Fan Yating, Chen Ye, Yang Hua, Chen Na, Gu Xiangshuai, Feng Xiaoliang, Fang Chao, Yin Yuan, Deng Hongxin, Dai Lei
Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Huidong General Surgery Department of Zigong Fourth People's Hospita, Zigong, 643000, China.
Transl Oncol. 2025 Aug;58:102431. doi: 10.1016/j.tranon.2025.102431. Epub 2025 May 27.
Colitis-associated colorectal cancer (CAC), which stems from inflammatory bowel disease (IBD), exhibits a high mortality rate. Chronic inflammation can drive the development of colorectal cancer via diverse mechanisms; however, proteomic-level studies in this regard are currently scarce. The chemical drugs conventionally employed for treating IBD carry significant side effects, accentuating the exigency for novel therapeutic agents. We focused on carvacrol, a traditional Chinese medicine-derived monoterpene phenol with anti-inflammatory and antioxidant traits, though its role in colitis and CAC was unclear. Employing TMT-based proteomics, we identified the oxidative stress pathway as crucial in CAC, with ALB, ADAM10, and APCDD1 (hub genes) being vital. Using DSS and AOM/DSS mouse models, carvacrol significantly restored colonic length (p < 0.01) and re-established key tight junction proteins like ZO-1. It also downregulated mRNA levels of inflammatory mediators such as iNOS and IL-6. Moreover, 16S rRNA sequencing and fluorescence in situ hybridization (FISH) assays indicated that the potential mechanism might be ascribed to carvacrol's modulation of the abundance of specific microbiota, such as Lactobacillus, Escherichia coli/Shigella, and Lachnoclostridium. In subsequent investigations, we ascertained that carvacrol exerted remarkable efficacy in the AOM/DSS models, as it markedly reduced the number of colonic tumors (p < 0.05) and concurrently suppressed the disease activity index scores (p < 0.05). These results jointly suggest its prospective role in thwarting the progression of colitis-associated colorectal cancer. Collectively, our study substantiates that carvacrol efficiently safeguards the mucosal barrier and curbs tumorigenesis, potentially via the modulation of gut microbiota.
结肠炎相关结直肠癌（CAC）源于炎症性肠病（IBD），死亡率很高。慢性炎症可通过多种机制推动结直肠癌的发展；然而，目前这方面的蛋白质组学水平研究较少。传统上用于治疗IBD的化学药物有显著副作用，凸显了新型治疗药物的紧迫性。我们聚焦于香芹酚，一种具有抗炎和抗氧化特性的源自中药的单萜酚，但其在结肠炎和CAC中的作用尚不清楚。采用基于TMT的蛋白质组学，我们确定氧化应激途径在CAC中至关重要，其中ALB、ADAM10和APCDD1（枢纽基因）至关重要。使用葡聚糖硫酸钠（DSS）和氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）小鼠模型，香芹酚显著恢复了结肠长度（p<0.01），并重新建立了关键的紧密连接蛋白，如闭合蛋白1（ZO-1）。它还下调了炎症介质如诱导型一氧化氮合酶（iNOS）和白细胞介素-6（IL-6）的mRNA水平。此外，16S核糖体RNA测序和荧光原位杂交（FISH）分析表明，潜在机制可能归因于香芹酚对特定微生物群丰度的调节，如乳酸杆菌、大肠杆菌/志贺氏菌和瘤胃球菌属。在后续研究中，我们确定香芹酚在AOM/DSS模型中发挥了显著疗效，因为它显著减少了结肠肿瘤数量（p<0.05）并同时抑制了疾病活动指数评分（p<0.05）。这些结果共同表明其在阻止结肠炎相关结直肠癌进展方面的潜在作用。总体而言，我们的研究证实香芹酚可有效保护黏膜屏障并抑制肿瘤发生，可能是通过调节肠道微生物群实现的。
