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BMC Cancer
Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

Development and validation of a selenium metabolism regulators associated prognostic model for hepatocellular carcinoma

Authors: Huishan Sun, Junyu Long, Bangyou Zuo, Yiran Li, Yu Song, Minghang Yu, Ziyu Xun, Yanyu Wang, Xi Wang, Xinting Sang, Haitao Zhao

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

Selenium metabolism has been implicated in human health. This study aimed to identify a selenium metabolism regulator-based prognostic signature for hepatocellular carcinoma (HCC) and validate the role of INMT in HCC.

Methods

Transcriptome sequencing data and clinical information related to selenium metabolism regulators in TCGA liver cancer dataset were analysed. Next, a selenium metabolism model was constructed by multiple machine learning algorithms, including univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. Then, the potential of this model for predicting the immune landscape of different risk groups was evaluated. Finally, INMT expression was examined in different datasets. After knockdown of INMT, cell proliferation and colony formation assays were conducted.

Results

A selenium metabolism model containing INMT and SEPSECS was established and shown to be an independent predictor of prognosis. The survival time of low-risk patients was significantly longer than that of high-risk patients. These two groups had different immune environments. In different datasets, including TCGA, GEO, and our PUMCH dataset, INMT was significantly downregulated in HCC tissues. Moreover, knockdown of INMT significantly promoted HCC cell proliferation.

Conclusions

The current study established a risk signature of selenium metabolism regulators for predicting the prognosis of HCC patients. INMT was identified as a biomarker for poor prognosis of HCC.
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Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. 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.PubMed
2.
Zhang S, Sun K, Zheng R, Zeng H, Wang S, Chen R, Wei W, He J. Cancer incidence and mortality in China, 2015. J Natl Cancer Center. 2020;1(1):2–11.
3.
Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–32.PubMedCrossRef
4.
Dhir M, Melin AA, Douaiher J, Lin C, Zhen WK, Hussain SM, Geschwind JF, Doyle MB, Abou-Alfa GK, Are C. A review and update of treatment options and controversies in the management of hepatocellular carcinoma. Ann Surg. 2016;263(6):1112–25.PubMedCrossRef
5.
Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2021;21(2):1–22. PMID 34862480.
6.
7.
Rayman MP. The importance of selenium to human health. Lancet (London, England). 2000;356(9225):233–41.PubMedCrossRef
8.
9.
Carlisle AE, Lee N, Matthew-Onabanjo AN, Spears ME, Park SJ, Youkana D, Doshi MB, Peppers A, Li R, Joseph AB, et al. Selenium detoxification is required for cancer-cell survival. Nat Metab. 2020;2(7):603–11.PubMedPubMedCentralCrossRef
10.
Fukumoto Y, Yamada H, Matsuhashi K, Okada W, Tanaka YK, Suzuki N, Ogra Y. Production of a Urinary Selenium Metabolite, Trimethylselenonium, by Thiopurine S-Methyltransferase and Indolethylamine N-Methyltransferase. Chem Res Toxicol. 2020;33(9):2467–74.PubMedCrossRef
11.
12.
Hughes DJ, Kunická T, Schomburg L, Liška V, Swan N, Souček P. Expression of Selenoprotein Genes and Association with Selenium Status in Colorectal Adenoma and Colorectal Cancer. Nutrients. 2018;10(11):1812.
13.
Nunziata C, Polo A, Sorice A, Capone F, Accardo M, Guerriero E, Marino FZ, Orditura M, Budillon A, Costantini S. Structural analysis of human SEPHS2 protein, a selenocysteine machinery component, over-expressed in triple negative breast cancer. Sci Rep. 2019;9(1):16131.PubMedPubMedCentralCrossRef
14.
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47(W1):W556-w560.PubMedPubMedCentralCrossRef
15.
Bøvelstad HM, Nygård S, Størvold HL, Aldrin M, Borgan Ø, Frigessi A, Lingjaerde OC. Predicting survival from microarray data–a comparative study. Bioinformatics (Oxford, England). 2007;23(16):2080–7.PubMed
16.
He Y, Jiang Z, Chen C, Wang X. Classification of triple-negative breast cancers based on Immunogenomic profiling. J Exper Clin Cancer Res. 2018;37(1):327.CrossRef
17.
Becht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, Selves J, Laurent-Puig P, Sautès-Fridman C, Fridman WH, et al. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol. 2016;17(1):218.PubMedPubMedCentralCrossRef
18.
Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.PubMedPubMedCentralCrossRef
19.
Sun H, Li L, Li W, Yang F, Zhang Z, Liu Z, Du W. p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth. EMBO Rep. 2021;22(10):e52537.PubMedPubMedCentralCrossRef
20.
Xu W, Zhang X, Wu JL, Fu L, Liu K, Liu D, Chen GG, Lai PB, Wong N, Yu J. O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress. J Hepatol. 2017;67(2):310–20.PubMedCrossRef
21.
Shimada BK, Swanson S, Toh P, Seale LA. Metabolism of Selenium, Selenocysteine, and Selenoproteins in Ferroptosis in Solid Tumor Cancers. Biomolecules. 2022;12(11):1581.
22.
Kryukov GV, Castellano S, Novoselov SV, Lobanov AV, Zehtab O, Guigó R, Gladyshev VN. Characterization of mammalian selenoproteomes. Science (New York, NY). 2003;300(5624):1439–43.CrossRef
23.
Burk RF, Hill KE. Regulation of Selenium Metabolism and Transport. Annu Rev Nutr. 2015;35:109–34.PubMedCrossRef
24.
Anan Y, Yoshida M, Hasegawa S, Katai R, Tokumoto M, Ouerdane L, Łobiński R, Ogra Y. Speciation and identification of tellurium-containing metabolites in garlic, Allium sativum. Metall: Integr Biometal Sci. 2013;5(9):1215–24.
25.
Ogra Y, Ishiwata K, Takayama H, Aimi N, Suzuki KT. Identification of a novel selenium metabolite, Se-methyl-N-acetylselenohexosamine, in rat urine by high-performance liquid chromatography–inductively coupled plasma mass spectrometry and–electrospray ionization tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2002;767(2):301–12.CrossRef
26.
Zheng SF, Bao RK, Zhang QJ, Wang SC, Lin HJ. Endogenous Hydrogen Sulfide Promotes Apoptosis via Mitochondrial Pathways in the Livers of Broilers with Selenium Deficiency Exudative Diathesis Disease. Biol Trace Elem Res. 2018;186(1):249–57.PubMedCrossRef
27.
Li X, Ramadori P, Pfister D, Seehawer M, Zender L, Heikenwalder M. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21(9):541–57.PubMedCrossRef
28.
Sun B, Wang R, Li J, Jiang Z, Xu S. Dietary selenium affects selenoprotein W gene expression in the liver of chicken. Biol Trace Elem Res. 2011;143(3):1516–23.PubMedCrossRef
29.
Lawal G, Xiao Y, Rahnemai-Azar AA, Tsilimigras DI, Kuang M, Bakopoulos A, Pawlik TM. The Immunology of Hepatocellular Carcinoma. Vaccines. 2021;9(10):1184.
30.
Schomburg L, Hughes DJ. The missing link? The potential role of selenium in the development of liver cancer and significance for the general population. Expert Rev Gastroenterol Hepatol. 2017;11(8):707–9.PubMedCrossRef
31.
Lin Y, He F, Lian S, Xie B, Liu T, He J, Liu C: Selenium status in patients with chronic liver disease: a systematic review and meta-analysis. Nutrients. 2022;14(5):952.
32.
Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res. 1997;56(1):117–24.PubMedCrossRef
33.
Al-Noshokaty TM, Mesbah NM, Abo-Elmatty DM, Abulsoud AI, Abdel-Hamed AR. Selenium nanoparticles overcomes sorafenib resistance in thioacetamide induced hepatocellular carcinoma in rats by modulation of mTOR, NF-κB pathways and LncRNA-AF085935/GPC3 axis. Life Sci. 2022;303:120675.PubMedCrossRef
34.
Zhou JN, Zhang B, Wang HY, Wang DX, Zhang MM, Zhang M, Wang XK, Fan SY, Xu YC, Zeng Q, et al. A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c-Myc Transcription Activity Inhibition in Liver Cancer. Adv Sci (Weinheim, Baden-Wurttemberg, Germany). 2022;9(22):2201166.
35.
Kim I, Choi YS, Song JH, Choi EA, Park S, Lee EJ, Rhee JK, Kim SC, Chang S. A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells. Mol Oncol. 2018;12(9):1526–39.PubMedPubMedCentralCrossRef
36.
Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy? Trends Pharmacol Sci. 2006;27(8):432–7.PubMedCrossRef
37.
Chu UB, Vorperian SK, Satyshur K, Eickstaedt K, Cozzi NV, Mavlyutov T, Hajipour AR, Ruoho AE. Noncompetitive inhibition of indolethylamine-N-methyltransferase by N, N-dimethyltryptamine and N, N-dimethylaminopropyltryptamine. Biochemistry. 2014;53(18):2956–65.PubMedCrossRef
38.
Lu SC, Mato JM. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 2012;92(4):1515–42.PubMedCrossRef
39.
Parkhitko AA, Jouandin P, Mohr SE, Perrimon N. Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species. Aging Cell. 2019;18(6):e13034.PubMedPubMedCentralCrossRef
40.
Kopantzev EP, Monastyrskaya GS, Vinogradova TV, Zinovyeva MV, Kostina MB, Filyukova OB, Tonevitsky AG, Sukhikh GT, Sverdlov ED. Differences in gene expression levels between early and later stages of human lung development are opposite to those between normal lung tissue and non-small lung cell carcinoma. Lung Cancer (Amsterdam, Netherlands). 2008;62(1):23–34.PubMedCrossRef
41.
Larkin SE, Holmes S, Cree IA, Walker T, Basketter V, Bickers B, Harris S, Garbis SD, Townsend PA, Aukim-Hastie C. Identification of markers of prostate cancer progression using candidate gene expression. Br J Cancer. 2012;106(1):157–65.PubMedCrossRef
42.
Jianfeng W, Yutao W, Jianbin B. Indolethylamine-N-Methyltransferase Inhibits Proliferation and Promotes Apoptosis of Human Prostate Cancer Cells: A Mechanistic Exploration. Front Cell Dev Biol. 2022;10:805402.PubMedPubMedCentralCrossRef
43.
Zhong S, Jeong JH, Huang C, Chen X, Dickinson SI, Dhillon J, Yang L, Luo JL. Targeting INMT and interrupting its methylation pathway for the treatment of castration resistant prostate cancer. J Exper Clin Cancer Res: CR. 2021;40(1):307.CrossRef
44.
López-Torres CD, Torres-Mena JE, Castro-Gil MP, Villa-Treviño S, Arellanes-Robledo J, Del Pozo-Yauner L, Pérez-Carreón JI. Downregulation of indolethylamine N-methyltransferase is an early event in the rat hepatocarcinogenesis and is associated with poor prognosis in hepatocellular carcinoma patients. J Gene Med. 2022;24(8):e3439.PubMedCrossRef
45.
Jiang Y, Shi X, Eagle K, Lin CY, Nakada DJB. Integrating enhancer profiling and CRISPR dropout screen revealed selenoprotein synthesis pathway as a new vulnerability in AML. Blood. 2019;134(Supplement_1):639.
46.
47.
Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18(8):525–43.PubMedPubMedCentralCrossRef
48.
49.
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–31.PubMedPubMedCentralCrossRef
50.
Ding W, Xu X, Qian Y, Xue W, Wang Y, Du J, Jin L, Tan Y. Prognostic value of tumor-infiltrating lymphocytes in hepatocellular carcinoma: A meta-analysis. Medicine. 2018;97(50):e13301.PubMedPubMedCentralCrossRef
51.
Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2012;16(7):705–43.PubMedPubMedCentralCrossRef
52.
Qin J, Huang X, Wang N, Zhou P, Zhang H, Chen Z, Liang K, Gong D, Zeng Q, Niu P, et al. Supranutritional selenium suppresses ROS-induced generation of RANKL-expressing osteoclastogenic CD4(+) T cells and ameliorates rheumatoid arthritis. Clin Transl Immunol. 2021;10(9):e1338.CrossRef
53.
Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, Wei Y, Wan Y, Wang N, Zhou M, et al. Author Correction: Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22(12):1599.PubMedCrossRef
54.
Hu Y, Feng W, Chen H, Shi H, Jiang L, Zheng X, Liu X, Zhang W, Ge Y, Liu Y, et al. Effect of selenium on thyroid autoimmunity and regulatory T cells in patients with Hashimoto’s thyroiditis: A prospective randomized-controlled trial. Clin Transl Sci. 2021;14(4):1390–402.PubMedPubMedCentralCrossRef
55.
Dehghani M, Shokrgozar N, Ramzi M, Kalani M, Golmoghaddam H, Arandi N. The impact of selenium on regulatory T cell frequency and immune checkpoint receptor expression in patients with diffuse large B cell lymphoma (DLBCL). Cancer Immunol Immunother: CII. 2021;70(10):2961–9.PubMedCrossRef
56.
MolanouriShamsi M, Chekachak S, Soudi S, Gharakhanlou R, Quinn LS, Ranjbar K, Rezaei S, Shirazi FJ, Allahmoradi B, Yazdi MH, et al. Effects of exercise training and supplementation with selenium nanoparticle on T-helper 1 and 2 and cytokine levels in tumor tissue of mice bearing the 4 T1 mammary carcinoma. Nutrition (Burbank, Los Angeles County, Calif). 2019;57:141–7.CrossRef
57.
Huang LJ, Mao XT, Li YY, Liu DD, Fan KQ, Liu RB, Wu TT, Wang HL, Zhang Y, Yang B, et al. Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn’s disease. Immunity. 2021;54(8):1728-1744.e1727.PubMedCrossRef
58.
Carlson BA, Yoo MH, Shrimali RK, Irons R, Gladyshev VN, Hatfield DL, Park JM. Role of selenium-containing proteins in T-cell and macrophage function. Proc Nutr Soc. 2010;69(3):300–10.PubMedPubMedCentralCrossRef
59.
Kumari M, Purohit MP, Pahuja R, Patnaik S, Shukla Y, Kumar P, Gupta KC. Pro-inflammatory macrophage polarization enhances the anti-cancer efficacy of self-assembled galactomannan nanoparticles entrapped with hydrazinocurcumin. Drug Deliv Transl Res. 2019;9(6):1159–88.PubMedCrossRef
60.
Zhang L, Xia H, Xia K, Liu X, Zhang X, Dai J, Zeng Z, Jia Y. Selenium Regulation of the Immune Function of Dendritic Cells in Mice Through the ERK, Akt and RhoA/ROCK Pathways. Biol Trace Elem Res. 2021;199(9):3360–70.PubMedCrossRef
61.
Sun Z, Xu Z, Wang D, Yao H, Li S. Selenium deficiency inhibits differentiation and immune function and imbalances the Th1/Th2 of dendritic cells. Metallomics: Integr Biomet Sci. 2018;10(5):759–67.CrossRef
62.
Liu C, Lai H, Chen T. Boosting Natural Killer Cell-Based Cancer Immunotherapy with Selenocystine/Transforming Growth Factor-Beta Inhibitor-Encapsulated Nanoemulsion. ACS Nano. 2020;14(9):11067–82.PubMedCrossRef
63.
Pan S, Li T, Tan Y, Xu H. Selenium-containing nanoparticles synergistically enhance Pemetrexed&NK cell-based chemoimmunotherapy. Biomaterials. 2022;280:121321.PubMedCrossRef
Metadata
Title
Development and validation of a selenium metabolism regulators associated prognostic model for hepatocellular carcinoma
Authors
Huishan Sun
Junyu Long
Bangyou Zuo
Yiran Li
Yu Song
Minghang Yu
Ziyu Xun
Yanyu Wang
Xi Wang
Xinting Sang
Haitao Zhao
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10944-w

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