TDO2 Promotes the EMT of Hepatocellular Carcinoma Through Kyn-AhR Pathway.

Lei Li,Tao Wang,Qi Wo,Shanbao Li,Junming Xu,Xuebin Qin,Junyi Wu,Wanyue Cao,Zhengqian Chen

doi:10.3389/fonc.2020.562823

Abstract

Tryptophan 2,3-dioxygenase (TDO2), an enzyme involved in tryptophan (Trp) metabolism has been linked with some malignant traits of various cancers. Kyn, the main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was also demonstrated to activate aryl hydrocarbon receptor (AhR), which may regulate cancer growth and invasion in some malignancies. However, whether TDO2 participates in the metastasis and invasion of HCC has not been explored before. The underlying mechanism played by TDO2 in this process still requires further investigation. Here, we demonstrated that overexpression of TDO2 correlates with advanced stage or malignant traits in HCC patients. Knockdown or inhibition of TDO2 suppressed the migration and invasion of HCC cells in vitro and in vivo. Epithelial to mesenchymal transition (EMT) is an essential program happened in the initial phase of cancer metastasis. We found that in HCC cells, TDO2 promoted the EMT process evidenced by altered levels of biomarkers for EMT. Mechanically, TDO2 regulated the Kyn production in HCC cell via activated aryl hydrocarbon receptor (AhR). Together, these results indicate that TDO2 promotes the EMT of hepatocellular carcinoma through activating Kyn-AhR pathway, thereby participating in the metastasis and invasion of HCC.

Highlights

Liver cancer, the fifth most common cancer, ranks the second leading cause of cancer-related death worldwide [1, 2]
We demonstrated that Hepatocellular carcinoma (HCC) with vascular invasion had higher TDO2 expression at transcriptional and translational level than HCC without vascular invasion (Figures 1B, C)
The analysis of corelationship of TDO2 expression level and overall survival of HCC patients showed a shorter survival time in high TDO2 group than in low TDO2 group, while no statistical significance reached (Figure 1D). These results indicate that the upregulated expression of TDO2 is related to malignancy grade, which may contribute to the invasion and metastasis of HCC, and further influencing the prognosis of patients

Summary

Introduction

The fifth most common cancer, ranks the second leading cause of cancer-related death worldwide [1, 2]. Hepatocellular carcinoma (HCC) is the major forms of primary liver cancer. Overall prognosis for HCC patients remains poor due to the highly metastatic and aggressive biological features of HCC, which leading to advanced clinical stages and high recurrence rate of HCC patients [3, 4]. Tryptophan 2,3-dioxygenase (TDO2), encoded by gene Tdo, is expressed normally at high levels in the liver. It acts as the first and rate-limiting step of tryptophan (Trp) metabolism along kynurenine (Kyn) pathway and maintains systemic tryptophan levels [5]. The main product of Trp metabolism pathway catalyzed by TDO2 and indoleamine 2,3-dioxygenase (IDO) in tumor cells, was demonstrated

Methods

Results

Conclusion