Nishimura Nobutaka, Miyake Makito, Onishi Sayuri, Tomizawa Mitsuru, Shimizu Takuto, Onishi Kenta, Hori Shunta, Morizawa Yosuke, Gotoh Daisuke, Nakai Yasushi, Tanaka Nobumichi, Fujimoto Kiyohide
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan.
Department of Prostate Brachytherapy, Nara Medical University, 840 Shijo-cho, Kashihara 634-8522, Nara, Japan.
Cancers (Basel). 2024 Dec 8;16(23):4112. doi: 10.3390/cancers16234112.
: 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. : The expression of two clock genes, and , 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. : We observed the circadian rhythm of intracellular PPIX accumulation, which was potentially regulated by the clock genes and . 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. : 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.
非肌肉浸润性膀胱癌患者的标准推荐是5-氨基酮戊酸介导的光动力诊断。原卟啉IX（PPIX）在细胞内积累所引起的荧光强度在不同肿瘤和患者之间存在差异。本研究调查了暴露于5-氨基酮戊酸的膀胱尿路上皮癌细胞内PPIX积累的昼夜节律。在两种膀胱癌细胞系UM-UC-3和J82以及小鼠异种移植模型中评估了两个时钟基因的表达及其对细胞内PPIX积累的影响。我们评估了血红素合成途径中可能影响细胞内PPIX积累昼夜节律的酶。根据手术开始时间将四组患者分为：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，对膀胱肿瘤光动力诊断辅助经尿道切除术中捕获图像的红色荧光强度进行定量并比较。我们观察到细胞内PPIX积累的昼夜节律，其可能受时钟基因调控。血红素合成途径中涉及的两种酶，粪卟啉原氧化酶和亚铁螯合酶，呈现昼夜节律。荧光强度在中午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。我们的研究结果表明，基于昼夜节律优化膀胱癌光动力诊断辅助经尿道切除术中光动力诊断的时间，可能有助于提高肿瘤检测和治疗效果。
