Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2022

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

System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma

Authors: Cheng Yan, Yandie Niu, Liukai Ma, Lifang Tian, Jiahao Ma

Published in: Journal of Translational Medicine | Issue 1/2022

Login to get access

Abstract

Background

Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported.

Methods

Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan–Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC.

Results

Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells.

Conclusion

In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC.
Appendix
Available only for authorised users
Literature
1.
EAFTSOT Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69(1):182–236.CrossRef
2.
3.
Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson AB, Mariotto A, Lake AJ, Wilson R, Sherman RL. Annual report to the nation on the status of cancer 1975–2014 featuring survival. J Natl Cancer Inst. 2017;109(9):30.CrossRef
4.
Duan C, Liu M, Zhang Z, Ma K, Bie P. Radiofrequency ablation versus hepatic resection for the treatment of early-stage hepatocellular carcinoma meeting milan criteria: a systematic review and meta-analysis. World J Surg Oncol. 2013;11(1):1–9.CrossRef
5.
Schwartz M, Roayaie S, Konstadoulakis M. Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol. 2007;4(7):424–32.PubMedCrossRef
6.
Han K, Kim JH. Transarterial chemoembolization in hepatocellular carcinoma treatment: barcelona clinic liver cancer staging system. World J Gastroenterol. 2015;21(36):10327.PubMedPubMedCentralCrossRef
7.
Kim B-E, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol. 2008;4(3):176–85.PubMedCrossRef
8.
Rae T, Schmidt P, Pufahl R, Culotta V, O’Halloran VT. Undetectable intracellular free copper the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284(5415):805–8.PubMedCrossRef
9.
10.
Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375(6586):1254–61.PubMedPubMedCentralCrossRef
11.
12.
Tang D, Chen X, Kroemer G. Cuproptosis: a copper-triggered modality of mitochondrial cell death. Cell Res. 2022;32(5):417–8.PubMedCrossRef
13.
14.
Davis CI, Gu X, Kiefer RM, Ralle M, Gade TP, Brady DC. Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics. 2020;12(12):1995–2008.PubMedCrossRef
15.
Therneau T, Lumley T. R survival package. Vienna: R Core Team; 2013.
16.
17.
Greenwood PE, Nikulin MS. A guide to chi-squared testing. Hoboken: John Wiley and Sons; 1996.
18.
Harrell FE Jr, Harrell MFE Jr, Hmisc D. Package ‘rms.’ Nashville: Vanderbilt University; 2017.
19.
Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. In: von Stechow Louise, editor. Cancer systems biology. New York: Springer; 2018. p. 243–59.CrossRef
20.
Hsiung T-H, Olejnik S, Huberty CJ. Comment on a wilcox test statistic for comparing means when variances are unequal. J Educ Stat. 1994;19(2):111–8.CrossRef
21.
22.
Alexa A, Rahnenführer J. Gene set enrichment analysis with topGO. Bioconductor Improv. 2009;27:1–26.
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.PubMedPubMedCentralCrossRef
24.
Adamus A, Müller P, Nissen B, Kasten A, Timm S, Bauwe H, Seitz G, Engel N. GCSH antisense regulation determines breast cancer cells’ viability. Sci Rep. 2018;8(1):1–13.CrossRef
25.
Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W. Lipoic acid biosynthesis defects. J Inherit Metab Dis. 2014;37(4):553–63.PubMedCrossRef
26.
Bingham PM, Stuart SD, Zachar Z. Lipoic acid and lipoic acid analogs in cancer metabolism and chemotherapy. Expert Rev Clin Pharmacol. 2014;7(6):837–46.PubMedCrossRef
27.
Novotny L, Rauko P, Cojocel C. Alpha-lipoic acid-the potential for use in cancer therapy minireview. Neoplasma-Bratislava. 2008;55(2):81.
28.
Al-Grawi EDC, Al-Awsi GRL. Expression of CDKN2A (P16/Ink4a) among colorectal cancer patients: a cohort study. J Pharm Sci Res. 2018;10(5):1145–7.
29.
30.
Zhou Y, Wang X-b, Qiu X-p, Zhang S, Wang C, Zheng F. CDKN2A promoter methylation and hepatocellular carcinoma risk: a meta-analysis. Clin Res Hepatol Gastroenterol. 2018;42(6):529–41.PubMedCrossRef
31.
32.
33.
Zhao R, Choi BY, Lee M-H, Bode AM, Dong Z. Implications of genetic and epigenetic alterations of CDKN2A (p16INK4a) in cancer. EBioMedicine. 2016;8:30–9.PubMedPubMedCentralCrossRef
34.
35.
36.
Cheng H, Huang H, Huang G. Synthesis and antitumor activity of epothilone B. Eur J Med Chem. 2018;157:925–34.PubMedCrossRef
37.
Ko J-H, Lee S-G, Yang WM, Um J-Y, Sethi G, Mishra S, Shanmugam MK, Ahn KS. The application of embelin for cancer prevention and therapy. Molecules. 2018;23(3):621.PubMedCentralCrossRef
38.
Wang D-G, Sun Y-B, Ye F, Li W, Kharbuja P, Gao L, Zhang DY, Suo J. Anti-tumor activity of the X-linked inhibitor of apoptosis (XIAP) inhibitor embelin in gastric cancer cells. Mol Cell Biochem. 2014;386(1):143–52.PubMedCrossRef
39.
Jehan Z, Al-obaisi KAR, Uddin S, Al-Kuraya K. Embelin induces autophagy in ovarian cancer cells. Cancer Res. 2012;72:2265–2265.CrossRef
40.
Kaya TT, Turgut NH, Ataseven H, Koyluoglu G. Effects of a multikinase inhibitor motesanib (AMG 706) alone and combined with the selective DuP-697 COX-2 inhibitor on colorectal cancer cells. Asian Pac J Cancer Prev. 2016;17(3):1103–10.PubMedCrossRef
41.
42.
43.
Zhang Q, Ma S, Liu B, Liu J, Zhu R, Li M. Chrysin induces cell apoptosis via activation of the p53/Bcl-2/caspase-9 pathway in hepatocellular carcinoma cells. Exp Ther Med. 2016;12(1):469–74.PubMedPubMedCentralCrossRef
44.
Huang Q, Zhan L, Cao H, Li J, Lyu Y, Guo X, Zhang J, Ji L, Ren T, An J. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12(6):999–1014.PubMedPubMedCentralCrossRef
45.
Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT. Cancer chemoprevention mechanisms mediated through the Keap1–Nrf2 pathway. Antioxid Redox Signal. 2010;13(11):1713–48.PubMedCrossRef
46.
Locatelli C, Jardim JKB, Zancanaro V. Role of antioxidants in the treatment of hepatocellular carcinoma: integrative review. Res, Soc Dev. 2021;10(1):e46310112028–e46310112028.CrossRef
47.
Chachay VS, Kirkpatrick CM, Hickman IJ, Ferguson M, Prins JB, Martin JH. Resveratrol–pills to replace a healthy diet? Br J Clin Pharmacol. 2011;72(1):27–38.PubMedPubMedCentralCrossRef
48.
Xie Q, Yang Y, Wang Z, Chen F, Zhang A, Liu C. Resveratrol-4-O-D-(2’-galloyl)-glucopyranoside isolated from polygonum cuspidatum exhibits anti-hepatocellular carcinoma viability by inducing apoptosis via the JNK and ERK pathway. Molecules. 2014;19(2):1592–602.PubMedPubMedCentralCrossRef
49.
Aglan HA, Ahmed HH, El-Toumy SA, Mahmoud NS. Gallic acid against hepatocellular carcinoma: an integrated scheme of the potential mechanisms of action from in vivo study. Tumor Biol. 2017;39(6):1010428317699127.CrossRef
50.
Lima KG, Krause GC, Schuster AD, Catarina AV, Basso BS, De Mesquita FC, Pedrazza L, Marczak ES, Martha BA, Nunes FB. Gallic acid reduces cell growth by induction of apoptosis and reduction of IL-8 in HepG2 cells. Biomed Pharmacother. 2016;84:1282–90.PubMedCrossRef
51.
Sakka L, Delétage N, Chalus M, Aissouni Y, Sylvain-Vidal V, Gobron S, Coll G. Assessment of citalopram and escitalopram on neuroblastoma cell lines: cell toxicity and gene modulation. Oncotarget. 2017;8(26):42789.PubMedPubMedCentralCrossRef
52.
Liu Y-C, Chen VC-H, Lu M-L, Lee M-J, McIntyre RS, Majeed A, Lee Y, Chen Y-L. The association between selective serotonin reuptake inhibitors (SSRIs) use and the risk of bladder cancer: a nationwide population-based cohort study. Cancers. 2020;12(5):1184.PubMedCentralCrossRef
53.
Ahmadian E, Eftekhari A, Fard JK, Babaei H, Nayebi AM, Mohammadnejad D, Eghbal MA. In vitro and in vivo evaluation of the mechanisms of citalopram-induced hepatotoxicity. Arch Pharmacal Res. 2017;40(11):1296–313.CrossRef
54.
Taler M, Gil-Ad I, Brener I, Hornfeld SH, Weizman A. Complex effects of sertraline and citalopram on in vitro murine breast cancer proliferation and on in vivo progression and anxiety level. Int J Mol Sci. 2022;23(5):2711.PubMedPubMedCentralCrossRef
55.
Pinter M, Jain RK. Targeting the renin-angiotensin system to improve cancer treatment implications for immunotherapy. Sci Transl Med. 2017;9(410):5616.CrossRef
56.
Taskin E, Guven C. Local renin-angiotensin system at liver and crosstalk with hepatic diseases. In: Tolekova Anna Naidenova, editor. Renin-Angiotensin System-Past Present and Future. London: IntechOpen; 2017.
57.
Zhang H-F, Gao X, Wang X, Chen X, Huang Y, Wang L, Xu Z-W. The mechanisms of renin–angiotensin system in hepatocellular carcinoma: from the perspective of liver fibrosis, HCC cell proliferation, metastasis and angiogenesis, and corresponding protection measures. Biomed Pharmacother. 2021;141: 111868.PubMedCrossRef
58.
Almutlaq M, Alamro AA, Alamri HS, Alghamdi AA, Barhoumi T. The effect of local renin angiotensin system in the common types of cancer. Front Endocrinol. 2021;12: 736361.CrossRef
59.
Feng L-H, Sun H-C, Zhu X-D, Zhang S-Z, Li K-S, Li X-L, Li Y, Tang Z-Y. Renin-angiotensin inhibitors were associated with improving outcomes of hepatocellular carcinoma with primary hypertension after hepatectomy. Ann Transl Med. 2019;7:23.CrossRef
60.
Song LN, Liu JY, Shi TT, Zhang YC, Xin Z, Cao X, Yang JK. Angiotensin-(1–7), the product of ACE2 ameliorates NAFLD by acting through its receptor mas to regulate hepatic mitochondrial function and glycolipid metabolism. FASEB J. 2020;34(12):16291–306.PubMedCrossRef
61.
Ji Y, Chen H, Gow W, Ma L, Jin Y, Hui B, Yang Z, Wang Z. Potential biomarkers Ang II/AT1R and S1P/S1PR1 predict the prognosis of hepatocellular carcinoma. Oncol Lett. 2020;20(5):1–1.CrossRef
62.
Takagi H, Kaji K, Nishimura N, Ishida K, Ogawa H, Takaya H, Kawaratani H, Moriya K, Namisaki T, Akahane T. The angiotensin II receptor blocker losartan sensitizes human liver cancer cells to lenvatinib-mediated cytostatic and angiostatic effects. Cells. 2021;10(3):575.PubMedPubMedCentralCrossRef
63.
Egami K, Murohara T, Shimada T, Sasaki K-i, Shintani S, Sugaya T, Ishii M, Akagi T, Ikeda H, Matsuishi T. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest. 2003;112(1):67–75.PubMedPubMedCentralCrossRef
64.
Facciorusso A, Del Prete V, Crucinio N, Muscatiello N, Carr BI, Di Leo A, Barone M. Angiotensin receptor blockers improve survival outcomes after radiofrequency ablation in hepatocarcinoma patients. J Gastroenterol Hepatol. 2015;30(11):1643–50.PubMedCrossRef
65.
Marisi G, Passardi A, Scartozzi M, Silvestris N, Valgiusti M, Ulivi P, Faloppi L, Brunetti O, Giovanni LF, Gardini AC. Ang-2 polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib. Ann Oncol. 2017;28:1–2.CrossRef
66.
Pinter M, Weinmann A, Wörns M-A, Hucke F, Bota S, Marquardt JU, Duda DG, Jain RK, Galle PR, Trauner M. Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United European Gastroenterol J. 2017;5(7):987–96.PubMedPubMedCentralCrossRef
67.
Takeshita Y, Takamura T, Ando H, Hamaguchi E, Takazakura A, Matsuzawa-Nagata N, Kaneko S. Cross talk of tumor necrosis factor-α and the renin–angiotensin system in tumor necrosis factor-α-induced plasminogen activator inhibitor-1 production from hepatocytes. Eur J Pharmacol. 2008;579(1–3):426–32.PubMedCrossRef
68.
Pereira RM, dos Santos RAS, da Costa Dias FL, Teixeira MM. E silva ACS: renin-angiotensin system in the pathogenesis of liver fibrosis. World J Gastroenterol. 2009;15(21):2579.PubMedPubMedCentralCrossRef
69.
Munshi MK, Uddin MN, Glaser SS. The role of the renin–angiotensin system in liver fibrosis. Exp Biol Med. 2011;236(5):557–66.CrossRef
70.
71.
72.
Habarou F, Hamel Y, Haack TB, Feichtinger RG, Lebigot E, Marquardt I, Busiah K, Laroche C, Madrange M, Grisel C. Biallelic mutations in LIPT2 cause a mitochondrial lipoylation defect associated with severe neonatal encephalopathy. Am J Hum Genet. 2017;101(2):283–90.PubMedPubMedCentralCrossRef
73.
Soreze Y, Boutron A, Habarou F, Barnerias C, Nonnenmacher L, Delpech H, Mamoune A, Chrétien D, Hubert L, Bole-Feysot C. Mutations in human lipoyltransferase gene LIPT1cause a leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase. Orphanet J Rare Dis. 2013;8(1):1–9.CrossRef
74.
Tort F, Ferrer-Cortès X, Thió M, Navarro-Sastre A, Matalonga L, Quintana E, Bujan N, Arias A, García-Villoria J, Acquaviva C. Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes. Hum Mol Genet. 2014;23(7):1907–15.PubMedCrossRef
75.
Chen Y, Xu T, Xie F, Wang L, Liang Z, Li D, Liang Y, Zhao K, Qi X, Yang X. Evaluating the biological functions of the prognostic genes identified by the pathology atlas in bladder cancer. Oncol Rep. 2021;45(1):191–201.PubMedCrossRef
76.
77.
Metadata
Title
System analysis based on the cuproptosis-related genes identifies LIPT1 as a novel therapy target for liver hepatocellular carcinoma
Authors
Cheng Yan
Yandie Niu
Liukai Ma
Lifang Tian
Jiahao Ma
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2022
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-022-03630-1

Other articles of this Issue 1/2022

Journal of Translational Medicine 1/2022 Go to the issue

Research

Identifying CCR5 coreceptor populations permissive for HIV-1 entry and productive infection: implications for in vivo studies

Research

Pan-cancer analyses of pyroptosis with functional implications for prognosis and immunotherapy in cancer

Research

Transcriptomic profiling of pemphigus lesion infiltrating mononuclear cells reveals a distinct local immune microenvironment and novel lncRNA regulators

Research

Superior physical and mental health of healthy volunteers before and five years after mobilized stem cell donation

Research

Prognostic and predictive value of radiomic signature in stage I lung adenocarcinomas following complete lobectomy

Research

Autoimmune gene expression profiling of fingerstick whole blood in Chronic Fatigue Syndrome
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits