Dou Fangzhou, Hu Shasha, Lu Daoran, Gao Jianjun
Department of Pharmacology, School of Pharmacy, Qingdao University, Qingdao, Shandong, China.
Department of Pathology, The affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Drug Discov Ther. 2025 Jul 4;19(3):200-207. doi: 10.5582/ddt.2025.01022. Epub 2025 Jun 20.
Chronic inflammation in the colon has been recognized as a key pathogenic mechanism driving colorectal cancer development. TRPA1 (transient receptor potential ankyrin 1), a key member of the TRP cation channel superfamily, is closely implicated in inflammatory processes and has emerged as a promising therapeutic target for anti-inflammatory drug development. However, the precise role of TRPA1 in colorectal carcinogenesis and its potential as a therapeutic target for colorectal cancer (CRC) remain incompletely understood. In this study, we demonstrate that Trpa1 knockout significantly exacerbates DSS-induced colitis-associated tumorigenesis in murine models, a phenomenon mechanistically linked to Trpa1 deficiency-mediated aggravation of inflammatory bowel pathology. RNAseq and gene knockout effect analysis revealed a consistently low expression pattern of TRPA1 across colorectal cancer cell lines (n = 58, median log2(TPM+1) = 0.025), with limited impact on cell viability upon TRPA1 knockout. Notably, analysis of human clinical specimens revealed substantial downregulation of TRPA1 expression in CRC compared to adjacent normal tissues. Kaplan-Meier survival analysis further indicated that patients with TRPA1-low tumors exhibited significantly poorer overall survival outcomes. These collective data suggest a tumor-suppressive role for TRPA1 in colorectal carcinogenesis, potentially through its immunomodulatory functions within the colitis-cancer transformation axis.
结肠中的慢性炎症已被认为是驱动结直肠癌发生发展的关键致病机制。TRPA1（瞬时受体电位锚蛋白1）是TRP阳离子通道超家族的关键成员，与炎症过程密切相关，已成为抗炎药物开发中一个有前景的治疗靶点。然而，TRPA1在结直肠癌发生中的精确作用及其作为结直肠癌（CRC）治疗靶点的潜力仍未完全明确。在本研究中，我们证明Trpa1基因敲除显著加剧了小鼠模型中由葡聚糖硫酸钠（DSS）诱导的结肠炎相关肿瘤发生，这一现象在机制上与Trpa1缺乏介导的炎症性肠病病理加重有关。RNA测序和基因敲除效应分析显示，TRPA1在结直肠癌细胞系中（n = 58，中位数log2(TPM + 1) = 0.025）呈现持续低表达模式，TRPA1基因敲除对细胞活力影响有限。值得注意的是，对人类临床标本的分析显示，与相邻正常组织相比，CRC中TRPA1表达显著下调。Kaplan-Meier生存分析进一步表明，TRPA1低表达肿瘤患者的总生存结局显著较差。这些综合数据表明，TRPA1在结直肠癌发生中可能具有肿瘤抑制作用，可能是通过其在结肠炎-癌症转化轴内的免疫调节功能实现的。
