Constitutive TDO2 expression promotes liver cancer progression by an autocrine IL-6 signaling pathway

Abstract

Background Increased tryptophan (Trp) metabolism by indoleamine 2,3-dioxygenase (IDO)/tryptophan 2,3-dioxygenase (TDO) represents one of the most studied pathways for immunosuppression in tumor tissues. However, the pro-tumor effects induced by Trp metabolism remain controversial. Methods The paraffin sections of tumor tissues were obtained from patients with liver cancer and examined by immunohistochemical staining to investigate the role of Trp metabolic enzymes. To further confirm the pro-tumor effects induced by TDO2, we established TDO2 overexpression SMC-7721 and HepG2 liver cancer cell lines, and western blotting, cell proliferation, and colony formation were evaluated. Meanwhile, liver cancer subcutaneous mice models were established, and the tumorigenic rates of SMC-7721 cells, tumor volume and survival of bearing mice were calculated. In addition, the survival data of liver cancer patients from The Cancer Genome Atlas (TCGA) database were downloaded to analyze the effect of TDO2 expression on the survival of patients with liver cancer. Results Here, we showed that constitutive TDO2 expression gave rise to liver cancer through upregulation of Trp metabolism. And the TDO2 expression was positively correlated with the poor prognosis in liver cancer patients. TDO2 expression in tumor cells accounted for the release of kynurenine (Kyn), which activated aryl hydrocarbon receptor (AhR) to promote liver cancer cells proliferation. Mechanistically, we found that AhR expression contributed to the secretion of Interleukin-6 (IL-6), thereby promoting tumor cells proliferation through the STAT3 and NF-kB/TIM4 signals. Interrupt of AhR signals by PDM2 revealed improved outcomes in subcutaneous tumor-bearing mice. Conclusions Together, our study showed that the TDO2/Kyn/AhR/IL-6 signaling pathway was a novel mechanism underlying the malignancy of liver cancer, and suggested that AhR signals might be a valuable therapeutic target for tumor therapy.

Pancancer Analysis of Revealed TDO2 as a Biomarker of Prognosis and Immunotherapy

“…In the present study, we identified that TDO2 is highly expressed in 20 types of cancer, including BLCA, BRCA, CESC, COAD, ESCA, GBM, HNSC, KIRC, LUAD, LUSC, OV, PAAD, PRAD, READ, SKCM, STAD, TGCT, THCA, UCEC, and UCS, which are in line with previous findings [8][9][10][24][25][26][27][28]. However, Wu et al found that TDO2 was overexpressed in HCC, and their overexpression was correlated with tumor progression and poor prognosis [29,30], which contradicts our current results. On the other hand, Yu et al investigated the expression of TDO2 in HCC tissues compared with paired adjacent normal tissues and found that there was downregulation of TDO2 expression in HCC, which agrees with our results [31].…”

Immune-related genes probably increase the occurrence of Interstitial Lung Disease in Dermatomyositis

“…Similar to SLAMF7, no studies have reported a role for TDO2 in DM or ILD. However, in other diseases, such as hepatocellular carcinoma, it has been found that TDO2 expression contributes to the secretion of interleukin-6 (IL-6), which promotes tumour cell proliferation through STAT3 and NF-kB/TIM4 signalling [29]. In osteoarthritis patients, TDO2 levels were signi cantly and positively correlated with IL-1β and TNF-α levels, suggesting that high levels of TDO2 in the synovium may correlate with pro-in ammatory cytokines and the severity of osteoarthritis [30].…”

The Kynurenine Pathway and Cancer: Why Keep It Simple When You Can Make It Complicated

“…The recent determination of the metabolic landscape of cancer cell lines confirms that accumulation and secretion of kynurenine are correlated with IDO (mainly IDO1 ) and TDO transcriptional expression, with some cancer cell lines expressing both enzymes [ 61 ]. In vivo, the serum kynurenine/tryptophan ratio has been directly associated with either IDO1 or TDO2 expression and is correlated with disease progression in multiple cancer types, including breast, lung, colon and liver carcinomas [ 62 , 63 , 64 , 65 ]. Notably, while IDO1 is overexpressed in gliomas, the kynurenine/tryptophan ratio is not predictive of disease progression in that tumor model [ 66 ], suggesting that the biological significance of this ratio is not universal.…”

“…Mechanistically, both IDO1-driven tryptophan depletion and AhR activation contribute to cytokine production [ 70 , 71 ]. In liver cancer, the production of IL6 in response to the activation of TDO2-kynurenine-AHR signaling was also demonstrated to activate STAT3 and NF-κB/TIM4 signals to sustain cell proliferation, demonstrating additional protumoral properties of autocrine IL6 signaling pathways [ 65 ].…”