Fanconi Anemia Pathway Activation by FOXM1 is Critical to Bladder Cancer Recurrence and Anticancer Drug Resistance

Abstract

Although the 5-year survival rate of patients diagnosed with nonmuscle invasive bladder cancer (NMIBC) has reached 85%, more than 50% of patients suffer from frequent recurrences. To identify molecular targets associated with recurrence of NMIBC, we analyzed gene expression data and found that FOXM1 and FANCD2 were involved in recurrence. Therefore, we investigated how these genes were involved in the mechanism of recurrence and confirmed their usefulness as biomarkers. Investigation have shown that FOXM1 directly regulated the transcription of FANCD2, which is the key gene of the Fanconi anemia (FA) pathway. Depletion of FOXM1 resulted in DNA repair defects in the FA pathway and in decreased resistance to chemotherapy. Thus, the FANCD2-associated FA pathway activated by FOXM1 is an important mechanism involved in chemotherapy-related recurrence. In conclusion, FOXM1 and FANCD2 can be used as prognostic factors that are associated with high risk of recurrence and with anticancer drug resistance properties in NMIBC patients.

A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy

“…NMIBC is clinically heterogeneous [ 5 ]. Despite considerable effort [ 7 , 8 , 9 , 10 , 11 ], the clinical heterogeneity of NMIBC means that there is a great need to identify subtypes with biological and clinical relevance. Here, we used data from multiple NMIBC patient cohorts to carry out transcriptome profiling analyses.…”

“…Considerable effort has been devoted to uncovering the molecular characteristics and establishing prognostic models of NMIBC [ 7 , 8 , 9 , 10 , 11 , 19 ]. Recent transcriptomic profiling investigations revealed several distinct molecular subtypes relevant to tumor heterogeneity [ 7 ] and responsiveness of BCG therapy [ 8 ].…”

“…The DP.BCG+ subtype clearly showed strong alteration of cell cycle or DNA repair systems ( Figure 5 A). In this subtype, FOXM1 , TOP2A , CCNB1 , CCNB2 , and CDC25A participate in DNA repair and are activated during disease relapse [ 9 , 10 , 11 , 20 ] or play a role in the prognosis of other cancers [ 21 , 22 ], thereby supporting the poor prognostic characteristics of the DP.BCG+ subtype.…”

“…Much research has been conducted to better understand tumor heterogeneity at a molecular level and to establish prognostic models of NMIBC [ 7 , 8 , 9 , 10 , 11 ]. Although most studies of bladder cancer focused primarily on MIBC [ 12 , 13 , 14 ], or on combined analysis of NMIBC and MIBC [ 15 ], recent studies have examined NMIBC exhibiting several distinct molecular subtypes in an attempt to address tumor heterogeneity [ 7 ] and responsiveness to BCG therapy [ 8 ].…”

FOXM1 and β-catenin are potential prognostic markers in muscle-invasive bladder carcinoma

“…Yang et al [12] reported that in bladder carcinoma cells, downregulation of FOXM1 suppress cell migration and invasion. Roh et al [13] reported that FOXM1 can be used as a useful tumor marker that are associated with anticancer drug resistance properties in NMIBC patients. Chen et al [14] con rmed upregulation of FOXM1 was related to bad progression free survival of NMIBC patients.…”