利用数据库信息分析NAMPT与肝癌的病理特征和免疫浸润的关联性

doi:10.6040/j.issn.1671-7554.0.2022.0913

摘要/Abstract

摘要： 目的分析烟酰胺磷酸核糖转移酶(NAMPT)在肝细胞癌(HCC)中的表达,并研究其与肝癌患者病理特征及免疫浸润的关系。方法利用TIMER数据库获得NAMPT在HCC中的表达数据。通过UALCAN数据库分析NAMPT表达与血清甲胎蛋白(AFP)之间的相关性。从TCGA-LIHC中下载肝癌转录组RNA-Seq数据,提取NAMPT和免疫相关分子 mRNA表达量。利用估计算法和单样本基因集富集分析(ssGSEA),评估NAMPT高低表达组间免疫成分、基质成分的数量和免疫细胞浸润丰度及计算免疫相关分子表达有无差异;分析NAMPT表达与免疫细胞浸润的关联性。结果 TIMER数据库显示,NAMPT mRNA在HCC中的表达低于癌旁组织(P<0.05)。UALCAN数据库检测发现,NAMPT表达和血清AFP呈负向低度相关(r=-0.464, P<0.05)。基质细胞占比、免疫细胞占比和肿瘤细胞纯度在NAMPT高低表达组间存在统计学差异(P<0.05)。ssGSEA分析发现,20种免疫细胞在NAMPT高表达组中的浸润程度高于NAMPT低表达组(P<0.05)。免疫相关分子NKG2D、CD40、FAS、ELANE、PDL1、PDL2在两组中的表达差异有统计学意义(P<0.05)。TIMER数据库分析发现,NAMPT的表达与巨噬细胞(r=0.125, P=0.021)、中性粒细胞(r=0.284, P<0.001)和树突状细胞(r=0.131, P=0.016)浸润呈正向低度相关,与肿瘤纯度呈负向低度相关(r=-0.137, P=0.011)。结论 NAMPT与临床病理参数具有一定相关性,并能在一定程度反映肝癌患者免疫微环境的状态。本研究为鉴别肝癌免疫治疗获益人群提供了新的线索。

关键词: 烟酰胺磷酸核糖转移酶, 肝细胞癌, 生物信息学, 免疫浸润, 肿瘤免疫微环境

Abstract: Objective To analyze the expression profile of nicotinamide phosphoribosyltransferase(NAMPT)in hepatocellular carcinoma(HCC), and to explore the relationship between NAMPT expression and immune infiltration and clinicopathological features. Methods The expression profile of NAMPT in HCC was obtained from TIMER database. Based on UALCAN database, the correlation between NAMPT and alpha fetal protein(AFP)level was analyzed. Hepatocellular carcinoma transcriptome RNA-seq dataset was downloaded from TCGA-LIHC, and the mRNA expressions of NAMPT and immune-related molecules were extracted. The number of immune components, matrix components and the abundance of immune cell infiltration and the differences in the expression of immune-related molecules between high-NAMPT and low-NAMPT groups were evaluated using the estimation algorithm and the single sample gene set enrichment analysis(ssGSEA), respectively. Differences of above variables were compared. The relevance between NAMPT and immune cell infiltration was analyzed. Results TIMER database showed that the expression of NAMPT in HCC was lower than that in adjacent tissues(P<0.05). UALCAN database revealed that there was a negative low correlation between NAMPT expression and serum AFP level (r=-0.464, P<0.05). There were significant differences in stromal cell proportion, immune cell proportion and tumor cell purity(P<0.05)between high-NAMPT and low-NAMPT groups. ssGSEA analysis identified the infiltration levels of 20 immune cells were higher in the high-NAMPT group(P<0.05). The expressions of immune-related genes including NKG2D, CD40, FAS, ELANE,PDL1 and PDL2 were significantly different between the two groups(P<0.05). TIMER database showed NAMPT had a low positive correlation with macrophages(r=0.125, P=0.021), neutrophils(r=0.284, P<0.001), and dendritic cells(r=0.131, P=0.016), but a low negative correlation with tumor purity(r=-0.137, P=0.011). Conclusion NAMPT expression is correlated with clinicopathological features, and can reflect the status of immune microenvironment in HCC patients. Our study may provide a new clue for identifying the beneficiaries of HCC immunotherapy.

Key words: Nicotinamide phosphoribosyltransferase, Hepatocellular carcinoma, Bioinformatics, Immune infiltration, Tumor immune microenvironment

中图分类号:

R574

常晴,刘佳,曲爱林,杨咏梅. 利用数据库信息分析NAMPT与肝癌的病理特征和免疫浸润的关联性[J]. 山东大学学报 (医学版), 2023, 61(4): 26-36.

CHANG Qing, LIU Jia, QU Ailin, YANG Yongmei. Association of NAMPT with pathological features and immune infiltration of hepatocellular carcinoma using database information[J]. Journal of Shandong University (Health Sciences), 2023, 61(4): 26-36.

参考文献

[1] 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[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[2] Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features[J]. Gastroenterology, 2017, 153(3): 812-826.
[3] Vogel A, Cervantes A, Chau I, et al. Corrigendum to "Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up": [Annals of Oncology 29 suppl. 4(2018)v238-iv255] [J]. Ann Oncol, 2022, 33(6): 666.
[4] Zhao J, Zhu XC, Wu XS, et al. Identification of miR-4644 as a suitable endogenous normalizer for circulating miRNA quantification in hepatocellular carcinoma[J]. J Cancer, 2020, 11(23): 7032-7044.
[5] Hao X, Sun G, Zhang Y, et al. Targeting immune cells in the tumor microenvironment of HCC: new opportunities and challenges[J]. Front Cell Dev Biol, 2021, 9: 775462. doi: 10.3389/fcell.2021.775462.
[6] Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors[J]. Cancer Cell, 2020, 37(4): 443-455.
[7] Hanahan D. Hallmarks of cancer: new dimensions[J]. Cancer Discov, 2022, 12(1): 31-46.
[8] Moore AM, Zhou L, Cui J, et al. NAD(+)depletion by type I interferon signaling sensitizes pancreatic cancer cells to NAMPT inhibition[J]. Proc Natl Acad Sci USA, 2021, 118(8): e2012469118. doi: 10.1073/pnas.2012469118.
[9] Gasparrini M, Audrito V. NAMPT: a critical driver and therapeutic target for cancer[J]. Int J Biochem Cell Biol, 2022, 145: 106189. doi:10.1016/j.biocel.2022.103189.
[10] Lucena-Cacace A, Otero-Albiol D, Jiménez-García MP, et al. NAMPT is a potent oncogene in colon cancer progression that modulates cancer stem cell properties and resistance to therapy through sirt1 and PARP[J]. Clin Cancer Res, 2018, 24(5): 1202-1215.
[11] Lucena-Cacace A, Otero-Albiol D, Jiménez-García MP, et al. NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis[J]. Oncotarget, 2017, 8(59): 99514-99530.
[12] Franceschini N, Oosting J, Tamsma M, et al. Targeting the NAD salvage synthesis pathway as a novel therapeutic strategy for osteosarcomas with low NAPRT expression[J]. Int J Mol Sci, 2021, 22(12): 6273. doi: 10.3390/ijms22126273.
[13] Zhang H, Zhang N, Liu Y, et al. Epigenetic regulation of NAMPT by NAMPT-AS drives metastatic progression in triple-negative breast cancer[J]. Cancer Res, 2019, 79(13): 3347-3359.
[14] Audrito V, Managò A, Gaudino F, et al. NAD-biosynthetic and consuming enzymes as central players of metabolic regulation of innate and adaptive immune responses in cancer[J]. Front Immunol, 2019, 10: 1720. doi: 10.3389/fimmu.2019.01720.
[15] Guo HJ, Li HY, Chen ZH, et al. NAMPT promotes hepatitis B virus replication and liver cancer cell proliferation through the regulation of aerobic glycolysis[J]. Oncol Lett, 2021, 21(5):390.
[16] Li T, Fan J, Wang B, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells[J]. Cancer Res, 2017, 77(21): e108-e110.
[17] Chandrashekar DS, Karthikeyan SK, Korla PK, et al. UALCAN: An update to the integrated cancer data analysis platform[J]. Neoplasia, 2022, 25: 18-27. doi: 10.1016/j.neo.2022.01.001.
[18] Hilmi M, Vienot A, Rousseau B, et al. Immune therapy for liver cancers[J]. Cancers(Basel), 2019, 12(1): 77.
[19] Xing M, Wang X, Kiken RA, et al. Immunodiagnostic Biomarkers for hepatocellular carcinoma(HCC): the first step in detection and treatment[J]. Int J Mol Sci, 2021, 22(11): 6139. doi:10.3390/ijms22116139.
[20] Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III Trial[J]. J Clin Oncol, 2020, 38(3): 193-202.
[21] El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088): 2492-2502.
[22] Chowdhry S, Zanca C, Rajkumar U, et al. NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling[J]. Nature, 2019, 569(7757): 570-575.
[23] Chen H, Wang S, Zhang H, et al. Nicotinamide phosphoribosyltransferase(Nampt)in carcinogenesis: new clinical opportunities[J]. Expert Rev Anticancer Ther, 2016, 16(8): 827-838.
[24] Adya R, Tan BK, Chen J, et al. Nuclear factor-kappaB induction by visfatin in human vascular endothelial cells: its role in MMP-2/9 production and activation[J]. Diabetes Care, 2008, 31(4): 758-760.
[25] Ma R, Wu Y, Zhai Y, et al. Exogenous pyruvate represses histone gene expression and inhibits cancer cell proliferation via the NAMPT-NAD+-SIRT1 pathway[J]. Nucleic Acids Res, 2019, 47(21): 11132-11150.
[26] Guo X, Tan S, Wang T, et al. NAD(+)salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity[J]. Hepatology, 2022. doi: 10.1002/hep.32658.
[27] Deng Y, Song Z, Huang L, et al. Tumor purity as a prognosis and immunotherapy relevant feature in cervical cancer[J]. Aging(Albany NY), 2021, 13(22): 24768-24785.
[28] Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma[J]. Gut, 2017, 66(2): 342-351.
[29] Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: facts and hopes[J]. Clin Cancer Res, 2017, 23(22): 6764-6770.
[30] Park H, Jung JH, Jung MK, et al. Effects of transarterial chemoembolization on regulatory T cell and its subpopulations in patients with hepatocellular carcinoma[J]. Hepatol Int, 2020, 14(2): 249-258.
[31] Korniotis S, Saichi M, Trichot C, et al. GM-CSF-activated human dendritic cells promote Tfh1 cell polarization in a CD40-dependent manner[J]. J Cell Sci, 2022, 135(21): jcs260298. doi: 10.1242/jcs.260298.
[32] Wang Y, Wang F, Wang L, et al. NAD(+)supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells[J]. Cell Rep, 2021, 36(6): 109516. doi: 10.1016/j.celrep.2021.109516.
[33] Lv H, Lv G, Chen C, et al. NAD(+)metabolism maintains inducible PD-L1 expression to drive tumor immune evasion[J]. Cell Metab, 2021, 33(1): 110-127.
[34] Ganesh K, Stadler ZK, Cercek A, et al. Immunotherapy in colorectal cancer: rationale, challenges and potential[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(6): 361-375.

多维度评价

Viewed

Full text

Abstract

Cited

Shared

Discussed