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Purpose: To identify the role of a set of microRNAs and their target genes and protein expression levels in the pathogenesis of bladder cancer with a muscular invasion (T2–T4) and non-muscular invasion (T1). Methods: In 157 patients, bladder specimen was examined for the expression of a set of miRNAs including let-7a-5p, miRNA-449a-5p, miRNA-145-3P, miRNA-124-3P, miRNA-138-5p, and miRNA-23a-5p and their targeted genes; β-catenin, WNT7A, IRS2, FZD4, SOS1, HDAC1, HDAC2, HIF1α, and PTEN using the qRT-PCR technique. The prognostic effect of miRNAs and their targeted genes on cancer-specific survival (CSS) was evaluated in pT2–pT4 stages. Results: pT1 was found in 40 patients while pT2–4 was found in 117 patients. The expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P significantly decreased in pT2–4 compared with pT1 (p < 0.001), in contrast, miR-23a-5P increased significantly in pT2–pT4 compared with pT1 (p < 0.001). Moreover, the expression of miR-145 did not show a significant change (p = 0.31). Higher expression levels of WNT7A, β-catenin, IRS2, FZD4, and SOS1 genes were observed in pT2–pT4 compared with pT1, whereas HDAC1, HDAC2, HIF1α, and PTEN genes were downregulated in pT2–pT4 compared with pT1. Lower CSS was significantly associated with lower expression of let-7a-5P, miR-124-3P, miR-449a-5P, and miR-138-5P. Higher expression of β-catenin, FZD4, IRS2, WNT7a, and SOS1 was significantly associated with worse CSS. In contrast, lower levels of HDAC1, HDAC2, HIF1α, and PTEN were associated with lower CSS. Conclusion: Our results support let-7a-5P, miR-124-3P, miR-138-5P, and their target genes can be developed as accurate biomarkers for prognosis in bladder cancer with a muscular invasion.

Objectives To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette–Guérin (BCG) induction in high‐risk non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)‐2 and IL‐10 by solid‐phase enzyme‐linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF‐α), cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) and transcription factors (TFs) (GATA‐binding protein 3 [GATA3], T‐box expressed in T cells [T‐bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase‐polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression). Results Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL‐2 and serum TNF‐α increased in all patients, serum CTLA‐4 and FoxP3+ showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF‐α fold change and urinary IL‐10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow‐up of 37 (20–88) months, 104 (56%) patients developed recurrence. Urinary IL‐10, serum CTLA‐4, T‐bet+, FoxP3+ change patterns and GATA3+/T‐bet+ ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL‐10, serum CTLA‐4, serum T‐bet+ change patterns and GATA3+/T‐bet+ ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively). Conclusions Urinary IL‐10 and serum TNF‐α can significantly predict ICR. Moreover, change pattern of urinary IL‐10, serum CTLA‐4, TFs (GATA3, T‐bet and FoxP3) and GATA3+/T‐bet+ ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.