Skip to main content
Top
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Hepatocellular Carcinoma | Research

Prediction of hepatocellular carcinoma prognosis and immunotherapeutic effects based on tryptophan metabolism-related genes

Authors: Chen Xue, Xinyu Gu, Yalei Zhao, Junjun Jia, Qiuxian Zheng, Yuanshuai Su, Zhengyi Bao, Juan Lu, Lanjuan Li

Published in: Cancer Cell International | Issue 1/2022

Login to get access

Abstract

Background

L-tryptophan (Trp) metabolism involved in mediating tumour development and immune suppression. However, comprehensive analysis of the role of the Trp metabolism pathway is still a challenge.

Methods

We downloaded Trp metabolism-related genes’ expression data from different public databases, including TCGA, Gene Expression Omnibus (GEO) and Hepatocellular Carcinoma Database (HCCDB). And we identified two metabolic phenotypes using the ConsensusClusterPlus package. Univariate regression analysis and lasso Cox regression analysis were used to establish a risk model. CIBERSORT and Tracking of Indels by DEcomposition (TIDE) analyses were adopted to assess the infiltration abundance of immune cells and tumour immune escape.

Results

We identified two metabolic phenotypes, and patients in Cluster 2 (C2) had a better prognosis than those in Cluster 1 (C1). The distribution of clinical features between the metabolic phenotypes showed that patients in C1 tended to have higher T stage, stage, grade, and death probability than those of patients in C2. Additionally, we screened 739 differentially expressed genes (DEGs) between the C1 and C2. We generated a ten-gene risk model based on the DEGs, and the area under the curve (AUC) values of the risk model for predicting overall survival. Patients in the low-risk subgroup tended to have a significantly longer overall survival than that of those in the high-risk group. Moreover, univariate analysis indicated that the risk model was significantly correlated with overall survival. Multivariate analysis showed that the risk model remained an independent risk factor in hepatocellular carcinoma (p < 0.0001).

Conclusions

We identified two metabolic phenotypes based on genes of the Trp metabolism pathway, and we established a risk model that could be used for predicting prognosis and guiding immunotherapy in patients with hepatocellular carcinoma.
Appendix
Available only for authorised users
Literature
2.
go back to reference Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.PubMedCrossRef Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.PubMedCrossRef
3.
go back to reference Khorsandi SE, Heaton N. Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence. Transl Gastroenterol Hepatol. 2016;1:25.PubMedPubMedCentralCrossRef Khorsandi SE, Heaton N. Optimization of immunosuppressive medication upon liver transplantation against HCC recurrence. Transl Gastroenterol Hepatol. 2016;1:25.PubMedPubMedCentralCrossRef
7.
go back to reference Khan MA, Zubair H, Anand S, Srivastava SK, Singh S, Singh AP. Dysregulation of metabolic enzymes in tumour and stromal cells: Role in oncogenesis and therapeutic opportunities. Cancer Lett. 2020;473:176–85.PubMedPubMedCentralCrossRef Khan MA, Zubair H, Anand S, Srivastava SK, Singh S, Singh AP. Dysregulation of metabolic enzymes in tumour and stromal cells: Role in oncogenesis and therapeutic opportunities. Cancer Lett. 2020;473:176–85.PubMedPubMedCentralCrossRef
8.
go back to reference Giannone G, Ghisoni E, Genta S, Scotto G, Tuninetti V, Turinetto M, et al. Immuno-metabolism and microenvironment in cancer: key players for immunotherapy. Int J Mol Sci. 2020;21:4414.PubMedCentralCrossRef Giannone G, Ghisoni E, Genta S, Scotto G, Tuninetti V, Turinetto M, et al. Immuno-metabolism and microenvironment in cancer: key players for immunotherapy. Int J Mol Sci. 2020;21:4414.PubMedCentralCrossRef
9.
go back to reference Fiore A, Murray PJ. Tryptophan and indole metabolism in immune regulation. Curr Opin Immunol. 2021;70:7–14.PubMedCrossRef Fiore A, Murray PJ. Tryptophan and indole metabolism in immune regulation. Curr Opin Immunol. 2021;70:7–14.PubMedCrossRef
10.
go back to reference Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017;76:167–82.PubMedCrossRef Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017;76:167–82.PubMedCrossRef
11.
go back to reference Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18:379–401.PubMedCrossRef Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18:379–401.PubMedCrossRef
12.
go back to reference Krishnamurthy S, Gilot D, Ahn SB, Lam V, Shin JS, Guillemin GJ, et al. Involvement of Kynurenine Pathway in hepatocellular carcinoma. Cancers (Basel). 2021;13:5180.PubMedPubMedCentralCrossRef Krishnamurthy S, Gilot D, Ahn SB, Lam V, Shin JS, Guillemin GJ, et al. Involvement of Kynurenine Pathway in hepatocellular carcinoma. Cancers (Basel). 2021;13:5180.PubMedPubMedCentralCrossRef
13.
go back to reference Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing KL, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol. 2018;15:447–57.PubMedPubMedCentralCrossRef Zhai L, Ladomersky E, Lenzen A, Nguyen B, Patel R, Lauing KL, et al. IDO1 in cancer: a Gemini of immune checkpoints. Cell Mol Immunol. 2018;15:447–57.PubMedPubMedCentralCrossRef
14.
15.
go back to reference Komiya T, Huang CH. Updates in the clinical development of epacadostat and other indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for human cancers. Front Oncol. 2018;8:423.PubMedPubMedCentralCrossRef Komiya T, Huang CH. Updates in the clinical development of epacadostat and other indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for human cancers. Front Oncol. 2018;8:423.PubMedPubMedCentralCrossRef
16.
go back to reference Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumour antigen-specific T cells. Oncotarget. 2016;7:37762–72.PubMedPubMedCentralCrossRef Jochems C, Fantini M, Fernando RI, Kwilas AR, Donahue RN, Lepone LM, et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumour antigen-specific T cells. Oncotarget. 2016;7:37762–72.PubMedPubMedCentralCrossRef
17.
go back to reference Xue C, Gu X, Li L. Immune classifier-based signatures provide good prognostic stratification and predict the clinical benefits of immune-based therapies for hepatocellular carcinoma. Cancer Cell Int. 2021;21:471.PubMedPubMedCentralCrossRef Xue C, Gu X, Li L. Immune classifier-based signatures provide good prognostic stratification and predict the clinical benefits of immune-based therapies for hepatocellular carcinoma. Cancer Cell Int. 2021;21:471.PubMedPubMedCentralCrossRef
18.
go back to reference Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.PubMedPubMedCentralCrossRef Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.PubMedPubMedCentralCrossRef
19.
20.
go back to reference Wang YY, Wang ZX, Hu YD, Wang L, Li N, Zhang B, et al. Current status of pathway analysis in genome-wide association study. Yi Chuan. 2017;39:707–16.PubMed Wang YY, Wang ZX, Hu YD, Wang L, Li N, Zhang B, et al. Current status of pathway analysis in genome-wide association study. Yi Chuan. 2017;39:707–16.PubMed
21.
go back to reference Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.PubMedPubMedCentralCrossRef Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.PubMedPubMedCentralCrossRef
25.
go back to reference Lurje I, Werner W, Mohr R, Roderburg C, Tacke F, Hammerich L. In Situ vaccination as a strategy to modulate the immune microenvironment of hepatocellular carcinoma. Front Immunol. 2021;12: 650486.PubMedPubMedCentralCrossRef Lurje I, Werner W, Mohr R, Roderburg C, Tacke F, Hammerich L. In Situ vaccination as a strategy to modulate the immune microenvironment of hepatocellular carcinoma. Front Immunol. 2021;12: 650486.PubMedPubMedCentralCrossRef
26.
go back to reference Khan AA, Liu ZK, Xu X. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2021;20:511–20.PubMedCrossRef Khan AA, Liu ZK, Xu X. Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2021;20:511–20.PubMedCrossRef
27.
go back to reference Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321-337.e10.PubMedPubMedCentralCrossRef Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321-337.e10.PubMedPubMedCentralCrossRef
28.
go back to reference Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021;18:112–27.PubMedCrossRef Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol. 2021;18:112–27.PubMedCrossRef
29.
go back to reference Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–40.PubMedCrossRef Platten M, Wick W, Van den Eynde BJ. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. 2012;72:5435–40.PubMedCrossRef
30.
31.
go back to reference Giusti RM, Maloney EM, Hanchard B, Morgan OS, Steinberg SM, Wachter H, et al. Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma. Cancer Epidemiol Biomarkers Prev. 1996;5:699–704.PubMed Giusti RM, Maloney EM, Hanchard B, Morgan OS, Steinberg SM, Wachter H, et al. Differential patterns of serum biomarkers of immune activation in human T-cell lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis, and adult T-cell leukemia/lymphoma. Cancer Epidemiol Biomarkers Prev. 1996;5:699–704.PubMed
32.
go back to reference Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, et al. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer. 2010;67:361–5.PubMedCrossRef Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, Hahimoto D, et al. Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer. 2010;67:361–5.PubMedCrossRef
33.
go back to reference Huang A, Fuchs D, Widner B, Glover C, Henderson DC, Allen-Mersh TG. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer. 2002;86:1691–6.PubMedPubMedCentralCrossRef Huang A, Fuchs D, Widner B, Glover C, Henderson DC, Allen-Mersh TG. Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer. 2002;86:1691–6.PubMedPubMedCentralCrossRef
34.
go back to reference Zhai L, Dey M, Lauing KL, Gritsina G, Kaur R, Lukas RV, et al. The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy. J Clin Neurosci. 2015;22:1964–8.PubMedPubMedCentralCrossRef Zhai L, Dey M, Lauing KL, Gritsina G, Kaur R, Lukas RV, et al. The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy. J Clin Neurosci. 2015;22:1964–8.PubMedPubMedCentralCrossRef
35.
go back to reference Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Häcker G, et al. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol. 2009;183:145–54.PubMedCrossRef Brenk M, Scheler M, Koch S, Neumann J, Takikawa O, Häcker G, et al. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J Immunol. 2009;183:145–54.PubMedCrossRef
36.
go back to reference Chung DJ, Rossi M, Romano E, Ghith J, Yuan J, Munn DH, et al. Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood. 2009;114:555–63.PubMedPubMedCentralCrossRef Chung DJ, Rossi M, Romano E, Ghith J, Yuan J, Munn DH, et al. Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood. 2009;114:555–63.PubMedPubMedCentralCrossRef
37.
go back to reference Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181:5396–404.PubMedCrossRef Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181:5396–404.PubMedCrossRef
38.
go back to reference Fallarino F, Grohmann U, Puccetti P. Indoleamine 2,3-dioxygenase: from catalyst to signaling function. Eur J Immunol. 2012;42:1932–7.PubMedCrossRef Fallarino F, Grohmann U, Puccetti P. Indoleamine 2,3-dioxygenase: from catalyst to signaling function. Eur J Immunol. 2012;42:1932–7.PubMedCrossRef
39.
go back to reference Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: diagnosis prognosis and treatment response assessment. Cells. 2020;9:1370.PubMedCentralCrossRef Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: diagnosis prognosis and treatment response assessment. Cells. 2020;9:1370.PubMedCentralCrossRef
40.
go back to reference Hu H, Xu L, Chen Y, Luo SJ, Wu YZ, Xu SH, et al. The Upregulation of Trophinin-Associated Protein (TROAP) predicts a poor prognosis in hepatocellular carcinoma. J Cancer. 2019;10:957–67.PubMedPubMedCentralCrossRef Hu H, Xu L, Chen Y, Luo SJ, Wu YZ, Xu SH, et al. The Upregulation of Trophinin-Associated Protein (TROAP) predicts a poor prognosis in hepatocellular carcinoma. J Cancer. 2019;10:957–67.PubMedPubMedCentralCrossRef
41.
go back to reference Jin L, Zhou Y, Chen G, Dai G, Fu K, Yang D, et al. EZH2-TROAP pathway promotes prostate cancer progression via TWIST signals. Front Oncol. 2020;10: 592239.PubMedCrossRef Jin L, Zhou Y, Chen G, Dai G, Fu K, Yang D, et al. EZH2-TROAP pathway promotes prostate cancer progression via TWIST signals. Front Oncol. 2020;10: 592239.PubMedCrossRef
42.
go back to reference Li K, Zhang R, Wei M, Zhao L, Wang Y, Feng X, et al. TROAP promotes breast cancer proliferation and metastasis. Biomed Res Int. 2019;2019:6140951.PubMedPubMedCentral Li K, Zhang R, Wei M, Zhao L, Wang Y, Feng X, et al. TROAP promotes breast cancer proliferation and metastasis. Biomed Res Int. 2019;2019:6140951.PubMedPubMedCentral
43.
go back to reference Zhao ZQ, Wu XJ, Cheng YH, Zhou YF, Ma XM, Zhang J, et al. TROAP regulates cell cycle and promotes tumour progression through Wnt/β-Catenin signaling pathway in glioma cells. CNS Neurosci Ther. 2021;27:1064–76.PubMedCentralCrossRef Zhao ZQ, Wu XJ, Cheng YH, Zhou YF, Ma XM, Zhang J, et al. TROAP regulates cell cycle and promotes tumour progression through Wnt/β-Catenin signaling pathway in glioma cells. CNS Neurosci Ther. 2021;27:1064–76.PubMedCentralCrossRef
44.
go back to reference Jing K, Mao Q, Ma P. Decreased expression of TROAP suppresses cellular proliferation, migration and invasion in gastric cancer. Mol Med Rep. 2018;18:3020–6.PubMed Jing K, Mao Q, Ma P. Decreased expression of TROAP suppresses cellular proliferation, migration and invasion in gastric cancer. Mol Med Rep. 2018;18:3020–6.PubMed
45.
go back to reference Gao B, Wang L, Zhang Y, Zhang N, Han M, Liu H, et al. MiR-532-3p suppresses cell viability, migration and invasion of clear cell renal cell carcinoma through targeting TROAP. Cell Cycle. 2021;20:1578–88.PubMedPubMedCentralCrossRef Gao B, Wang L, Zhang Y, Zhang N, Han M, Liu H, et al. MiR-532-3p suppresses cell viability, migration and invasion of clear cell renal cell carcinoma through targeting TROAP. Cell Cycle. 2021;20:1578–88.PubMedPubMedCentralCrossRef
46.
go back to reference Song Y, Zhuang G, Li J, Zhang M. BAIAP2L2 facilitates the malignancy of prostate cancer (PCa) via VEGF and apoptosis signaling pathways. Genes Genomics. 2021;43:421–32.PubMedCrossRef Song Y, Zhuang G, Li J, Zhang M. BAIAP2L2 facilitates the malignancy of prostate cancer (PCa) via VEGF and apoptosis signaling pathways. Genes Genomics. 2021;43:421–32.PubMedCrossRef
47.
go back to reference Guo H, Peng J, Hu J, Chang S, Liu H, Luo H, et al. BAIAP2L2 promotes the proliferation, migration and invasion of osteosarcoma associated with the Wnt/β-catenin pathway. J Bone Oncol. 2021;31: 100393.PubMedPubMedCentralCrossRef Guo H, Peng J, Hu J, Chang S, Liu H, Luo H, et al. BAIAP2L2 promotes the proliferation, migration and invasion of osteosarcoma associated with the Wnt/β-catenin pathway. J Bone Oncol. 2021;31: 100393.PubMedPubMedCentralCrossRef
48.
go back to reference Zhi T, Jiang K, Xu X, Yu T, Zhou F, Wang Y, et al. ECT2/PSMD14/PTTG1 axis promotes the proliferation of glioma through stabilizing E2F1. Neuro Oncol. 2019;21:462–73.PubMedCrossRef Zhi T, Jiang K, Xu X, Yu T, Zhou F, Wang Y, et al. ECT2/PSMD14/PTTG1 axis promotes the proliferation of glioma through stabilizing E2F1. Neuro Oncol. 2019;21:462–73.PubMedCrossRef
49.
go back to reference Lin X, Yang Y, Guo Y, Liu H, Jiang J, Zheng F, et al. PTTG1 is involved in TNF-α-related hepatocellular carcinoma via the induction of c-myc. Cancer Med. 2019;8:5702–15.PubMedPubMedCentralCrossRef Lin X, Yang Y, Guo Y, Liu H, Jiang J, Zheng F, et al. PTTG1 is involved in TNF-α-related hepatocellular carcinoma via the induction of c-myc. Cancer Med. 2019;8:5702–15.PubMedPubMedCentralCrossRef
50.
go back to reference Liu J, Li W, Zhao H. CFHR3 is a potential novel biomarker for hepatocellular carcinoma. J Cell Biochem. 2020;121:2970–80.PubMedCrossRef Liu J, Li W, Zhao H. CFHR3 is a potential novel biomarker for hepatocellular carcinoma. J Cell Biochem. 2020;121:2970–80.PubMedCrossRef
Metadata
Title
Prediction of hepatocellular carcinoma prognosis and immunotherapeutic effects based on tryptophan metabolism-related genes
Authors
Chen Xue
Xinyu Gu
Yalei Zhao
Junjun Jia
Qiuxian Zheng
Yuanshuai Su
Zhengyi Bao
Juan Lu
Lanjuan Li
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-022-02730-8

Other articles of this Issue 1/2022

Cancer Cell International 1/2022 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine