Single-cell RNA sequencing reveals the epithelial cell heterogeneity and invasive subpopulation in human bladder cancer.

Bladder cancer represents a highly heterogeneous disease characterized by distinct histological, molecular and clinical phenotypes, and a detailed analysis of tumor cell invasion and crosstalks within bladder tumor cells has not been determined. Here, we applied droplet-based single-cell RNA sequencing (scRNA-seq) to acquire transcriptional profiles of 36 619 single cells isolated from seven patients. Single cell transcriptional profiles matched well with the pathological basal/luminal subtypes. Notably, in T1 tumors diagnosed as luminal subtype, basal cells displayed characteristics of epithelial-mesenchymal transition (EMT) and mainly located at the tumor-stromal interface as well as micrometastases in the lamina propria. In one T3 tumor, muscle-invasive tumor showed significantly higher expression of cancer stem cell markers SOX9 and SOX2 than the primary tumor. We additionally analyzed communications between tumor cells and demonstrated its relevance to basal/luminal phenotypes. Overall, our single-cell study provides a deeper insight into the tumor cell heterogeneity associated with bladder cancer progression.

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma.

BACKGROUND: As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. METHODS: Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34ßE12+ /P63+ /PAP- /PSA- ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. RESULTS: The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. CONCLUSIONS: This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

Granulocytic myeloid-derived suppressor cells correlate with outcomes undergoing neoadjuvant chemotherapy for bladder cancer.

OBJECTIVES: It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with neoadjuvant chemotherapy (NAC). This study sought to evaluate whether the proportion of granulocytic myeloid-derived suppressor cells (G-MDSCs) and monocytic myeloid-derived suppressor cells could correlate with pathologic response in bladder cancer patients receiving NAC. PATIENTS AND METHODS: Pretreatment peripheral blood levels of G-MDSCs and monocytic myeloid-derived suppressor cells were measured by flow cytometry. We divided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared outcomes of the two groups. RESULTS: A significant pathological response (pT0-1) was attained in 13% (6 of 45) of patients with high G-MDSCs compared with 58% (26 of 45) of patients with low G-MDSCs (P < 0.001). Patients with high G-MDSCs had significantly shorter disease specific survival and progression-free survival (both P < 0.001). In the multivariate analysis for survival, high G-MDSCs and pathological response emerged as independent prognostic factor for progression-free survival (P < 0.001 and P = 0.017) and disease-specific survival (P < 0.001 and P = 0.014). CONCLUSIONS: Pretreatment peripheral G-MDSCs may represent a potential marker for the outcome of patients treated with cisplatin-based NAC.

CD163+ macrophages predict a poor prognosis in patients with primary T1 high-grade urothelial carcinoma of the bladder.

PURPOSE: Macrophages are a major cell type that can infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. This study investigates the prognostic value of tumor-infiltrated CD163+ macrophages in patients with T1 high-grade (T1HG) bladder cancer. METHODS: CD163+ macrophages were assessed by immunohistochemistry in 94 T1HG bladder cancer samples. Kaplan-Meier analyses and Cox proportional hazards' regression models were applied to evaluate recurrence-free survival, progression-free survival and disease-specific survival. RESULTS: With a median follow-up of 60 months, 37 (39.4%) patients experienced disease recurrence, 14 (14.9%) progression, 11 (11.7%) disease-specific mortality. High CD163+ macrophages were associated with higher risk of disease recurrence and progression (P < 0.05, for both). In multivariate Cox proportional hazards regression analysis, high CD163+ macrophages were a significant negative predictor of recurrence-free survival, progression-free survival and disease-specific survival (P < 0.05 for all). CONCLUSION: CD163+ macrophages are a poor prognostic factor in T1HG bladder cancer. This finding provide the ground for further testing it in predicting the outcome of this challenging disease.

Curcumin inhibits cell proliferation and motility via suppression of TROP2 in bladder cancer cells.

Bladder cancer (BC) has become a serious health prob-lem and represents the second most commonly diagnosed urological tumor. Curcumin is a principal active natural component of turmeric and has long been used in Asia as a traditional herbal medicine. Curcumin suppresses cell growth in various types of cancer, including BC, by regulating numerous molecular signaling pathways. The human trophoblast cell surface antigen 2 (Trop2) belongs to the tumor-associated calcium signal transducer gene family. Trop2 has been described as a cancer driver and is deregulated in various types of cancer. However, whether Trop2 is involved in curcumin-induced BC cell inhibition remains to be elucidated. The present study hypothesized that Trop2 may be a promising target of curcumin in BC cells. It was found that Trop2 was closely involved in curcumin-induced cell proliferation suppression, mobility inhibition, apoptosis, and cell cycle arrest in BC cells. Curcumin decreased the expression of Trop2 and its downstream target cyclin E1, and increased the level of p27. The overexpression of Trop2 enhanced the oncogenic activity of BC cells, whereas downregulation of the expression of Trop2 suppressed cell proliferation and mobility, increased apoptosis, and sensitized BC cells to curcumin treatment. Therefore, Trop2 may be a promising target of curcumin in BC cells and the inhibition of Trop2 may be an important method for the therapeutic management of patients with BC.

An unusual intragenic promoter of PIWIL2 contributes to aberrant activation of oncogenic PL2L60.

PIWIL2-like (PL2L) protein 60 (PL2L60), a product of aberrantly activated PIWIL2 gene, is widely expressed in various types of tumors and may promote tumorigenesis. However, the mechanisms underlying the activation of expression of PL2L60 remain unknown. In this study, an intragenic promoter responsible for the activation of PL2L60 within the human PIWIL2 gene has been identified, cloned and characterized. The promoter of PL2L60 is located in the intron 10 of the host gene PIWIL2. Bioinformatic and mutagenic analysis reveals that this intragenic promoter within the sequence of 50 nucleotides contains two closely arranged cis-acting elements specific for the hepatic leukemia factor (HLF) in the positive strand and signal transducer and activator of transcription 3 (STAT3) in the negative strand. Chromatin immunoprecipitation analysis demonstrates that both the HLF and polymerase II (Pol II), a hallmark of active promoters, directly bind to the sequence, although STAT3 does not. Knockdown of HLF and STAT3 alone or both by RNA interference significantly reduced both promoter activity and the PL2L60 protein expression, although there is no additive effect. The expression of PL2L60 proteins was enhanced when host gene Piwil2 was genetically disrupted in a murine cell model. Taken together, we have identified a PL2L60-specific intragenic promoter in the host gene of PIWIL2, which is interdependently activated by HLF and STAT3 through steric interaction. This activation is dependent on cellular milieu rather than the integrity of host gene PIWIL2, highlighting a novel, important mechanism for a cancer-causing gene to be activated during tumorigenesis.

Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer.

Bladder cancer (BC) is one of the most commonly occurring cancers, with a high recurrence rate and poor outcomes in cases of relapsed metastatic disease. Here, we analyzed the markers and significance of myeloid-derived suppressor cells (MDSCs) for BC development and progression. MDSC markers were examined in peripheral blood from 113 BC patients and 20 healthy volunteers. We identified CD11b+CD33lowHLA-DR- CD3- cells as markers of MDSCs in peripheral blood from BC patients. We also demonstrated that MDSC numbers are higher in BC patients than healthy donors, and that MDSC numbers correlate with the clinical grade, stage, and poor prognosis. In addition, serum IL-6 levels are decreased in BC patients with higher MDSC counts. IL-6 blockade increases induction of MDSCs in vitro. Low IL-6 levels inhibit activation of Stat3, resulting in the increased formation of MDSCs in BC. These results indicate that the MDSCs numbers may serve as a novel prognostic marker in BC patients, and that targeting IL-6 signaling may be a promising strategy for BC treatment.

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells.

Notch signaling has been reported to play an essential role in tumorigenesis. Several studies have suggested that Notch receptors could be oncoproteins or tumor suppressors in different types of human cancers. Emerging evidence has suggested that Notch pathway regulates cell growth, apoptosis, cell cycle, and metastasis. In the current study, we explore whether Notch-1 could regulate the cell invasion and migration as well as EMT (epithelial-mesenchymal transition) in prostate cancer cells. We found that overexpression of Notch-1 enhanced cell migration and invasion in PC-3 cells. However, downregulation of Notch-1 retarded cell migration and invasion in prostate cancer cells. Importantly, we observed that overexpression of Notch-1 led to EMT in PC-3 cells. Notably, we found that EMT-type cells are associated with EMT markers change and cancer stem cell phenotype. Taken together, we concluded that downregulation of Notch-1 could be a promising approach for inhibition of invasion in prostate cancer cells, which could be useful for the treatment of metastatic prostate cancer.

A novel treatment strategy for newly diagnosed high-grade T1 bladder cancer: Gemcitabine and cisplatin adjuvant chemotherapy-A single-institution experience.

BACKGROUND: Management of high-grade T1 (formerly T1G3) bladder cancer continues to be controversial. Should patients with T1G3 bladder cancer have an immediate radical cystectomy or should they receive intravesical bacillus Calmette-Guérin-preserving bladder? Gemcitabine and cisplatin (GC) adjuvant chemotherapy may help to strike a balance between intravesical and early cystectomy. For purposes of this study, we continue to refer high-grade T1 lesion as "T1G3." OBJECTIVE: To evaluate the characteristics and the long-term outcome of GC adjuvant chemotherapy in T1G3 bladder cancer after transurethral resection of bladder tumor (TURBT). MATERIALS AND METHODS: We retrospectively reviewed 48 patients who were newly diagnosed with T1G3 bladder cancer between January 2009 and December 2012. A total of 48 patients received 4 cycles of GC adjuvant chemotherapy after TURBT. One month after 4 cycles of GC adjuvant chemotherapy, response was evaluated by re-TURBT. Median follow-up was 59.5 (range: 18-70) months, all patients have been observed for more than 3 years. Salvage cystectomy was recommended for patients with persistent disease and for tumor progression after initial complete response. RESULT: Complete response was achieved in 44 (91.7%) patients. Of complete responders, 5 patients experienced recurrence and 5 patients showed progression. The progression rate and disease-specific survival rate were 10.4% and 91.7% at 3 years, respectively. More than 80% of survivors preserved their bladder. Kaplan-Meier curves showed that concomitant carcinoma in situ (CIS) was the only factor that had an influence on progression-free survival (P = 0.022) and disease-specific survival (P = 0.017). Concomitant CIS was the prognostic factor for progression rate and disease-specific survival rate at 3 years (P = 0.008 and P = 0.035). CONCLUSION: GC adjuvant chemotherapy is a safe conservative treatment for T1G3 bladder cancer, but effective is really a phase II study. Patients with T1G3 bladder cancer with concomitant CIS should be treated more aggressively because of the high risk of progression.

Depletion of astrocyte elevated gene-1 suppresses tumorigenesis through inhibition of Akt activity in bladder cancer cells.

Astrocyte elevated gene-1 (AEG-1) has been reported to promote tumorigenesis, however the molecular mechanisms by which AEG-1-induced bladder cancer progression has remained elusive. Here, we identified that depletion of AEG-1 in bladder cancer cells suppressed cell growth. Moreover, we observed that down-regulation of AEG-1 induced apoptosis and inhibited cell migration and invasion. Furthermore, depletion of AEG-1 inhibited Akt activity and suppressed Bcl-2 expression, but upregulated the levels of p21 and p27. Our findings reveal that AEG-1 carries out its oncogenic function via activation of the Akt pathway. Therefore, inhibition of AEG-1 could be a novel treatment approach for bladder cancer.

Metformin can block precancerous progression to invasive tumors of bladder through inhibiting STAT3-mediated signaling pathways.

BACKGROUND: Metformin is the first line of oral antidiabetic drug in the biguanide class for treatment of type 2 diabetes. Increasing evidence has suggested that it is a potential anti-tumor drug. However, the mechanisms underlying inhibiting tumor development remain elusive, especially in bladder tumors. METHODS: T24 and J82 cell lines were used as an in vitro model, and 24 female SD rats were used to build an N-methyl-N-nitrosourea (MNU)-induced orthotopic rat bladder cancer model. Transfection of lentivirus-based shRNA was used to construct the STAT3-KNOCKDOWN T24 cell line. After metformin treatment, the viability of bladde cancer cells was determined by CCK8. Cell cycle distribution and apoptosis were assessed by flow cytometry. The migration and invasion abilities of cells were evaluated by wound healing and transwell asssays. The inactivation of stat3 pahtway was examined by qRTPCR, western blot and Immunofluorescence. RESULTS: Metformin can effectively inhibit precancerous progression to invasive cancer in an MNU-induced rat orthotopic bladder tumor model, although it could not completely suppress normal cells transforming into tumor cells. While the MNU could induce 50 % rats (4/8) to develop invasive bladder cancers, the rats co-administrated with metformin failed to develop invasive tumors but retained at precancerous or non-invasive stages, exhibiting as dysplasia, papillary tumor and/or carcinoma in situ (CIS). Accordingly, phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is a well known oncogene, was significantly inhibited in the tumors of rats treated with metformin. In vitro experiments revealed that the metformin could efficiently inhibit STAT3 activation, which was associated with the cell cycle arrest, reduction of cell proliferation, migration and invasiveness, and increase in apoptotic cell death of bladder cancer cell lines. CONCLUSIONS: These findings provide for the first time the evidence that metformin can block precancerous lesions progressing to invasive tumors through inhibiting the activation of STAT3 pathway, and may be used for treatment of the non-invasive bladder cancers to prevent them from progression to invasive tumors.

AEG-1 is associated with tumor progression in nonmuscle-invasive bladder cancer.

Astrocyte elevated gene-1 (AEG-1), a novel oncoprotein, has been implicated in oncogenesis and cancer progression in various types of human cancers. Here, immunohistochemistry was used to detect AEG-1 expression in nonmuscle-invasive bladder cancer (NMIBC), and these data were examined for correlation with clinicopathological parameters, and prognosis. Immunohistochemical analysis revealed that AEG-1 expression was significantly higher in bladder cancer tissues than that in normal tissues. High expression of AEG-1 was found in 45 % of bladder cancers and significantly associated with tumor grade (P = 0.002) and progression (P = 0.028). The Kaplan-Meier survival analysis demonstrated that AEG-1 expression was significantly associated with shorter progression-free survival (P = 0.0011). Multivariate analysis further demonstrated that AEG-1 was an independent prognostic factor for patients with BC. AEG-1 protein may contribute to the malignant progression of bladder cancer, and present as a novel marker to predict the progression of NMIBC.

Renal mucinous tubular and spindle cell carcinoma: a report of 8 cases and review of the literature.

BACKGROUND: Mucinous tubular and spindle cell carcinoma of kidney (MTSCC-K) is a rare variant of renal tumor. The current data show most of MTSCCs are of low malignant potential and rare cases metastatic to lymph nodes have been reported; however, the recorded computed tomography (CT) and follow up data are limited. MATERIAL AND METHOD: In the present study, we retrospectively analyzed CT and clinicopathological data of eight patients with renal MTSCC-K. RESULTS: A total of eight cases, including six females and two males, were included in this analysis with a mean age of 48.4 (range 25 to 81) years. Mean tumor size was 4.2 (range 2.5 to 10.0) cm. Preoperative CT demonstrated that all tumors were slightly enhanced on both corticomedullary and nephrographic phase, which was different from many other renal cell carcinomas. Three of them were treated with open radical nephrectomy, three with laparoscopic radical nephrectomy and the other two with laparoscopic partial nephrectomy. No postoperative therapy was applied. Patients were followed up for 15 to 64 months and there was no evidence of recurrence and metastasis. CONCLUSIONS: The MTSCC-K has special clinicopathological characteristics, low degree of malignancy and relative good prognosis. The diagnosis mainly depends on the histopathological examination and CT may help to differentiate with papillary renal cell carcinoma. Surgical treatment is recommended and additional therapies are not necessary. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8435581771088249.

Ductal adenocarcinoma of the prostate: immunohistochemical findings and clinical significance.

INTRODUCTION: To investigate the clinical features, diagnosis, treatment, and prognosis of ductal adenocarcinoma of the prostate. METHODS: The clinicopathological and immunohistochemical data of seven patients with ductal adenocarcinoma of the prostate were retrospectively analyzed. All patients underwent physical examination, magnetic resonance imaging (MRI), bone scan, cystoscopy, and computed tomography (CT) scan. The level of prostate-specific antigen (PSA) before and after surgery was assessed. Different prostate cancer markers were used for immunohistochemical staining. RESULTS: The mean age of the seven patients diagnosed with prostatic ductal adenocarcinoma in this study was 76.2 years (range 57-88). Five patients presented with intermittent and painless gross hematuria, one patient with progressive dysuria, and one patient with elevated serum PSA on routine health examination. The level of PSA before surgery ranged from 1.3 to 45.0 ng/mL. Immunohistochemical staining results of the prostatic ductal adenocarcinoma confirmed positivity for PSA, prostatic acid phosphatase, androgen receptor, and alpha-methyacyl co-enzyme A (CoA)-reductase markers. Two of the patients underwent bilateral orchiectomy combined with anti-androgen therapy, three underwent transurethral resection of prostate, one received radical prostatectomy, and one received medical castration therapy. The clinical outcomes of all patients were satisfactory, based on follow-up data. The symptoms of hematuria and dysuria were ameliorated well, and the postoperative PSA level decreased below 4.0 ng/mL. Recurrence or metastasis of disease was not detected on MRI and bone scan. CONCLUSION: Ductal adenocarcinoma of the prostate is a rare subtype of prostate carcinoma, the diagnosis of which could be based on pathological and immunohistochemical examination. Earlier management promises better prognosis.

Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells.

To explore the mechanism and synergistic effect of vitamin A and vitamin D in inducing apoptosis of prostate cancer cells. The cell proliferation activity was determined by MTT assay. The proportion of apoptotic cells was analyzed by FACS and fluorescence intensity. TUNEL was used to evaluate vitamin A and vitamin D's induction of apoptosis in prostate cancer cells. The protein and mRNA expression level of Cyclin D1 and Bax were determined by real time-PCR and western blot. The results of MTT showed vitamin A and vitamin D's inhibition on proliferation ratio in prostate cancer cells is time and concentration dependent. FACS and fluorescence intensity analysis proved that the proportion of apoptotic cells increased after vitamin A and vitamin D treatment. TUNEL showed vitamin A and vitamin D induced prostate cancer cells apoptosis. The combination of vitamin A and vitamin D markedly enhanced the expression of Bax and reduced the expression of Cyclin D1 by real time-PCR and western blot assay. In conclusion, vitamin A and vitamin D could synergistically induce apoptosis in prostate cancer cells.

Increased expression of forkhead box M1 protein is associated with poor prognosis in clear cell renal cell carcinoma.

Forkhead box protein M1 (FoxM1) is crucial in the regulation of various biological processes, including cell proliferation, organogenesis, and angiogenesis. Overexpression of FoxM1 is associated with carcinogenesis. In this study, immunohistochemistry was carried out to examine FoxM1 expression in clear cell renal cell carcinoma (ccRCC), and these data were examined for correlation with clinicopathological parameters and prognosis. FoxM1 protein had high expression in 37 of 87 cases of ccRCC (42.5 %), which was significantly higher than in normal tissues, and FoxM1 overexpression was significantly associated with tumor stage (P = 0.005) and recurrence (P = 0.027). The Kaplan-Meier survival analysis demonstrated that FoxM1 expression was significantly associated with shorter recurrence-free survival and overall survival (P = 0.007 and P = 0.008, respectively). Multivariate analysis further demonstrated that FoxM1 was an independent prognostic factor for patients with ccRCC. So FoxM1 might be a potential molecular marker to predict the prognosis of patients with ccRCC.

MCP-1-induced histamine release from mast cells is associated with development of interstitial cystitis/bladder pain syndrome in rat models.

OBJECTIVE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by overexpression of monocyte chemoattractant protein-1 (MCP-1) in bladder tissues and induction of mast cell (MC) degranulation. This study was undertaken to explore the mechanism of action of MCP-1 in the development of IC/BPS. METHODS: A rat model of IC/BPS was developed by perfusing bladders of nine SPF- grade female Sprague-Dawley rats with protamine sulfate and lipopolysaccharide (PS+LPS). MCP-1 and histamine levels in bladder tissue and urine were detected by immunohistochemistry and ELISA. MC degranulation was measured by immunofluorescence techniques and chemokine (C-C motif) receptor 2 (CCR2) was assayed by flow cytometry. RESULTS: Increased MCP-1 expression in bladder tissue and elevated MCP-1 and histamine levels were observed in the urine of LS+LPS-treated rats. This was accompanied by the expression of CCR2 on MC surfaces, suggesting MCP-1 may induce MC degranulation through CCR2. Exposure to LPS stimulated MCP-1 expression in bladder epithelial cells, and exposure to MCP-1 induced histamine release from MCs. CONCLUSIONS: MCP-1 upregulation in IC/BPS is one of possible contributing factors inducing histamine release from MCs. CCR2 is involved in the process of mast cell degranulation in bladder tissues. These changes may contribute to the development of symptoms of IC/BPS.

Application of pyrosequencing technique for improved detection of K-Ras mutation in formalin-fixed and paraffin-embedded prostate carcinoma tissues in Chinese patients.

BACKGROUND: The purpose of this study was to comparatively evaluate the efficacy of pyrosequencing (PS) and Sanger sequencing (SS) methods for detecting K-Ras codon 12 and 13 mutations in formalin-fixed paraffin-embedded (FFPE) prostate cancer (PCa) samples from Chinese patients. METHODS: The cancer cell lines, including the LS174T G12D mutant (GGT to GAT) and the COLO320 wild-type, were tested to determine the limitation of detection and reproducibility of the PS method. In addition, 101 PCa patient samples, 13 benign prostatic hyperplasia (BPH) and 12 normal adjacent tissue samples, were assayed by PS and SS to evaluate their detection abilities for K-Ras mutations in codons 12 and 13. RESULTS: The PS assay was able to reproducibly detect 5% mutant alleles and had an intra-assay variability of 4.21% and inter-assay variability of 11.37%. The PS assay detected a higher number of K-Ras mutations in PCa samples than the SS assay (8.91% vs. 3.96%). Correlation and stratification analyses of the PCa samples and K-Ras mutation status revealed no associations between age, serum prostate specific antigen (PSA), depth of invasion (pT category), or Gleason score. CONCLUSIONS: We demonstrated that the PS method detected more K-Ras mutations in codons 12 and 13 of FFPE prostate cancer samples from Chinese patients than the traditional SS method. In addition, the K-Ras mutation was more frequent in Chinese population than in Western populations but was similar to that of other Eastern populations, suggesting that these K-Ras mutations may contribute to the pathogenesis of prostate carcinoma in Asian patients.

Increased expression of HMGB1 is associated with poor prognosis in human bladder cancer.

BACKGROUND AND OBJECTIVE: High-mobility group box 1 (HMGB1) is a versatile protein with intranuclear and extracellular functions that is involved in numerous biological and pathological processes, such as transcription, DNA repair, and response to infection and inflammation. HMGB1 overexpression has been reported in a variety of human cancers. However, the clinical significance of HMGB1 expression in bladder cancer (BC) remains unclear. This study is aimed to investigate the correlations between HMGB1 expression and prognosis in patients with BC. METHODS: HMGB1 protein expression in 164 primary BC tissue specimens was analyzed by immunohistochemistry, and its association with clinicopathologic factors and prognosis was also analyzed. RESULTS: HMGB1 protein had high expression in 87 of 164 cases of BC (53%). HMGB1 overexpression was significantly associated with tumor grade (P < 0.001), and stage (P = 0.001). The Kaplan-Meier survival analysis demonstrated that HMGB1 expression was significantly associated with shorter disease-free survival and overall survival (both P < 0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with BC. CONCLUSIONS: HMGB1 might be a new molecular marker to predict the prognosis of patients with BC.

UHRF1 is associated with tumor recurrence in non-muscle-invasive bladder cancer.

Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel anti-apoptotic gene, and overexpression of UHRF1 is involved in tumorigenicity. Here, immunohistochemistry was used to detect UHRF1 expression in non-muscle-invasive bladder cancer (NMIBC), and these data were examined for correlation with clinicopathological parameters and prognosis. The UHRF1 expression rate was 49.2% in a total of 118 bladder cancer tissues, which was significantly higher than in normal tissues, and UHRF1 expression has a significantly positive correlation with tumor grade (P = 0.027) and recurrence (P = 0.013). Survival analysis showed that UHRF1 high expression patients' mean survival time (42.59 months) was significantly shorter than that (71.36 months) of UHRF1 low expression patients (P = 0.0002). Multivariate analysis showed that UHRF1 overexpression was an independent prognostic factor for tumor recurrence (P < 0.0001). So UHRF1 may be a molecular marker to predict the recurrence of NMIBC.