Background/Objectives: The standard recommendation for patients with non-muscle invasive bladder cancer is 5-aminolevulinic acid-mediated photodynamic diagnosis. The intensity of the fluorescence caused by the intracellular accumulation of protoporphyrin IX (PPIX) varies among tumors and patients. This study investigated the circadian rhythm of intracellular PPIX accumulation in bladder urothelial cancer cells exposed to 5-aminolevulinic acid.Methods: The expression of two clock genes,PER2andBMAL1, and their impact on intracellular PPIX accumulation were evaluated in two bladder cancer cell lines, UM-UC-3 and J82, and mouse xenograft models. We evaluated the enzymes involved in the heme synthesis pathway that potentially affect the circadian rhythm of intracellular PPIX accumulation. The red fluorescence intensity of the images captured during photodynamic diagnosis-assisted transurethral resection of bladder tumors was quantified and compared among the four groups according to surgery start time: 9 a.m.–11 a.m., 11 a.m.–1 p.m., 1–3 p.m., and 3–5 p.m.Results: We observed the circadian rhythm of intracellular PPIX accumulation, which was potentially regulated by the clock genesPER2andBMAL1. Two enzymes involved in the heme synthesis pathway, coproporphyrinogen oxidase and ferrochelatase, exhibit a circadian rhythm. The fluorescence intensity started gradually increasing at 12 p.m., and the highest level was observed in patients who underwent surgery between 3 and 5 p.m.Conclusions: Our findings suggest that it may be possible to optimize the timing of the photodynamic diagnosis in photodynamic diagnosis-assisted transurethral resection of bladder cancer based on the circadian rhythm to improve tumor detection and treatment outcomes.
背景/目的：对于非肌层浸润性膀胱癌患者，标准推荐采用5-氨基酮戊酸介导的光动力诊断。由细胞内原卟啉IX（PPIX）积累引起的荧光强度在不同肿瘤和患者中存在差异。本研究探讨了膀胱尿路上皮癌细胞在5-氨基酮戊酸暴露下细胞内PPIX积累的昼夜节律。方法：在两种膀胱癌细胞系（UM-UC-3和J82）及小鼠异种移植模型中，评估了两个时钟基因PER2和BMAL1的表达及其对细胞内PPIX积累的影响。我们评估了可能影响细胞内PPIX积累昼夜节律的血红素合成途径相关酶。对光动力诊断辅助经尿道膀胱肿瘤切除术中捕获图像的红色荧光强度进行量化，并按手术开始时间分为四组进行比较：上午9点至11点、上午11点至下午1点、下午1点至3点、下午3点至5点。结果：我们观察到细胞内PPIX积累存在昼夜节律，这可能受时钟基因PER2和BMAL1调控。血红素合成途径中的两种酶——粪卟啉原氧化酶和铁螯合酶表现出昼夜节律性。荧光强度从中午12点开始逐渐增加，在下午3点至5点接受手术的患者中观察到最高水平。结论：我们的研究结果表明，基于昼夜节律优化光动力诊断辅助经尿道膀胱癌切除术中光动力诊断的时机，可能有助于提高肿瘤检测和治疗效果。
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