TDO2 overexpression correlates with poor prognosis, cancer stemness, and resistance to cetuximab in bladder cancer

Abstract

Background Bladder cancer (BC) is the 10th most common cancer in the world. BC with muscle invasion results in a poor prognosis and is usually fatal. Cancer cell metabolism has an essential role in the development and progression of tumors. Expression of tryptophan 2,3‐dioxygenase (TDO2) is associated with tumor progression and worse survival in some other cancers. However, no studies have been performed to uncover the biofunctional roles of TDO2 in BC. Aim This study aim to investigate the clinicopathologic significance of TDO2 in BC. Methods and results TDO2 expression was evaluated by qRT‐PCR and immunohistochemistry in an integrated analysis with the Cancer Genome Atlas (TCGA) and other published datasets. TDO2 overexpression was significantly associated with T classification, N classification, and M classification, tumor stage, recurrence, and basal type, and with the expression of CD44 and aldehyde dehydrogenase 1 (ALDH1) in BC. High TDO2 expression correlated with poor outcome of BC patients. Using BC cell lines with knockdown and forced expression of TDO2, we found that TDO2 was involved in the growth, migration, and invasiveness of BC cells. Moreover, TDO2 was found to be crucial for spheroid formation in BC cells. Importantly, TDO2 promoted BC cells resistance to cetuximab through integration of the EGFR pathway. Conclusion Our results indicate that TDO2 might take an essential part in BC progression and could be a potential marker for targeted therapy in BC.

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.…”

“…TDO2 is found predominantly in the liver under physiological conditions [7]. Recently, increas-ing evidence has confirmed that TDO2 is also involved in the occurrence and development of many cancers, such as colorectal, breast, esophagus, and bladder cancer [8][9][10]. Studies 9 Disease Markers have found that liver metastasis of colon cancer could be accelerated by activating the TDO2-Kyn-AhR pathway [11].…”

Dexamethasone Promotes a Stem-Like Phenotype in Human Melanoma Cells via Tryptophan 2,3 Dioxygenase

“…Our results demonstrate, for the first time, that dex stimulates the formation of melanospheres in a TDO-dependent mechanism. In Pham’s study ( Pham Q. T. et al, 2021 ), TDO was shown to be up regulated in bladder cancer cells, stimulating their growth and invasiveness. Interestingly, TDO was found to be necessary for spheroid formation in these cells, suggesting that it could be a potential marker for targeted therapy in bladder cancer ( Pham QT.…”

Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B‐cell Lymphoma and NK/T‐cell Lymphoma

“…Overexpression of TDO2 in tumors, such as breast cancer, hepatocellular carcinoma, and bladder cancer, is correlated with poor prognosis and therapy resistance. [20][21][22][23] Recently, increased interleukin-4induced-1 (IL4I1) expression has been reported to catabolize Trp into Kyn and has been implicated in immune regulatory functions in cancer and metastasis. 24 However, the role of Trp metabolism in DLBCL or NK/ TCL remains unclear.…”