Effect of irradiation on the expression of E-cadherin and β-catenin in early and late radiation sequelae of the urinary bladder and its modulation by NF-κB inhibitor thalidomide

Abstract

Purpose In a previous study we have shown in a mouse model that administration of nuclear factor-kappa B (NF-κB) inhibitor thalidomide has promising therapeutic effects on early radiation cystitis (ERC) and late radiation sequelae (LRS) of the urinary bladder. The aim of this study was to evaluate in the same mice the effect of thalidomide on adherens junction (AJ) proteins in ERC and LRS. Methods Urothelial expressions of E‑cadherin and β‑catenin were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) bladder specimens over 360 days post single-dose irradiation on day 0. First, the effect of irradiation on AJ expression and then effects of thalidomide on irradiation-induced AJ alterations were assessed using three different treatment times. Results Irradiation provoked a biphasic upregulation of E‑cadherin and β‑catenin in the early phase. After a mild decrease of E‑cadherin and a pronounced decrease of β‑catenin at the end of the early phase, both increased again in the late phase. Early administration of thalidomide (day 1–15) resulted in a steeper rise in the first days, an extended and increased expression at the end of the early phase and a higher expression of β‑catenin alone at the beginning of the late phase. Conclusion Upregulation of AJ proteins is an attempt to compensate irradiation-induced impairment of urothelial barrier function. Early administration of thalidomide improves these compensatory mechanisms by inhibiting NF-κB signaling and its interfering effects.

Intravesical IR‐780 instillation prevents radiation cystitis by protecting urothelial integrity

“…The urinary mucosa initially defends the underlying muscularis propria against pathogenic, chemical, and mechanical stimuli. The biphasic effect of radiation on the urothelium is well depicted in preclinical models 15–18 . An early phase with loss of urothelium cell number was delineated before 15,16 .…”

“…The biphasic effect of radiation on the urothelium is well depicted in preclinical models. [15][16][17][18] An early phase with loss of urothelium cell number was delineated before. 15,16 Zwaans et al 17 uncovered that the expression of uroplakin 3 in umbrella cells and adherens junction protein E-cadherin decreased at 4 and 8 weeks postirradiation.…”

“…15,16 Zwaans et al 17 uncovered that the expression of uroplakin 3 in umbrella cells and adherens junction protein E-cadherin decreased at 4 and 8 weeks postirradiation. Interestingly, Krischak et al 18 described the expression of E-cadherin and β-catenin compensatively increased to restore the urinary barrier in the early phase. Urothelial hyperplasia is characterized by cell number, 15,16 Ki67, 16 EGFR, 16 uroplakin 3 17 and E-cadherin 18 expression was observed compared with nonirradiated control by the late response phase.…”

“…Interestingly, Krischak et al 18 described the expression of E‐cadherin and β‐catenin compensatively increased to restore the urinary barrier in the early phase. Urothelial hyperplasia is characterized by cell number, 15,16 Ki67, 16 EGFR, 16 uroplakin 3 17 and E‐cadherin 18 expression was observed compared with nonirradiated control by the late response phase. During the clinical course of radiation cystitis, the urothelium will also exhibit a proliferative activity dependent on irradiation dose at around 6–12 months 4 .…”

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

“…The main constituents of the so-called adherens junctions (AJs) are cadherin (Cad)-family members (Cads), which are Ca 2+ -dependent, membrane-embedded proteins that connect cells via homophilic interaction [93]. In the cytoplasm, Cads are connected to various proteins, amongst others α-catenin, p120, vinculin or β-catenin [22,[94][95][96]. These adaptor proteins are comparable to the integrin-linked intracellular mechanotransducers, as they connect Cads to the actin cytoskeleton.…”