Ren Xiaoxue, Wu Yanqing, Song Tongtong, Yang Qingxia, Zhou Qianying, Lin Jie, Xu Lixia, Xiang Bangde, Chen Zebin, Zhang Ying
Department of Oncology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Department of Gastroenterology and Hepatology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
J Gastroenterol Hepatol. 2025 Apr;40(4):1004-1015. doi: 10.1111/jgh.16879. Epub 2025 Jan 13.
Clonorchis sinensis infection is an important risk factor for intrahepatic cholangiocarcinoma (ICC). C. sinensis positive (C.s+) ICC patients had much shorter overall survival (OS) compared with C. sinensis negative (C.s-) group. This study aims to explore the impact and underlying mechanism of C. sinensis infection on ICC progression.
In this study, ICC patients underwent surgery from two medical centers enrolled. RNA sequencing was used to determine the downstream activated pathways and genes. Furthermore, we demonstrated the potential mechanism of C. sinensis infection in promoting ICC progression through in vitro co culture systems and two animal models.
Through RNA sequencing, we found fatty acid metabolism and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly elevated in C.s+ ICCs. Then, we found excretory/secretory products (ESPs) secreted by C. sinensis could significantly upregulate the expression of transcription factor E2F1, thereby promoting FASN expression and fatty acid synthesis in tumor cells, which ultimately accelerating tumor progression. However, the promotive effect disappeared when FASN was knocked down. Meanwhile, ESPs could promote tumor growth, increasing FASN expression and free fatty acid level in both subcutaneous and orthotopic mouse models.
This study indicates that C. sinensis infection could upregulate the level of FASN and activate fatty acid synthesis pathway, thereby accelerating ICC progression. This provides a new insight for the clinical treatment of ICC with C. sinensis infection.
华支睾吸虫感染是肝内胆管癌（ICC）的重要危险因素。与华支睾吸虫阴性（C.s-）组相比，华支睾吸虫阳性（C.s+）的ICC患者总生存期（OS）短得多。本研究旨在探讨华支睾吸虫感染对ICC进展的影响及其潜在机制。
本研究纳入了来自两个医疗中心接受手术的ICC患者。采用RNA测序确定下游激活的通路和基因。此外，我们通过体外共培养系统和两种动物模型证明了华支睾吸虫感染促进ICC进展的潜在机制。
通过RNA测序，我们发现脂肪酸代谢以及催化长链脂肪酸合成的关键酶脂肪酸合酶（FASN）的表达在C.s+ ICC中显著升高。然后，我们发现华支睾吸虫分泌的排泄/分泌产物（ESPs）可显著上调转录因子E2F1的表达，从而促进肿瘤细胞中FASN的表达和脂肪酸合成，最终加速肿瘤进展。然而，当FASN被敲低时，这种促进作用消失。同时，ESPs可促进肿瘤生长，在皮下和原位小鼠模型中均增加FASN表达和游离脂肪酸水平。
本研究表明，华支睾吸虫感染可上调FASN水平并激活脂肪酸合成途径，从而加速ICC进展。这为伴有华支睾吸虫感染的ICC临床治疗提供了新的见解。
