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.
Highlights
Bladder cancer (BC) is the fifth most frequent cancer among men, with an estimated 549,393 new diagnoses and 199,922 BC deaths per year worldwide (2018) [1]
We found that recurrence was significantly increased in the high expression group of FOXM1 compared to the low expression group of FOXM1 in both Korean cohorts (GSE13507) and European cohorts (GSE5479) (Figure 1A)
The results showed that the expression of these genes was significantly higher in recurrent cancer tissues than it was in primary cancer tissues (p = 0.004; FOXM1 and p = 0.001; FANCD2 by two sample t-test, Figure 6A)
Summary
Bladder cancer (BC) is the fifth most frequent cancer among men, with an estimated 549,393 new diagnoses and 199,922 BC deaths per year worldwide (2018) [1]. Cancers 2020, 12, 1417 groups, high-risk NMIBC (T1, with high grade/G3, and/or carcinoma in situ (CIS)) results in poor prognosis and additional intravesical bacillus Calmette-Guerin (BCG) and anticancer drug treatments (doxorubicin (DOX) and mitomycin C (MMC)) are recommended after surgery [5]. Despite these treatments, more than 50% of patients with NMIBC develop recurrence, and 10% to 30% of recurrent patients progress to MIBC [6]. These reports indicate that traditional indicators such as tumor grade,
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