AATF is Overexpressed in Human Bladder Cancer and Regulates Chemo-Sensitivity Through Survivin

Abstract

Objective Dysregulation of apoptosis antagonizing transcription factor (AATF) has been reported to be closely associated with human cancers. However, its involvement in human bladder cancer (BC) remains unexplored. This study aimed to investigate the clinical significance and biological roles of AATF in human bladder cancers. Methods AATF protein expression was examined in 107 cases of bladder cancer tissues using immunohistochemistry. AATF plasmid transfection and small interfering RNA (siRNA) knockdown were performed in T24 and 5637 cell lines. CCK-8, colony formation, annexin V/PI, JC-1 staining, and Western blotting were carried out to investigate the biological roles and underlying mechanisms of AATF in bladder cancer cells. Results Our results showed that AATF expression was upregulated in human bladder cancer specimens and correlated with T stage. Analysis of the Oncomine database showed elevation of AATF mRNA in BC tissues. The Cancer Genome Atlas (TCGA) data suggested that high AATF expression correlated with poor patient survival. Western blotting showed that AATF protein expression was higher in BC cell lines compared to normal bladder transitional epithelial cell line SV-HUC-1. CCK-8 and colony assays showed that ectopic AATF expression upregulated cell growth rate and colony numbers. CCK-8, annexin V/propidium iodide (PI), JC-1 assays and Western blotting showed that AATF overexpression decreased cisplatin sensitivity, downregulated cisplatin-induced apoptosis and upregulated mitochondrial membrane potential, with decreased cytochrome c and cleaved-PARP expression. AATF siRNA knockdown showed the opposite effects. Mechanistically, AATF overexpression upregulated cyclin E and Survivin at both mRNA and protein levels. The decreased cisplatin sensitivity/apoptosis induced by ectopic AATF were reversed after treatment with Survivin inhibitor YM155. Conclusion Our results showed that AATF was overexpressed in human bladder cancers and promoted malignant behavior by regulating cyclin E and Survivin, indicating AATF could serve as a malignant biomarker and potential therapeutic target in BC.

Predictive Value of the Log Odds of Negative Lymph Nodes/T Stage as a Novel Prognostic Factor in Bladder Cancer Patients After Radical Cystectomy

“…It is conducive to follow-up consultation, postoperative treatment and clinical trials. For BLCA patients receiving RC, the prognosis not only correlates with T stage and biological characteristics ( 14 , 15 ), but also with the degree of lymph node dissection ( 5 , 11 ). However, so far, effective and objective indicators to evaluate the impact of individualized lymph node resection are still lacking.…”

“…There was no statistical difference in the clinical variables between the primary cohort and internal validation cohort. Among all BLCA patients receiving RC, the median ELN, NLN and LONT count (IQR) were 14 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), 13 (7-23) and 0.7 (0.5-1.0), respectively. The majority of them were between 63 and 76 years old (44.6%), male (66.7%), white (86.8%) and married (61.1%).…”

“…In the external validation cohort from our medical center, the median ELN, NLN and LONT count (IQR) were 17 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), 16 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) and 0.8 (0.6-1.0), respectively. In addition, the majority of them were between 63 and 76 years old (59.3%), male (81.4%), and married (62.8%).…”

“…In fact, the T stage is a powerful risk factor for BLCA and represents the major tumor features. An increasing number of studies have suggested that T stage is closely associated with prognosis and tumor biological features (13)(14)(15). T stage can represent the biological characteristics of tumor.…”

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“…For BLCA patients receiving RC, the prognosis not only correlates with T stage and biological characteristics (14,15), but also with the degree of lymph node dissection (5,11). However, so far, effective and objective indicators to evaluate the impact of individualized lymph node resection are still lacking.…”