BACKGROUNDDysregulation of apoptosis has been implicated not only in carcinogenesis and tumor progression but also in tumor recurrence. We investigated whether the expression of X-linked inhibitor of apoptosis (XIAP) might predict early recurrence in patients with non-muscular invasive bladder cancer.

METHODSThe cohort comprised 176 consecutive patients with primary superficial bladder cancer treated with transurethral resection. Immunohistochemical staining using the standard avidin-biotin-peroxidase technique and RT-PCR were used to detect XIAP protein and mRNA expressions in cancer tissues. The relationship between XIAP expression and clinicopathological characteristics, cancer recurrence were analyzed.

RESULTSXlAP expression was observed in 108 cases (61.4%) and no expression in 68. There was no correlation between XIAP expression rate and the tumor pathological grade, but was an apparent trend toward the increased XIAP levels from well (G1) to poor (G3) differentiated cancer. Eighty-two (46.6%) patients experienced tumor recurrence at a mean of 28.6 months of the follow-up; 66 of them expressed XIAP (61.1%) and 16 were XIAP negative (23.5%). Twelve patients presented with invasive disease at the time of relapse and all of them expressed XIAP. Patients without XIAP expression or with low tumor grades had significantly higher recurrence-free survival than those with XIAP expression (log rank test P = 0.0015) or high tumor grades (log rank test P < 0.001). Multivariate analysis revealed that XIAP expression, tumor grade, and tumor number were independent predictors for the recurrence of non-muscular invasive bladder cancer (P = 0.004, 0.016, and 0.043, respectively).

CONCLUSIONSXIAP may be considered as a new independent prognostic marker for early recurrence of non-muscular invasive bladder cancer.

Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; analysis ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local ; Prognosis ; Prospective Studies ; Urinary Bladder Neoplasms ; chemistry ; mortality ; pathology ; X-Linked Inhibitor of Apoptosis Protein ; analysis ; genetics

The incidence rates of urinary bladder cancer continue to rise yearly, and thus new therapeutic approaches and early diagnostic markers for bladder cancer are urgently needed. Thus, identifying the key mediators and molecular mechanisms responsible for the survival of bladder cancer has valuable implications for the development of therapy. In this study, the role of BLT2, a receptor for leukotriene B4 (LTB4) and 12(S)-hydroxyeicosatetraenoic acid (HETE), in the survival of bladder cancer 253J-BV cells was investigated. We found that the expression of BLT2 is highly elevated in bladder cancer cells. Also, we observed that blockade of BLT2 with an antagonist or BLT2 siRNA resulted in cell cycle arrest and apoptotic cell death, suggesting a role of BLT2 in the survival of human bladder cancer 253J-BV cells. Further experiments aimed at elucidating the mechanism by which BLT2 mediates survival revealed that enhanced level of reactive oxygen species (ROS) are generated via a BLT2-dependent up-regulation of NADPH oxidase members NOX1 and NOX4. Additionally, we observed that inhibition of ROS generation by either NOX1/4 siRNAs or treatment with an ROS-scavenging agent results in apoptotic cell death in 253J-BV bladder cancer cells. These results demonstrated that a 'BLT2-NOX1/4-ROS' cascade plays a role in the survival of this aggressive bladder cancer cells, thus pointing to BLT2 as a potential target for anti-bladder cancer therapy.
*Apoptosis ; Blotting, Western ; Cell Proliferation ; Cells, Cultured ; Gene Expression Regulation, Neoplastic/*physiology ; Humans ; Leukotriene Antagonists/pharmacology ; NADPH Oxidase/antagonists & inhibitors/genetics/metabolism ; Phosphorylation ; RNA, Messenger/genetics ; RNA, Small Interfering/genetics ; Reactive Oxygen Species/*metabolism ; Receptors, Leukotriene B4/antagonists & inhibitors/*genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Tetrazoles/pharmacology ; Up-Regulation ; Urinary Bladder Neoplasms/*genetics/mortality

We performed gene expression profiling in bladder cancer patients to identify cancer-specific survival-related genes in muscle invasive bladder cancer (MIBC) patients. Sixty-two patients with MIBC were selected as the original cohort and another 118 MIBC patients were chosen as a validation cohort. The expression of USP18, DGCR2, and ZNF699 genes were measured and we analyzed the association between gene signatures and survival. USP18 and DGCR2, were significantly correlated to cancer-specific death (P=0.020, P=0.007, respectively). Cancer-specific survival in the low USP18 or DGCR2 expression group was significantly longer than the high expression group (P=0.018, P=0.006, respectively). In multivariate Cox regression analysis, a combination of USP18 and DGCR2 mRNA expression levels were significant risk factors for cancer-specific death (HR, 2.106; CI, 1.043-4.254, P=0.038). Overall survival and cancer-specific survival rates in the low-combination group were significantly longer than those in the high-expression group (P=0.001, both). In conclusion, decreased expressions of USP18 and DGCR2 were significantly associated with longer cancer-specific survival, and also the combination of two genes was correlated to a longer survival for MIBC patients. Thus, the combination of USP18 and DGCR2 expression was shown to be a reliable prognostic marker for cancer-specific survival in MIBC.
Adult ; Aged ; Aged, 80 and over ; Biological Markers/metabolism ; Carrier Proteins/genetics/metabolism ; Endopeptidases/genetics/*metabolism ; Female ; Gene Expression Profiling ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Muscle Neoplasms/*secondary ; Neoplasm Invasiveness ; Neoplasm Staging ; Platelet Glycoprotein GPIb-IX Complex/genetics/*metabolism ; Predictive Value of Tests ; ROC Curve ; Regression Analysis ; Risk Factors ; Urinary Bladder Neoplasms/*diagnosis/metabolism/*mortality/pathology