NCAPH在肺鳞癌中表达的临床意义及与免疫微环境浸润的关系

doi:10.3877/cma.j.issn.1674-0785.2023.04.014

目的

分析非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H（NCAPH）在肺鳞癌（LUSC）中的表达及其与临床特征、预后、免疫细浸润的关系，并预测其生物学功能。

方法

根据癌症基因组图谱（TCGA）数据库中LUSC基因表达数据及临床信息，分析NCAPH在肿瘤组织和正常组织中的表达差异，分析NCAPH表达与LUSC临床特征的关系；并通过Kaplan-Meier法和COX回归分析NCAPH表达与LUSC患者预后的关系。通过GSEA富集分析预测NCAPH在LUSC中可能参与的信号通路。采用CIBERSORT反卷积算法分析NCAPH表达与免疫浸润的关系。

结果

NCAPH在LUSC肿瘤组织中高表达（P＜0.05），且与年龄、性别、临床分期、肿瘤大小、淋巴结转移及远处转移相关；生存分析表明NCAPH高表达组患者比低表达组患者预后差（P＜0.05），且NCAPH表达是LUSC的独立预后因素（HR=0.522，95%CI：0.358~0.762，P＜0.001）。富集分析结果表明NCAPH主要富集一系列生物学相关的过程，如细胞周期、DNA复制等。免疫浸润分析结果显示，LUSC肿瘤组织中NCAPH的高表达与幼稚B细胞、M1样巨噬细胞、活化NK细胞、滤泡辅助性T细胞的浸润成正相关（P＜0.05），与记忆B细胞、活化树突状细胞、静息NK细胞及活化记忆CD4⁺T细胞的浸润成负相关（P＜0.05）。

结论

NCAPH在LUSC中呈高表达状态，其高表达与LUSC患者的不良预后相关，且其表达水平与免疫浸润具有相关性。NCAPH有望成为LUSC诊断和预后相关的新标志物。

关键词: 肺鳞癌, NCAPH, 预后, 免疫浸润, 富集分析

Objective

To detect the expression of non-SMC condensin I complex subunit H (NCAPH) in lung squamous cell carcinoma (LUSC), to explore its relationship with clinical features, prognosis, and immune fine infiltration, and to predict its biological function.

Methods

NCAPH expression differences in tumor tissues and normal tissues, and the association between NCAPH expression and LUSC clinical characteristics were examined based on the LUSC gene expression data and clinical information in the Cancer Genome Atlas (TCGA) database. By using the Kaplan-Meier technique and COX regression, the association between NCAPH expression and the prognosis of LUSC patients was analyzed. Gene set enrichment analysis (GSEA) was used to identifty the potential signaling pathways involving NCAPH in LUSC. The CIBERSORT deconvolution technique was used to examine the association between NCAPH expression and immune cell infiltration.

Results

NCAPH expression was significantly upregulated in LUSC (P＜0.05), and it was correlated with age, gender, stage, tumor size, lymph node metastasis, and distant metastasis. Survival analysis revealed that patients with high NCAPH expression had a worse prognosis than those with low expression (P＜0.05), and NCAPH expression was an independent risk factor for the prognosis of LUSC (hazard ratio=0.522, 95% confidence interval (CI): 0.358-0.762, P＜0.001). GSEA enrichment analysis showed that NCAPH was mainly enriched a series of biologically related processes, such as cell cycle and DNA replication. Immuno-infiltration analysis showed that high expression of NCAPH in LUSC tumor tissues was positively correlated with the levels of naive B cells, M1 macrophages, activated NK cells, and follicular helper T cells (P＜0.05), and negatively correlated with the levels of memory B cells, activated dendritic cells, dormant NK cells, and activated CD4+ memory T cells (P＜0.05).

Conclusion

NCAPH is highly expressed in LUSC, and its high expression is associated with both immune infiltration and the poor prognosis of LUSC patients. NCAPH is anticipated to emerge as a potential diagnostic and prognostic marker for LUSC.

Key words: Lung squamous cell carcinoma, NCAPH, Prognosis, Immune infiltration, Gene set enrichment analysis

图1 NCAPH在肿瘤组织与正常组织中的差异表达。图a为NCAPH在不同肿瘤组织和正常组织中的表达；图b为NCAPH表达在LUSC肿瘤组织与正常组织中的差异；图c为NCAPH表达在LUSC配对肿瘤组织与正常组织中的差异；图d为NCAPH诊断LUSC的ROC曲线注：NCAPH为非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H；LUSC为肺鳞癌

图2 NCAPH表达与LUSC临床特征的相关性。图a为年龄；图b为性别；图c为临床分期；图d为肿瘤大小；图e为淋巴结有无转移；图f为有无远处转移注：NCAPH为非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H；LUSC为肺鳞癌

图3 NCAPH表达与LUSC患者预后的关系。图a为NCAPH高、低表达组生存曲线；图b为NCAPH多因素COX回归分析注：NCAPH为非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H；LUSC为肺鳞癌

表1 影响肺鳞癌患者预后的单因素及多因素Cox回归分析

临床特征	单因素		多因素
临床特征	HR（95%CI）	P值	HR（95%CI）	P值
年龄	0.727（0.528~1.000）	0.050	0.713（0.518~0.982）	0.038
性别	1.360（0.944~1.958）	0.099	1.302（0.902~1.880）	0.159
TNM分期	1.392（0.974-1.989）	0.070
T分期	1.412（0.973~2.048）	0.069	1.514（1.039~2.206）	0.031
N分期	1.062（0.780~1.444）	0.704
M分期	2.432（0.898~6.591）	0.080	2.423（0.887~6.617）	0.084
NCAPH	0.545（0.375~0.791）	0.001	0.522（0.358~0.762）	＜0.001

表1 影响肺鳞癌患者预后的单因素及多因素Cox回归分析

临床特征	单因素		多因素
临床特征	HR（95%CI）	P值	HR（95%CI）	P值
年龄	0.727（0.528~1.000）	0.050	0.713（0.518~0.982）	0.038
性别	1.360（0.944~1.958）	0.099	1.302（0.902~1.880）	0.159
TNM分期	1.392（0.974-1.989）	0.070
T分期	1.412（0.973~2.048）	0.069	1.514（1.039~2.206）	0.031
N分期	1.062（0.780~1.444）	0.704
M分期	2.432（0.898~6.591）	0.080	2.423（0.887~6.617）	0.084
NCAPH	0.545（0.375~0.791）	0.001	0.522（0.358~0.762）	＜0.001

图4 NCAPH基因GSEA富集结果注：NCAPH为非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H；GSEA为基因富集分析

图5 LUSC患者中NCAPH高低表达组免疫浸润情况。图a为22种免疫细胞占比的柱状图；图b为各种免疫细胞构成比箱型图；图c为各种免疫细胞分布图；图d为每种免疫细胞占比相关性热图注：NCAPH为非染色体结构维持蛋白凝缩蛋白复合体Ⅰ亚单位H；LUSC为肺鳞癌

图6 NCAPH表达与免疫细胞的相关性

1	Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries [J]. CA Cancer J Clin, 2021, 71(3): 209-249.
2	LI Y, GU J, XU F, et al. Transcriptomic and functional network features of lung squamous cell carcinoma through integrative analysis of GEO and TCGA data [J]. Sci Rep, 2018, 8(1): 15834.
3	Wang X, Ren X, Liu W, et al. Role of downregulated ADARB1 in lung squamous cell carcinoma [J]. Mol Med Rep, 2020, 21(3): 1517-1526.
4	Sun Y, Wang X, Wen H, et al. Expression and clinical significance of the NCAPH, AGGF1, and FOXC2 proteins in serous ovarian cancer [J]. Cancer Manag Res, 2021, 13: 7253-7262.
5	Lu H, Shi C, Wang S, Yang C, et al. Identification of NCAPH as a biomarker for prognosis of breast cancer [J]. Mol Biol Rep, 2020, 47(10): 7831-7842.
6	Wang M, Qiao X, Cooper T, et al. HPV E7-mediated NCAPH ectopic expression regulates the carcinogenesis of cervical carcinoma via PI3K/AKT/SGK pathway [J]. Cell Death Dis, 2020, 11(12): 1049.
7	Zhou W, Hu J, Zhao J. Non-SMC condensin I complex subunit H (NCAPH), a regulator of cell cycle, predicts poor prognosis in lung adenocarcinoma patients: a study mainly based on TCGA and GEO database [J]. Transl Cancer Res, 2020, 9(12): 7572-7587.
8	Kim B, Kim SW, Lim JY, et al. NCAPH is required for proliferation, migration and invasion of non-small-cell lung cancer cells [J]. Anticancer Res, 2020, 40(6): 3239-3246.
9	李军强, 杨志良, 王彦, 等. NCAPH基因敲除对胰腺癌细胞增殖迁移及侵袭能力的影响 [J]. 解放军医学杂志, 2022, 47(6): 555-560.
10	Newman AM, Liu CL, Green MR, et al. Robust enumeration of cell subsets from tissue expression profiles [J]. Nat Methods, 2015, 12(5): 453-457.
11	Meng Q, Dong Y, Tao H, et al. ALK-rearranged squamous cell carcinoma of the lung [J]. Thorac Cancer, 2021, 12(7): 1106-1114.
12	Yan JQ, Liu M, Ma YL, et al. Development of alternative splicing signature in lung squamous cell carcinoma [J]. Med Oncol, 2021, 38(5): 49.
13	Cheng Z, Yu C, Cui S, et al. circTP63 functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1 [J]. Nat Commun, 2019, 10(1): 3200.
14	Shimomura H, Sasahira T, Nakashima C, et al. Non-SMC condensin I Complex Subunit H (NCAPH) Is associated with lymphangiogenesis and drug resistance in oral squamous cell carcinoma [J]. J Clin Med, 2019, 9(1): 72.
15	Sun C, Huang S, Wang H, et al. Non-SMC condensin I complex subunit H enhances proliferation, migration, and invasion of hepatocellular carcinoma [J]. Mol Carcinog, 2019, 58(12): 2266-2275.
16	林家香. NCAPH在宫颈癌发生发展中的作用及其机制的初步研究 [D]. 济南: 山东大学, 2017.
17	Xiong Q, Fan S, Duan L, et al. NCAPH is negatively associated with Mcl-1 in non-small cell lung cancer [J]. Mol Med Rep, 2020, 22(4): 2916-2924.
18	Zhan SJ, Liu B, Linghu H. Identifying genes as potential prognostic indicators in patients with serous ovarian cancer resistant to carboplatin using integrated bioinformatics analysis [J]. Oncol Rep, 2018, 39(6): 2653-2663.
19	Yin L, Jiang LP, Shen QS, et al. NCAPH plays important roles in human colon cancer [J]. Cell Death Dis, 2017, 8(3): e2680.
20	Li B, Xiao Q, Shan L, et al. NCAPH promotes cell proliferation and inhibits cell apoptosis of bladder cancer cells through MEK/ERK signaling pathway [J]. Cell Cycle, 2022, 21(4): 427-438.
21	Wang HZ, Yang SH, Li GY, et al. Subunits of human condensins are potential therapeutic targets for cancers [J]. Cell Div, 2018, 13: 2.
22	Italiani P, Boraschi D. From Monocytes to M1/M2 Macrophages: phenotypical vs functional differentiation [J]. Front Immunol, 2014, 5: 514.
23	Mantovani A, Biswas SK, Galdiero MR, et al. Macrophage plasticity and polarization in tissue repair and remodelling [J]. J Pathol, 2013, 229(2): 176-185.
24	汪鹏, 仇建南, 王忠夏, 等. 肝癌微环境中肿瘤相关巨噬细胞的研究进展 [J]. 临床肝胆病杂志, 2023, 39(05): 1212-8.
25	Cheng H, Wang Z, Fu L, et al. Macrophage Polarization in the Development and Progression of Ovarian Cancers: An Overview [J]. Front Oncol, 2019, 9: 421.
26	Viana IMO, Roussel S, Defrêne J, et al. Innate and adaptive immune responses toward nanomedicines [J]. Acta Pharm Sin B, 2021, 11(4): 852-870.
27	张淑芬, 曾颖萍, 孟廷廷, 等. NK细胞的抗肿瘤机制及其在肿瘤靶向治疗中的应用研究进展 [J]. 药学学报, 2022, 57(1): 122-33+277.
28	Frese-Schaper M, Keil A, Yagita H, et al. Influence of natural killer cells and perforin-mediated cytolysis on the development of chemically induced lung cancer in A/J mice [J]. Cancer Immunol Immunother, 2014, 63(6): 571-580.
29	牛德红, 李岩. 辅助性T细胞与肺癌免疫 [J]. 国外医学(肿瘤学分册), 2005, (1): 56-8.
30	Gutiérrez-Melo N, Baumjohann D. T follicular helper cells in cancer [J]. Trends Cancer, 2023, 9(4): 309-325.
31	Balan S, Saxena M, Bhardwaj N. Dendritic cell subsets and locations [J]. Int Rev Cell Mol Biol, 2019, 348: 1-68.
32	李洋, 郭锋杰, 孟旭英, 等. 树突状细胞外泌体与肺癌免疫治疗 [J]. 天津医科大学学报, 2023, 29(1): 94-97.
33	Schneider T, Hoffmann H, Dienemann H, et al. Non-small cell lung cancer induces an immunosuppressive phenotype of dendritic cells in tumor microenvironment by upregulating B7-H3 [J]. J Thorac Oncol, 2011, 6(7): 1162-1168.
34	Borst J, Ahrends T, Bąbała N, et al. CD4(+) T cell help in cancer immunology and immunotherapy [J]. Nat Rev Immunol, 2018, 18(10): 635-647.

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NCAPH expression in lung squamous cell carcinoma: clinical significance and relationship with immune microenvironment infiltration

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NCAPH expression in lung squamous cell carcinoma: clinical significance and relationship with immune microenvironment infiltration