Clonorchis sinensis Promotes Intrahepatic Cholangiocarcinoma Progression by Activating FASN-Mediated Fatty Acid Metabolism.

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.