TDO2 promotes hepatocellular carcinoma by regulating tryptophan-kynurenine pathway

Objective: This study aims to investigate the impact of differentially expressed tryptophan 2,3-dioxygenase (TDO2) on hepatocellular carcinoma (HCC) growth and its role in regulating ADCY5 and PRKAR2B expression in cells and tissues. Methods: Serum amino acid profiles in patients with HCC were analyzed via metabolomics. Lentiviral transfection was used to knock down and overexpress TDO2 in cells, with corresponding subcutaneous tumor models established in nude mice. A rat model of primary hepatocellular carcinoma was generated through intraperitoneal injection of N-nitrosodiethylamine (DEN). Cellular responses were assessed using CCK8, Annexin V-PE/7ADD double staining, and scratch assays. Transcriptome sequencing was performed to analyze genetic alterations in subcutaneous tumor tissues, while RT-qPCR and Western blotting were employed to quantify mRNA and protein levels. Results: TDO2 knockdown inhibited hepatocellular carcinoma cell proliferation and migration, while promoting apoptosis. Conversely, TDO2 overexpression enhanced cell proliferation and migration. Moreover, ADCY5 overexpression reverses the tumor-suppressive effects elicited by TDO2 knockdown. Transcriptome sequencing revealed an association between TDO2 and the downstream genes ADCY5 and PRKAR2B. In both cellular and animal models, mRNA levels of ADCY5 and PRKAR2B were positively correlated with TDO2 expression. Conclusion: TDO2 may facilitate HCC growth and metastasis by activating ADCY5 expression and its downstream target PRKAR2B.