Prognosis prediction model for hepatocellular carcinoma based on autophagy related genes_Journal of Biomedical Engineering

Authors：

HUANG Wei , HAN Ning , DU Lingyao , CAO Dan ,  TANG Hong

Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

TANG Hong, Email: htang6198@hotmail.com

Keywords：

Hepatocellular carcinoma; Autophagy; Autophagy related genes; Prognostic model

DOI：

10.7507/1001-5515.202101090

Video：

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Autophagy is a programmed cell degradation process that is involved in a variety of physiological and pathological processes including malignant tumors. Abnormal induction of autophagy plays a key role in the development of hepatocellular carcinoma (HCC). We established a prognosis prediction model for hepatocellular carcinoma based on autophagy related genes. Two hundred and four differentially expressed autophagy related genes and basic information and clinical characteristics of 377 registered hepatocellular carcinoma patients were retrieved from the cancer genome atlas database. Cox risk regression analysis was used to identify autophagy-related genes associated with survival, and a prognostic model was constructed based on this. A total of 64 differentially expressed autophagy related genes were identified in hepatocellular carcinoma patients. Five risk factors related to the prognosis of hepatocellular carcinoma patients were determined by univariate and multivariate Cox regression analysis, including TMEM74, BIRC5, SQSTM1, CAPN10 and HSPB8. Age, gender, tumor grade and stage, and risk score were included as variables in multivariate Cox regression analysis. The results showed that risk score was an independent prognostic risk factor for patients with hepatocellular carcinoma (HR = 1.475, 95% CI = 1.280–1.699, P < 0.001). In addition, the area under the curve of the prognostic risk model was 0.739, indicating that the model had a high accuracy in predicting the prognosis of hepatocellular carcinoma. The results suggest that the new prognostic risk model for hepatocellular carcinoma, established by combining the molecular characteristics and clinical parameters of patients, can effectively predict the prognosis of patients.

Citation： HUANG Wei, HAN Ning, DU Lingyao, CAO Dan, TANG Hong. Prognosis prediction model for hepatocellular carcinoma based on autophagy related genes. Journal of Biomedical Engineering, 2022, 39(1): 120-127. doi: 10.7507/1001-5515.202101090 Copy

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2.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3.	Zhai W, Lim T K, Zhang T, et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun, 2017, 8(1): 1-9.
4.	Casak S J, Donoghue M, Fashoyin-Aje L, et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res, 2020, 27(7): 1836-1841.
5.	Nawy T. Tumor genetic analysis from single-cell RNA-seq data. Nat Methods, 2018, 15(8): 571.
6.	Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol, 2018, 19(6): 349-364.
7.	Perera R M, Stoykova S, Nicolay B N, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature, 2015, 524(7565): 361-365.
8.	Rao S, Tortola L, Perlot T, et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun, 2014, 5(1): 1-15.
9.	Yang A, Rajeshkumar N V, Wang X, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov, 2014, 4(8): 905-913.
10.	Yang S, Yang L, Li X, et al. New insights into autophagy in hepatocellular carcinoma: mechanisms and therapeutic strategies. Am J Cancer Res, 2019, 9(7): 1329-1353.
11.	Wang Y, Liu X, Guan G, et al. A risk classification system with five-gene for survival prediction of glioblastoma patients. Front Neurol, 2019, 10: 745.
12.	Yu C, Wang L, Lv B, et al. TMEM74, a lysosome and autophagosome protein, regulates autophagy. Biochem Biophys Res Commun, 2008, 369(2): 622-629.
13.	Sun Y, Li Q, Zhang J, et al. Autophagy regulatory molecule, TMEM74, interacts with BIK and inhibits BIK-induced apoptosis. Cell Signal, 2017, 36: 34-41.
14.	Sun Y, Chen Y, Zhang J, et al. TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A. Cell Death Dis, 2017, 8(8): e3031.
15.	Hagenbuchner J, Kiechl-kohlendorfer U, Obexer P, et al. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene, 2016, 35(16): 2052-2061.
16.	Lin T Y, Chan H H, Chen S H, et al. BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 2020, 16(7): 1296-1313.
17.	Liu S H, Hong Y, Markowiak S, et al. BIRC5 is a target for molecular imaging and detection of human pancreatic cancer. Cancer Lett, 2019, 457: 10-19.
18.	Wang L, Huang J, Jiang M, et al. Survivin (BIRC5) cell cycle computational network in human no-tumor hepatitis/cirrhosis and hepatocellular carcinoma transformation. J Cell Biochem, 2011, 112(5): 1286-1294.
19.	Denk H, Stumptner C, Abuja P M, et al. Sequestosome 1/p62-related pathways as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets, 2019, 23(5): 393-406.
20.	Umemura A, He F, Taniguchi K, et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell, 2016, 29(6): 935-948.
21.	Saito T, Ichimura Y, Taguchi K, et al. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun, 2016, 7: 12030.
22.	Duran A, Hernandez E D, Reina-campos M, et al. p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell, 2016, 30(4): 595-609.
23.	Vander Molen J, Frisse L M, Fullerton S M, et al. Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants. Am J Hum Genet, 2005, 76(4): 548-560.
24.	Horikawa Y, Oda N, Cox N J, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 2000, 26(2): 163-175.
25.	Hatta T, Iemura S I, Ohishi T, et al. Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B. Sci Rep, 2018, 8(1): 16756.
26.	Turner M D, Fulcher F K, Jones C V, et al. Calpain facilitates actin reorganization during glucose-stimulated insulin secretion. Biochem Biophys Res Commun, 2007, 352(3): 650-655.
27.	Moreno-Luna R, Abrante A, Esteban F, et al. Calpain 10 gene and laryngeal cancer: a survival analysis. Head Neck, 2011, 33(1): 72-76.
28.	Frances C P, Conde M C, Saez M E, et al. Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility. J Gastroenterol Hepatol, 2007, 22(12): 2298-2302.
29.	Chan D, Tsoi M Y, Liu C D, et al. Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma. World J Gastroenterol, 2013, 19(18): 2772-2780.
30.	Yang Z, Zhuang L, Szatmary P, et al. Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. Int J Med Sci, 2015, 12(3): 256-263.
31.	Wang C, Zhang Y, Guo K, et al. Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential. Int J Cancer, 2016, 138(8): 1824-1834.
32.	Matsushima-Nishiwaki R, Toyoda H, Takamatsu R, et al. Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Biochim Biophys Acta Mol Basis Dis, 2017, 1863(6): 1629-1639.

1. Yu M W, Lin C L, Liu C J, et al. Influence of metabolic risk factors on risk of hepatocellular carcinoma and liver-related death in men with chronic hepatitis B: a large cohort study. Gastroenterology, 2017, 153(4): 1006-1017.
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3. Zhai W, Lim T K, Zhang T, et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat Commun, 2017, 8(1): 1-9.
4. Casak S J, Donoghue M, Fashoyin-Aje L, et al. FDA approval summary: atezolizumab plus bevacizumab for the treatment of patients with advanced unresectable or metastatic hepatocellular carcinoma. Clin Cancer Res, 2020, 27(7): 1836-1841.
5. Nawy T. Tumor genetic analysis from single-cell RNA-seq data. Nat Methods, 2018, 15(8): 571.
6. Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol, 2018, 19(6): 349-364.
7. Perera R M, Stoykova S, Nicolay B N, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature, 2015, 524(7565): 361-365.
8. Rao S, Tortola L, Perlot T, et al. A dual role for autophagy in a murine model of lung cancer. Nat Commun, 2014, 5(1): 1-15.
9. Yang A, Rajeshkumar N V, Wang X, et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov, 2014, 4(8): 905-913.
10. Yang S, Yang L, Li X, et al. New insights into autophagy in hepatocellular carcinoma: mechanisms and therapeutic strategies. Am J Cancer Res, 2019, 9(7): 1329-1353.
11. Wang Y, Liu X, Guan G, et al. A risk classification system with five-gene for survival prediction of glioblastoma patients. Front Neurol, 2019, 10: 745.
12. Yu C, Wang L, Lv B, et al. TMEM74, a lysosome and autophagosome protein, regulates autophagy. Biochem Biophys Res Commun, 2008, 369(2): 622-629.
13. Sun Y, Li Q, Zhang J, et al. Autophagy regulatory molecule, TMEM74, interacts with BIK and inhibits BIK-induced apoptosis. Cell Signal, 2017, 36: 34-41.
14. Sun Y, Chen Y, Zhang J, et al. TMEM74 promotes tumor cell survival by inducing autophagy via interactions with ATG16L1 and ATG9A. Cell Death Dis, 2017, 8(8): e3031.
15. Hagenbuchner J, Kiechl-kohlendorfer U, Obexer P, et al. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene, 2016, 35(16): 2052-2061.
16. Lin T Y, Chan H H, Chen S H, et al. BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 2020, 16(7): 1296-1313.
17. Liu S H, Hong Y, Markowiak S, et al. BIRC5 is a target for molecular imaging and detection of human pancreatic cancer. Cancer Lett, 2019, 457: 10-19.
18. Wang L, Huang J, Jiang M, et al. Survivin (BIRC5) cell cycle computational network in human no-tumor hepatitis/cirrhosis and hepatocellular carcinoma transformation. J Cell Biochem, 2011, 112(5): 1286-1294.
19. Denk H, Stumptner C, Abuja P M, et al. Sequestosome 1/p62-related pathways as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets, 2019, 23(5): 393-406.
20. Umemura A, He F, Taniguchi K, et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell, 2016, 29(6): 935-948.
21. Saito T, Ichimura Y, Taguchi K, et al. p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun, 2016, 7: 12030.
22. Duran A, Hernandez E D, Reina-campos M, et al. p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell, 2016, 30(4): 595-609.
23. Vander Molen J, Frisse L M, Fullerton S M, et al. Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants. Am J Hum Genet, 2005, 76(4): 548-560.
24. Horikawa Y, Oda N, Cox N J, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 2000, 26(2): 163-175.
25. Hatta T, Iemura S I, Ohishi T, et al. Calpain-10 regulates actin dynamics by proteolysis of microtubule-associated protein 1B. Sci Rep, 2018, 8(1): 16756.
26. Turner M D, Fulcher F K, Jones C V, et al. Calpain facilitates actin reorganization during glucose-stimulated insulin secretion. Biochem Biophys Res Commun, 2007, 352(3): 650-655.
27. Moreno-Luna R, Abrante A, Esteban F, et al. Calpain 10 gene and laryngeal cancer: a survival analysis. Head Neck, 2011, 33(1): 72-76.
28. Frances C P, Conde M C, Saez M E, et al. Identification of a protective haplogenotype within CAPN10 gene influencing colorectal cancer susceptibility. J Gastroenterol Hepatol, 2007, 22(12): 2298-2302.
29. Chan D, Tsoi M Y, Liu C D, et al. Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma. World J Gastroenterol, 2013, 19(18): 2772-2780.
30. Yang Z, Zhuang L, Szatmary P, et al. Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. Int J Med Sci, 2015, 12(3): 256-263.
31. Wang C, Zhang Y, Guo K, et al. Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential. Int J Cancer, 2016, 138(8): 1824-1834.
32. Matsushima-Nishiwaki R, Toyoda H, Takamatsu R, et al. Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Biochim Biophys Acta Mol Basis Dis, 2017, 1863(6): 1629-1639.

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