Fig 1: Signaling pathways of M3R regulates proliferation of urothelium (hypothesis based on previous reports). (A) It was speculated that a certain concentration of ACh combined to the M3R and stimulates proliferation of normal urothelium. urothelium release of ACh. The autocrined and paracrined ACh also combined to M3R. But M3R in turn inhibited urothelial proliferation when the concentration of ACh reaches a high level. The mechanism maintains the normal metabolism of urothelium. (B) It was speculated that the mechanism has changed in bladder cancer. ACh increased due to the autocrine and paracrine signals from the bladder urothelium and sub-urothelium tissues. However, the negative feedback of M3R on urothelial proliferation failed. The PKC pathway serves an important role in the regulation of urothelial proliferation of M3R according to the existed data. It is possible that the Ca2+/DG-PKC pathway serves a major role in physiological while the PKC/MAPK/NF-?B pathway may serve a major role in bladder cancer cells. M3R, M1R, muscarinic cholinergic receptor 1; PKC/MAPK/NF-?B, protein kinase C/mitogen-activated protein kinase/nuclear factor-?B.
Fig 2: Expression of M1-5R of urothelium in OAB and bladder cancer and urgency in PFS. (A) Patients experiencing ‘daily =1’ urgency demonstrated significantly lower PFS, compared with those experiencing ‘daily <1’ (P=0.0496). (B) PFS in patients with invasive bladder cancer who underwent radical cystectomy. M3R expression was negatively associated with PFS (P=0.032). (C) Expression levels of mAChRs M1-5R in bladder mucosa of patients with OAB based on reverse transcription-polymerase chain reaction. (OAB group, M1-5, n=10, 9, 10, 10, 10; Control group, M1-5, n=11, 9, 11, 11, 11; P=0.56, 0.22, 0.56, 0.43, 0.92). (D) M1-5R proteins in bladder urothelium of patients with bladder cancer based on immunohistochemistry. M3R staining (*P<0.05) was less intense in patients with muscle-invasive bladder cancer, even though this group had more severe OAB-like symptoms. PFS, progression free survival; M1-5R, muscarinic cholinergic receptor 1–5; OAB, overactive bladder.
Fig 3: Expression of M3R in bladder cancer tissue. Representative immunostained photomicrographs indicating M3R expression in (A) bladder urothelium, (B) sub-urothelium and (C) detrusor of patients with bladder cancer. Differences in M3R staining intensity of urothelium between (D) invasive and non-invasive bladder cancer tissues and (E) muscle invasive and non-muscle invasive bladder cancer tissues (P=0.038, 0.017). Differences in M3R staining intensity of detrusor between (F) invasive and non-invasive bladder cancer tissues and (G) muscle invasive and non-muscle invasive bladder cancer tissues. (P=0.001, 0.001). (H) Differences in M3R staining intensity between tumor urothelium tissue and adjacent tissue (P=0.023). (I) Differences in M3R staining intensity in detrusor between patients with low-grades and high-grade bladder cancer (P=0.046). M3R, muscarinic cholinergic receptor 3.
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