Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Cell Death-related Genes and Characterization of Immune Microenvironment
-
Wei Wu
,
Yingji Wang
,
Xiaocheng Zhao
,
Ke Dong
,
Maode Li
,
Xiang An
,
Yingyan Xu
,
Shuai Wang
,
Dexin Li
Abstract
Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer.
This study aimed to elucidate the involvement of genes associated with 25 cell-death modalities in HCC development and progression. HCC transcriptomic datasets were integrated with curated cell death-related genes. Candidate genes were screened by differential expression analysis and protein–protein interaction network construction. Prognostic genes were identified using univariate Cox regression, proportional hazards assumption testing, and stepwise multivariate Cox regression. A risk score model and a nomogram were established, followed by risk stratification and analyses of immune infiltration, immune checkpoints, somatic mutations, and in silico drug sensitivity. Single-cell RNA sequencing was used to identify key cell types, infer temporal dynamics, and characterize intercellular communication, and findings were validated by quantitative real-time PCR (qRT-PCR).
MAPT, CDKN2A, NQO1, CHGA, SERPINE1, and RET were identified as prognostic genes, and the risk model and nomogram showed good prognostic performance. Immune profiling revealed significant differences in multiple immune cell subsets between risk groups, including activated CD4+ T cells. Notably, CDKN2A correlated with activated CD4+ T cells, NQO1 with natural killer cells, RET with CD4+ central memory cells, and SERPINE1 with activated dendritic cells; RET also showed the strongest positive correlation with HAVCR2. Mutation spectra differed across risk groups, and ten drugs displayed significant predicted IC50 differences; all six genes were negatively correlated with KIN001.135.
Single-cell analyses highlighted hepatocytes as a key cell type with strong hepatocyte–epithelial communication. qRT-PCR confirmed higher MAPT, CDKN2A, NQO1, and SERPINE1 expression in HCC tissues than in normal tissues.
1 Sung H, Ferlay J, Siegel RL, 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(3):209-49.
2. Petrick JL, Florio AA, Znaor A, et al. International trends in hepatocellular carcinoma incidence, 1978-2012. Int J Cancer. 2020;147(2):317-30.
3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-14.
4. Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma: Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol. 2023;93:20-35.
5. Kim J, Kang W, Sinn DH, et al. Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients. Clin Mol Hepatol. 2020;26(4):516-28.
6. Yang C, Zhang H, Zhang L, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20(4):203-22.
7. Machairas N, Tsilimigras DI, Pawlik TM. State-of-the-art surgery for hepatocellular carcinoma. Langenbecks Arch Surg. 2021;406(7):2151-62.
8. Garzali IU, Hargura AS, Ince V, Varol FI, Carr BI, Yilmaz S. Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis. Turk J Gastroenterol. 2023;34(12):1235-39.
9. Zhu XD, Huang C, Shen YH, et al. Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations. Liver Cancer. 2021;10(4):320-9.
10. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;394(10204):1145-58.
11. Jadlowiec CC, Taner T. Liver transplantation: Current status and challenges. World J Gastroenterol. 2016;22(18):4438-45.
12. Xian L, Zhao P, Chen X, et al. Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer. Cell Oncol (Dordr). 2022;45(5):1019-36.
13. Liu J, Hong M, Li Y, Chen D, Wu Y, Hu Y. Programmed Cell Death Tunes Tumor Immunity. Front Immunol. 2022;13:847345.
14. Deng M, Sun S, Zhao R, et al. The pyroptosis-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma. Mol Med. 2022;28(1):16.
15. Tasdemir-Yilmaz OE, Druckenbrod NR, Olukoya OO, et al. Diversity of developing peripheral glia revealed by single-cell RNA sequencing. Dev Cell. 2021;56(17):2516-35.e6.
16. Qin H, Abulaiti A, Maimaiti A, et al. Integrated machine learning survival framework develops a prognostic model based on inter-crosstalk definition of mitochondrial function and cell death patterns in a large multicenter cohort for lower-grade glioma. J Transl Med. 2023;21(1):588.
17. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal Cell Death. Physiol Rev. 2018;98(2):813-880.
18. Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021;2(3):100141.
19. Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77.
20. Zou KH, Tuncali K, Silverman SG. Correlation and simple linear regression. Radiology. 2003;227(3):617-622.
21. Wang X, Wang N, Zhong L, et al. Development and Validation of a Risk Prediction Model for Breast Cancer Prognosis Based on Depression-Related Genes. Front Oncol. 2022;12:879563.
22. Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747-1756.
23. Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One. 2014;9(9):e107468.
24. Stuart T, Butler A, Hoffman P, et al. Comprehensive Integration of Single-Cell Data. Cell. 2019;177(7):1888-902.e21.
25. Jin S, Guerrero-Juarez CF, Zhang L, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12(1):1088.
26. Matsuura K, Canfield K, Feng W, Kurokawa M. Metabolic Regulation of Apoptosis in Cancer. Int Rev Cell Mol Biol. 2016;327:43-87.
27. Gao YL, Wang N, Sun FR, Cao XP, Zhang W, Yu JT. Tau in neurodegenerative disease. Ann Transl Med. 2018;6(10):175.
28. Ikeda H, Taira N, Hara F, et al. The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells. Breast Cancer Res. 2010;12(3):R43.
29. Mimori K, Sadanaga N, Yoshikawa Y, et al. Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment. Br J Cancer. 2006;94(12):1894-7.
30. Smoter M, Bodnar L, Grala B, et al. Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. J Exp Clin Cancer Res. 2013;32(1):25.
31. Spicakova T, O'Brien MM, Duran GE, Sweet-Cordero A, Sikic BI. Expression and silencing of the microtubule-associated protein Tau in breast cancer cells. Mol Cancer Ther. 2010;9(11):2970-81.
32. Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50(25):5566-82.
33. Xu Y, Li N, Xiang R, Sun P. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem Sci. 2014;39(6):268-76.
34. Seo J, Seong D, Lee SR, Oh DB, Song J. Post-Translational Regulation of ARF: Perspective in Cancer. Biomolecules. 2020;10(8):1138.
35. Zhou Y, Wang XB, Qiu XP, Shuai Z, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: A meta-analysis. Clin Res Hepatol Gastroenterol. 2018;42(6):529-41.
36. Zhang X, Li X, Li Z, Wu X, Wu Y, You Q, et al. An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy. Org Lett. 2018;20(12):3635-38.
37. Kadela-Tomanek M, Bebenek E, Chrobak E, et al. Betulin-1,4-quinone hybrids: Synthesis, anticancer activity and molecular docking study with NQO1 enzyme. Eur J Med Chem. 2019;177:302-15.
38. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y. The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry. 2006;45(20):6372-8.
39. Nam ST, Hwang JH, Kim DH, et al. NQO1-Knockout Mice Are Highly Sensitive to Clostridium Difficile Toxin A-Induced Enteritis. J Microbiol Biotechnol. 2016;26(8):1446-51.
40. Siegel D, Dehn DD, Bokatzian SS, et al. Redox modulation of NQO1. PLoS One. 2018;13(1):e0190717.
41. Gravante G, Markiewicz D, Madeddu F, Giordano P. Colonic large-cell neuroendocrine tumours. Can J Surg. 2009;52(3):E49-51.
42. Han X, Xu X, Jin D, Wang D, Ji Y, Lou W. Clinicopathological characteristics and prognosis-related factors of resectable pancreatic neuroendocrine tumors: a retrospective study of 104 cases in a single Chinese center. Pancreas. 2014;43(4):526-31.
43. Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011;30 Suppl 1:3-7.
44. Planus E, Barlovatz-Meimon G, Rogers RA, Bonavaud S, Ingber DE, Wang N. Binding of urokinase to plasminogen activator inhibitor type-1 mediates cell adhesion and spreading. J Cell Sci. 1997;110(Pt 9):1091-8.
45. Schiavetti A, Foco M, Chiriaco D, et al. Venous thrombosis and procoagulant factors in high-risk neuroblastoma. J Pediatr Hematol Oncol. 2010;32(2):93-6.
46. Teng F, Zhang JX, Chen Y, et al. LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer. Mol Oncol. 2021;15(4):1234-55.
47. Wang D, Yang LY, Liu Z, Yu J, Zhang MJ, Zhang Y, et al. PAI-1 overexpression promotes invasion and migration of esophageal squamous carcinoma cells. Yi Chuan. 2020;42(3):287-95.
48. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167-214.
49. Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436-45.
50. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140(1):49-61.
51. Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med. 2021;218(1):e20200706.
52. Park JB, Lee CS, Jang JH, et al. Phospholipase signalling networks in cancer. Nat Rev Cancer. 2012;12(11):782-92.
53. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18(2):153-61.
54. Rohrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732-49.
55. Paone A, Marani M, Fiascarelli A, et al. SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation. Cell Death Dis. 2014;5(11):e1525.
56. Woo CC, Chen WC, Teo XQ, Radda GK, Lee PT. Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget. 2016;7(33):53005-17.
57. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-44.
58. Yun J, Rago C, Cheong I, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555-9.
59. Kumler I, Christiansen OG, Nielsen DL. A systematic review of bevacizumab efficacy in breast cancer. Cancer Treat Rev. 2014;40(8):960-73.
60. Nekvindova J, Mrkvicova A, Zubanova V, et al. Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450. Biochem Pharmacol. 2020;177:113912.
61. Ashida R, Okamura Y, Ohshima K, et al. CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma. Cancer Genomics Proteomics. 2017;14(6):445-53.
62. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41.
63. Man XB, Tang L, Qiu XH, Yang LQ, Cao HF, Wu MC, et al. Expression of cytochrome P4502E1 gene in hepatocellular carcinoma. World J Gastroenterol. 2004;10(11):1565-68.
64. Luo X, Huang W, Li S, et al. SOX12 Facilitates Hepatocellular Carcinoma Progression and Metastasis through Promoting Regulatory T-Cells Infiltration and Immunosuppression. Adv Sci (Weinh). 2024;11(36):e2310304.
65. Takata Y, Nakamoto Y, Nakada A, et al. Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. Cancer Lett. 2011;307(2):165-73.
66. Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2020;470:8-17.
67. Hall Z, Chiarugi D, Charidemou E, et al. Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma. Hepatology. 2021;73(3):1028-44.
68. Chen F, Sheng L, Zhou T, et al. Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling. J Exp Clin Cancer Res. 2023;42(1):110.
69. Chen RY, Yen CJ, Lin YJ, et al. CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis. Cell Death Dis. 2021;12(11):983.
2. Petrick JL, Florio AA, Znaor A, et al. International trends in hepatocellular carcinoma incidence, 1978-2012. Int J Cancer. 2020;147(2):317-30.
3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-14.
4. Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma: Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol. 2023;93:20-35.
5. Kim J, Kang W, Sinn DH, et al. Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients. Clin Mol Hepatol. 2020;26(4):516-28.
6. Yang C, Zhang H, Zhang L, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20(4):203-22.
7. Machairas N, Tsilimigras DI, Pawlik TM. State-of-the-art surgery for hepatocellular carcinoma. Langenbecks Arch Surg. 2021;406(7):2151-62.
8. Garzali IU, Hargura AS, Ince V, Varol FI, Carr BI, Yilmaz S. Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis. Turk J Gastroenterol. 2023;34(12):1235-39.
9. Zhu XD, Huang C, Shen YH, et al. Downstaging and Resection of Initially Unresectable Hepatocellular Carcinoma with Tyrosine Kinase Inhibitor and Anti-PD-1 Antibody Combinations. Liver Cancer. 2021;10(4):320-9.
10. Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2019;394(10204):1145-58.
11. Jadlowiec CC, Taner T. Liver transplantation: Current status and challenges. World J Gastroenterol. 2016;22(18):4438-45.
12. Xian L, Zhao P, Chen X, et al. Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer. Cell Oncol (Dordr). 2022;45(5):1019-36.
13. Liu J, Hong M, Li Y, Chen D, Wu Y, Hu Y. Programmed Cell Death Tunes Tumor Immunity. Front Immunol. 2022;13:847345.
14. Deng M, Sun S, Zhao R, et al. The pyroptosis-related gene signature predicts prognosis and indicates immune activity in hepatocellular carcinoma. Mol Med. 2022;28(1):16.
15. Tasdemir-Yilmaz OE, Druckenbrod NR, Olukoya OO, et al. Diversity of developing peripheral glia revealed by single-cell RNA sequencing. Dev Cell. 2021;56(17):2516-35.e6.
16. Qin H, Abulaiti A, Maimaiti A, et al. Integrated machine learning survival framework develops a prognostic model based on inter-crosstalk definition of mitochondrial function and cell death patterns in a large multicenter cohort for lower-grade glioma. J Transl Med. 2023;21(1):588.
17. Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC. Neuronal Cell Death. Physiol Rev. 2018;98(2):813-880.
18. Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021;2(3):100141.
19. Robin X, Turck N, Hainard A, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12:77.
20. Zou KH, Tuncali K, Silverman SG. Correlation and simple linear regression. Radiology. 2003;227(3):617-622.
21. Wang X, Wang N, Zhong L, et al. Development and Validation of a Risk Prediction Model for Breast Cancer Prognosis Based on Depression-Related Genes. Front Oncol. 2022;12:879563.
22. Mayakonda A, Lin DC, Assenov Y, Plass C, Koeffler HP. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 2018;28(11):1747-1756.
23. Geeleher P, Cox N, Huang RS. pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One. 2014;9(9):e107468.
24. Stuart T, Butler A, Hoffman P, et al. Comprehensive Integration of Single-Cell Data. Cell. 2019;177(7):1888-902.e21.
25. Jin S, Guerrero-Juarez CF, Zhang L, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12(1):1088.
26. Matsuura K, Canfield K, Feng W, Kurokawa M. Metabolic Regulation of Apoptosis in Cancer. Int Rev Cell Mol Biol. 2016;327:43-87.
27. Gao YL, Wang N, Sun FR, Cao XP, Zhang W, Yu JT. Tau in neurodegenerative disease. Ann Transl Med. 2018;6(10):175.
28. Ikeda H, Taira N, Hara F, et al. The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells. Breast Cancer Res. 2010;12(3):R43.
29. Mimori K, Sadanaga N, Yoshikawa Y, et al. Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment. Br J Cancer. 2006;94(12):1894-7.
30. Smoter M, Bodnar L, Grala B, et al. Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. J Exp Clin Cancer Res. 2013;32(1):25.
31. Spicakova T, O'Brien MM, Duran GE, Sweet-Cordero A, Sikic BI. Expression and silencing of the microtubule-associated protein Tau in breast cancer cells. Mol Cancer Ther. 2010;9(11):2970-81.
32. Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry. 2011;50(25):5566-82.
33. Xu Y, Li N, Xiang R, Sun P. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem Sci. 2014;39(6):268-76.
34. Seo J, Seong D, Lee SR, Oh DB, Song J. Post-Translational Regulation of ARF: Perspective in Cancer. Biomolecules. 2020;10(8):1138.
35. Zhou Y, Wang XB, Qiu XP, Shuai Z, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: A meta-analysis. Clin Res Hepatol Gastroenterol. 2018;42(6):529-41.
36. Zhang X, Li X, Li Z, Wu X, Wu Y, You Q, et al. An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy. Org Lett. 2018;20(12):3635-38.
37. Kadela-Tomanek M, Bebenek E, Chrobak E, et al. Betulin-1,4-quinone hybrids: Synthesis, anticancer activity and molecular docking study with NQO1 enzyme. Eur J Med Chem. 2019;177:302-15.
38. Asher G, Dym O, Tsvetkov P, Adler J, Shaul Y. The crystal structure of NAD(P)H quinone oxidoreductase 1 in complex with its potent inhibitor dicoumarol. Biochemistry. 2006;45(20):6372-8.
39. Nam ST, Hwang JH, Kim DH, et al. NQO1-Knockout Mice Are Highly Sensitive to Clostridium Difficile Toxin A-Induced Enteritis. J Microbiol Biotechnol. 2016;26(8):1446-51.
40. Siegel D, Dehn DD, Bokatzian SS, et al. Redox modulation of NQO1. PLoS One. 2018;13(1):e0190717.
41. Gravante G, Markiewicz D, Madeddu F, Giordano P. Colonic large-cell neuroendocrine tumours. Can J Surg. 2009;52(3):E49-51.
42. Han X, Xu X, Jin D, Wang D, Ji Y, Lou W. Clinicopathological characteristics and prognosis-related factors of resectable pancreatic neuroendocrine tumors: a retrospective study of 104 cases in a single Chinese center. Pancreas. 2014;43(4):526-31.
43. Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011;30 Suppl 1:3-7.
44. Planus E, Barlovatz-Meimon G, Rogers RA, Bonavaud S, Ingber DE, Wang N. Binding of urokinase to plasminogen activator inhibitor type-1 mediates cell adhesion and spreading. J Cell Sci. 1997;110(Pt 9):1091-8.
45. Schiavetti A, Foco M, Chiriaco D, et al. Venous thrombosis and procoagulant factors in high-risk neuroblastoma. J Pediatr Hematol Oncol. 2010;32(2):93-6.
46. Teng F, Zhang JX, Chen Y, et al. LncRNA NKX2-1-AS1 promotes tumor progression and angiogenesis via upregulation of SERPINE1 expression and activation of the VEGFR-2 signaling pathway in gastric cancer. Mol Oncol. 2021;15(4):1234-55.
47. Wang D, Yang LY, Liu Z, Yu J, Zhang MJ, Zhang Y, et al. PAI-1 overexpression promotes invasion and migration of esophageal squamous carcinoma cells. Yi Chuan. 2020;42(3):287-95.
48. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167-214.
49. Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22(3):436-45.
50. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell. 2010;140(1):49-61.
51. Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med. 2021;218(1):e20200706.
52. Park JB, Lee CS, Jang JH, et al. Phospholipase signalling networks in cancer. Nat Rev Cancer. 2012;12(11):782-92.
53. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer. Cell Metab. 2013;18(2):153-61.
54. Rohrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732-49.
55. Paone A, Marani M, Fiascarelli A, et al. SHMT1 knockdown induces apoptosis in lung cancer cells by causing uracil misincorporation. Cell Death Dis. 2014;5(11):e1525.
56. Woo CC, Chen WC, Teo XQ, Radda GK, Lee PT. Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget. 2016;7(33):53005-17.
57. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-44.
58. Yun J, Rago C, Cheong I, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325(5947):1555-9.
59. Kumler I, Christiansen OG, Nielsen DL. A systematic review of bevacizumab efficacy in breast cancer. Cancer Treat Rev. 2014;40(8):960-73.
60. Nekvindova J, Mrkvicova A, Zubanova V, et al. Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450. Biochem Pharmacol. 2020;177:113912.
61. Ashida R, Okamura Y, Ohshima K, et al. CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma. Cancer Genomics Proteomics. 2017;14(6):445-53.
62. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-41.
63. Man XB, Tang L, Qiu XH, Yang LQ, Cao HF, Wu MC, et al. Expression of cytochrome P4502E1 gene in hepatocellular carcinoma. World J Gastroenterol. 2004;10(11):1565-68.
64. Luo X, Huang W, Li S, et al. SOX12 Facilitates Hepatocellular Carcinoma Progression and Metastasis through Promoting Regulatory T-Cells Infiltration and Immunosuppression. Adv Sci (Weinh). 2024;11(36):e2310304.
65. Takata Y, Nakamoto Y, Nakada A, et al. Frequency of CD45RO+ subset in CD4+CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. Cancer Lett. 2011;307(2):165-73.
66. Zongyi Y, Xiaowu L. Immunotherapy for hepatocellular carcinoma. Cancer Lett. 2020;470:8-17.
67. Hall Z, Chiarugi D, Charidemou E, et al. Lipid Remodeling in Hepatocyte Proliferation and Hepatocellular Carcinoma. Hepatology. 2021;73(3):1028-44.
68. Chen F, Sheng L, Zhou T, et al. Loss of Ufl1/Ufbp1 in hepatocytes promotes liver pathological damage and carcinogenesis through activating mTOR signaling. J Exp Clin Cancer Res. 2023;42(1):110.
69. Chen RY, Yen CJ, Lin YJ, et al. CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis. Cell Death Dis. 2021;12(11):983.
| Files | ||
| Issue | Articles in Press | |
| Section | Original Article(s) | |
| Keywords | ||
| Hepatocellular carcinoma Immune infiltration Prognostic genes Single-cell analysis 25 types of cell death | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Wu W, Wang Y, Zhao X, Dong K, Li M, An X, Xu Y, Wang S, Li D. Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Cell Death-related Genes and Characterization of Immune Microenvironment. Iran J Allergy Asthma Immunol. 2026;:1-30.
