Alcohol dehydrogenase 4 is a TP53‑associated gene signature for the prediction of prognosis in hepatocellular carcinoma

Zhang,Yuan; Jiang,Hui-Hong; Wang,Zhen-Yu; Zhai,Bo; Lin,Mou-Bin

doi:10.3892/ol.2022.13589

Alcohol dehydrogenase 4 is a TP53‑associated gene signature for the prediction of prognosis in hepatocellular carcinoma

Authors:
- Yuan Zhang
- Hui-Hong Jiang
- Zhen-Yu Wang
- Bo Zhai
- Mou-Bin Lin
View Affiliations

Affiliations: Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai 200090, P.R. China, Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China
Published online on: November 8, 2022 https://doi.org/10.3892/ol.2022.13589
Article Number: 3
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Tumor protein p53 (TP53) is one of the most frequently mutated genes in hepatocellular carcinoma (HCC), an event that has been associated with a poor prognosis. Therefore, availability of an accurate prognostic signature would be beneficial for improving therapeutic efficacy and patient prognosis. In the present study, HCC genetic mutation data, transcriptomic data and clinical data were downloaded from The Cancer Genome Atlas database to screen for specific TP53‑associated signatures based on differentially expressed genes. Subsequently, the predictive value of any signatures found for the overall survival (OS) and the immune response were investigated, followed by validation in clinical specimens. The present study revealed 270 mutant genes, of which 28% were TP53 mutations. In addition, 81 upregulated genes and 27 downregulated genes were identified. Enrichment analysis revealed that mutant TP53 was particularly enriched for pathways associated with the cell cycle and cell metabolism, and whilst clustered, most enriched for terms associated with metabolic processes and the immune response. The alcohol dehydrogenase 4 (ADH4) gene was selected using univariate and multivariate Cox regression analysis. A nomogram was constructed to validate this prognostic signature. Patients in the low‑ADH4 expression group displayed significantly worse OS time regardless of the TP53 mutation status compared with the high‑ADH4 expression group. In addition, a higher degree of B‑cell infiltration was observed in the low‑ADH4 expression group, revealing differential immune microenvironments. Subsequently, ADH4 expression and the prognostic prediction values were validated further in clinical HCC samples by IHC assay, Risk score, OS analysis and ROC analysis. To conclude, these data suggest that the TP53‑associated immune‑metabolic signature is a specific and independent prognostic biomarker for patients with HCC that will help to facilitate novel immunotherapy development.

View Figures

View References

1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Petrick JL, Florio AA, Znaor A, Ruggieri D, Laversanne M, Alvarez CS, Ferlay J, Valery PC, Bray F and McGlynn KA: International trends in hepatocellular carcinoma incidence, 1978–2012. Int J Cancer. 147:317–330. 2020. View Article : Google Scholar : PubMed/NCBI
3	Pang Y, Liu Z, Han H, Wang B, Li W, Mao C and Liu S: Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation. J Hepatol. 73:1155–1169. 2020. View Article : Google Scholar : PubMed/NCBI
4	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
5	Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, Mariotto A, Lake AJ, Wilson R, Sherman RL, et al: Annual report to the nation on the status of cancer, 1975–2014, featuring survival. J Natl Cancer Inst. 109:djx0302017. View Article : Google Scholar : PubMed/NCBI
6	Zheng Y, Chen Z, Han Y, Han L, Zou X, Zhou B, Hu R, Hao J, Bai S, Xiao H, et al: Immune suppressive landscape in the human esophageal squamous cell carcinoma microenvironment. Nat Commun. 11:62682020. View Article : Google Scholar : PubMed/NCBI
7	Wang W and Zou W: Amino acids and their transporters in T cell immunity and cancer therapy. Mol Cell. 80:384–395. 2020. View Article : Google Scholar : PubMed/NCBI
8	Wu J and Cai J: Dilemma and challenge of immunotherapy for pancreatic cancer. Dig Dis Sci. 66:359–368. 2021. View Article : Google Scholar : PubMed/NCBI
9	Greer RL, Dong X, Moraes AC, Zielke RA, Fernandes GR, Peremyslova E, Vasquez-Perez S, Schoenborn AA, Gomes EP, Pereira AC, et al: Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat Commun. 7:133292016. View Article : Google Scholar : PubMed/NCBI
10	Wu R, Chen F, Wang N, Tang D and Kang R: ACOD1 in immunometabolism and disease. Cell Mol Immunol. 17:822–833. 2020. View Article : Google Scholar : PubMed/NCBI
11	Mouton AJ, Li X, Hall ME and Hall JE: Obesity, hypertension, and cardiac dysfunction: Novel roles of immunometabolism in macrophage activation and inflammation. Circ Res. 126:789–806. 2020. View Article : Google Scholar : PubMed/NCBI
12	Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, Li X, Babur O, Hsu TK, Lichtarge O, et al: Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep. 28:1370–1384.e5. 2019. View Article : Google Scholar : PubMed/NCBI
13	Olivier M, Hollstein M and Hainaut P: TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2:a0010082010. View Article : Google Scholar : PubMed/NCBI
14	Mogi A and Kuwano H: TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol. 2011:5839292011. View Article : Google Scholar : PubMed/NCBI
15	Duffy MJ, Synnott NC and Crown J: Mutant p53 as a target for cancer treatment. Eur J Cancer. 83:258–265. 2017. View Article : Google Scholar : PubMed/NCBI
16	Silwal-Pandit L, Langerød A and Børresen-Dale AL: TP53 mutations in breast and ovarian cancer. Cold Spring Harb Perspect Med. 7:a0262522017. View Article : Google Scholar : PubMed/NCBI
17	Yang C, Huang X, Li Y, Chen J, Lv Y and Dai S: Prognosis and personalized treatment prediction in TP53-mutant hepatocellular carcinoma: An in silico strategy towards precision oncology. Brief Bioinform. 22:bbaa1642021. View Article : Google Scholar : PubMed/NCBI
18	Meng F, Wu L, Dong L, Mitchell AV, James Block C, Liu J, Zhang H, Lu Q, Song WM, Zhang B, et al: EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming. Nat Commun. 10:50332019. View Article : Google Scholar : PubMed/NCBI
19	Jiang P, Gu S, Pan D, Fu J, Sahu A, Hu X, Li Z, Traugh N, Bu X, Li B, et al: Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat Med. 24:1550–1558. 2018. View Article : Google Scholar : PubMed/NCBI
20	Telloni SM: Tumor staging and grading: A primer. Methods Mol Biol. 1606:1–17. 2017. View Article : Google Scholar : PubMed/NCBI
21	Pinero F, Dirchwolf M and Pessôa MG: Biomarkers in hepatocellular carcinoma: Diagnosis, prognosis and treatment response assessment. Cells. 9:13702020. View Article : Google Scholar : PubMed/NCBI
22	Golonka RM and Vijay-Kumar M: Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome. Adv Cancer Res. 149:171–255. 2021. View Article : Google Scholar : PubMed/NCBI
23	Sonbol MB, Riaz IB, Naqvi SAA, Almquist DR, Mina S, Almasri J, Shah S, Almader-Douglas D, Uson Junior PLS, Mahipal A, et al: Systemic therapy and sequencing options in advanced hepatocellular carcinoma: A systematic review and network meta-analysis. JAMA Oncol. 6:e2049302020. View Article : Google Scholar : PubMed/NCBI
24	Llovet JM, Montal R, Sia D and Finn RS: Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 15:599–616. 2018. View Article : Google Scholar : PubMed/NCBI
25	Zhang Y, Yan Q, Gong L, Xu H, Liu B, Fang X, Yu D, Li L, Wei T, Wang Y, et al: C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism. Oncogene. 40:1147–1161. 2021. View Article : Google Scholar : PubMed/NCBI
26	Wang Q, Tan Y, Jiang T, Wang X, Li Q, Dong L, Liu X and Xu G: Metabolic reprogramming and its relationship to survival in hepatocellular carcinoma. Cells. 11:10662022. View Article : Google Scholar : PubMed/NCBI
27	Jühling F, Hamdane N, Crouchet E, Li S, El Saghire H, Mukherji A, Fujiwara N, Oudot MA, Thumann C, Saviano A, et al: Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma. Gut. 70:157–169. 2021. View Article : Google Scholar : PubMed/NCBI
28	Machairas N, Tsilimigras DI and Pawlik TM: Current landscape of immune checkpoint inhibitor therapy for hepatocellular carcinoma. Cancers (Basel). 14:20182022. View Article : Google Scholar : PubMed/NCBI
29	Mantovani F, Collavin L and Del Sal G: Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 26:199–212. 2019. View Article : Google Scholar : PubMed/NCBI
30	Li L, Li M and Wang X: Cancer type-dependent correlations between TP53 mutations and antitumor immunity. DNA Repair (Amst). 88:1027852020. View Article : Google Scholar : PubMed/NCBI
31	Agupitan AD, Neeson P, Williams S, Howitt J, Haupt S and Haupt Y: P53: A guardian of immunity becomes its saboteur through mutation. Int J Mol Sci. 21:34522020. View Article : Google Scholar : PubMed/NCBI
32	Jelski W and Szmitkowski M: Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in the cancer diseases. Clin Chim Acta. 395:1–5. 2008. View Article : Google Scholar : PubMed/NCBI
33	Lercher A, Baazim H and Bergthaler A: Systemic immunometabolism: Challenges and opportunities. Immunity. 53:496–509. 2020. View Article : Google Scholar : PubMed/NCBI
34	Piñeiro Fernández J, Luddy KA, Harmon C and O'Farrelly C: Hepatic tumor microenvironments and effects on NK cell phenotype and function. Int J Mol Sci. 20:41312019. View Article : Google Scholar : PubMed/NCBI
35	Garnelo M, Tan A, Her Z, Yeong J, Lim CJ, Chen J, Lim KH, Weber A, Chow P, Chung A, et al: Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 66:342–351. 2017. View Article : Google Scholar : PubMed/NCBI
36	Giannone G, Ghisoni E, Genta S, Scotto G, Tuninetti V, Turinetto M and Valabrega G: Immuno-metabolism and microenvironment in cancer: Key players for immunotherapy. Int J Mol Sci. 21:44142020. View Article : Google Scholar : PubMed/NCBI
37	Nogueira JA, Ono-Nita SK, Nita ME, de Souza MM, do Carmo EP, Mello ES, Scapulatempo C, Paranaguá-Vezozzo DC, Carrilho FJ and Alves VA: 249 TP53 mutation has high prevalence and is correlated with larger and poorly differentiated HCC in Brazilian patients. BMC Cancer. 9:2042009. View Article : Google Scholar : PubMed/NCBI
38	Liu X, Li T, Kong D, You H, Kong F and Tang R: Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma. BMC Cancer. 20:12042020. View Article : Google Scholar : PubMed/NCBI
39	Edmondson HA and Steiner PE: Primary carcinoma of the liver: A study of 100 cases among 48,900 necropsies. Cancer. 7:462–503. 1954. View Article : Google Scholar : PubMed/NCBI