprehensive assessment of TAGLN expression in BLCA was performed in three cohorts with a total of 847 patients. The potential effects of TAGLN on BLCA were further determined using clinical genomic analyses that guided the subsequent functional and mechanistic studies. In vitro migration, invasion assays and in vivo metastatic mouse model were performed to explore the biological functions of TAGLN in BLCA cells. Immunofluorescence, western blot and correlation analysis were used to investigate the molecular mechanisms of TAGLN.

Findings: TAGLN was highly expressed in BLCA and correlated with advanced prognostic features. TAGLN promoted cell colony formation and cell migration and invasion both in vitro and in vivo by inducing invadopodia formation and epithelial-mesenchymal transition, during which a significant correlation between TAGLN and Slug was observed. The progression-dependent correlation between TGF-β and TAGLN was analysed at both the cellular and tissue levels, while TGF-β-mediated migration was abolished by the suppression of TAGLN.

Interpretation: Overall, TAGLN is a promising novel prognosis biomarker of BLCA, and its metastatic mechanisms indicate that TAGLN may represent a novel target agent that can be utilized for the clinical management of invasive and metastatic BLCA. FUND: This work was supported by the National Natural Science Foundation of China [81772703, 81672546, 81602253]; the Natural Science Foundation of Beijing [71772219, 7152146]. and Innovative Fund for Doctoral Students of Peking University Health Science Center (BUM2018BSS002). Funders had no role in the design of the study, data collection, data analysis, interpretation, or the writing of this report.
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http://dx.doi.org/10.1016/j.ebiom.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796540PMC
September 2019