上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2024 , Vol. 44 >Issue 3: 312 - 324

DOI: https://doi.org/10.3969/j.issn.1674-8115.2024.03.003

论著 · 基础研究

香叶基香叶基焦磷酸合成酶在肺鳞状细胞癌中的表达及临床意义

  • 王鑫 ,
  • 王晓霞 ,
  • 李彦庆 ,
  • 郑永鑫 ,
  • 乌杰 ,
  • 任猛 ,
  • 贾向东 ,
  • 许天祥
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  • 1.内蒙古科技大学包头医学院研究生院，包头 014060
    2.内蒙古自治区人民医院腹部肿瘤外科，呼和浩特 010017
    3.内蒙古自治区人民医院重症医学科，呼和浩特 010017
    4.内蒙古医科大学研究生院，呼和浩特 010000
王　鑫（1996—），男，硕士生；电子信箱：1363166062@qq.com
王晓霞（1983—），女，主任医师，博士；电子信箱：xiaoxiawang_2012@163.com。第一联系人：（王鑫、王晓霞并列第一作者）
许天祥，电子信箱：122784509@qq.com。

收稿日期: 2023-09-13

  录用日期: 2023-12-28

  网络出版日期: 2024-03-28

基金资助

内蒙古自治区自然科学基金(2023LHMS08052);内蒙古自治区人民医院博士科研启动基金(2020BS06);内蒙古自治区卫生健康科技计划项目(202201012);内蒙古自治区人民医院院内基金(2020YN06);内蒙古医科大学联合项目(YKD2022LH015);内蒙古医学科学院公立医院科研联合基金科技项目(2023GLLH0012)

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Expression and clinical significance of geranylgeranyl diphosphate synthase1 (GGPS1) in lung squamous cell carcinoma

  • Xin WANG ,
  • Xiaoxia WANG ,
  • Yanqing LI ,
  • Yongxin ZHENG ,
  • Jie WU ,
  • Meng REN ,
  • Xiangdong JIA ,
  • Tianxiang XU
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  • 1.Graduate School of Baotou Medical College, Inner Mongolia University of Science & Technology, Baotou 014060, China
    2.Abdominal Tumor Surgery, Inner Mongolia People′s Hospital, Hohhot 010017, China
    3.Critical Care Medicine, Inner Mongolia People′s Hospital, Hohhot 010017, China
    4.Graduate School of Inner Mongolia Medical University, Hohhot 010000, China
XU Tianxiang, E-mail: 122784509@qq.com.

Received date: 2023-09-13

  Accepted date: 2023-12-28

  Online published: 2024-03-28

Supported by

Natural Science Foundation of Inner Mongolia Autonomous Region(2023LHMS08052);Scientific Research Start-up Fund for Doctoral of Inner Mongolia People′s Hospital(2020BS06);Health Science and Technology Planning Project of Inner Mongolia Autonomous Region(202201012);In-Hospital Fund of Inner Mongolia People′s Hospital(2020YN06);Joint project of Inner Mongolia Medical University(YKD2022LH015);Joint Scientific Research Foundation of Public Hospital of Inner Mongolia Academy of Medical Sciences(2023GLLH0012)

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摘要

目的·利用生物信息学和免疫组织化学法探究在肺鳞状细胞癌（lung squamous cell carcinoma，LUSC）组织中香叶基香叶基焦磷酸合成酶（geranylgeranyl diphosphate synthase 1，GGPS1）的表达及其临床意义。方法·首先从UCSC Xena平台下载LUSC组织与配对正常组织的转录组数据，使用R语言进行数据标准化和差异表达分析，并利用UALCAN数据库进行验证；采用UALCAN和LinkedOmics数据库分析LUSC患者中GGPS1表达与临床病理特征关系；利用Kaplan-Meier Plotter数据库探究LUSC患者GGPS1表达对预后的影响。应用最小绝对收缩和选择算子（least absolute shrinkage and selection operator，LASSO）回归分析筛选基因相关系数及风险评分。通过列线图和校正曲线评价GGPS1对LUSC的诊断价值。采用STRING、GeneMANIA数据库构建GGPS1蛋白质相互作用（protein-protein interaction，PPI）网络。运用R语言挑选与GGPS1相关差异基因，并进行基因本体论（Gene Ontology，GO）和京都基因和基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）富集分析。采用免疫组织化学法检测LUSC患者GGPS1表达情况，并分析其与临床病理特征和预后的相关性。结果·通过TIMER2.0数据库检索到GGPS1在多数肿瘤中表达均升高，且在LUSC中呈高表达。UCSC Xena、UALCAN数据库中GGPS1在LUSC的表达高于癌旁组织（均P<0.05）。UALCAN和LinkedOmics数据库发现GGPS1在指标分期较晚患者中的表达水平更高，且Kaplan-Meier Plotter数据库显示LUSC患者GGPS1高表达总生存期（overall survival，OS）较短（P<0.05）。基于LASSO回归评估LUSC患者有较好的风险预测效能。构建LUSC患者的个体化预测模型具有最佳预测准确度。GO、KEGG结果显示，GGPS1相关基因主要与蛋白质代谢、调节脂质和胆固醇代谢过程、尼古丁成瘾、磷脂酰肌醇3激酶（phosphatidylinositol3-kinase，PI3K）/蛋白激酶B（protein kinase B，AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）、过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptors，PPAR）信号通路等有关。GGPS1的代谢功能可能促进肿瘤发生。免疫组化结果提示GGPS1主要定位于细胞质中，且LUSC组织中表达高于癌旁组织（P<0.05），GGPS1高表达与LUSC患者肿瘤大小、淋巴结转移和TNM分期有关（均P<0.05），且GGPS1表达高的患者OS明显短于低表达者（P=0.000）。多因素Cox回归分析提示GGPS1可作为LUSC的独立预后因素。结论·相较于正常肺组织，GGPS1在LUSC中表达显著升高，尤其在肿瘤体积较大、淋巴结转移阳性及晚期的患者中表达升高更明显；且GGPS1过表达是LUSC患者预后差的独立预测因子。GGPS1有望成为新的LUSC诊治和预防的分子靶点。

关键词： 香叶基香叶基焦磷酸合成酶; 肺鳞状细胞癌; 生物信息学; 免疫组织化学; 临床意义

本文引用格式

王鑫 , 王晓霞 , 李彦庆 , 郑永鑫 , 乌杰 , 任猛 , 贾向东 , 许天祥 . 香叶基香叶基焦磷酸合成酶在肺鳞状细胞癌中的表达及临床意义[J]. 上海交通大学学报（医学版）, 2024 , 44(3) : 312 -324 . DOI: 10.3969/j.issn.1674-8115.2024.03.003

Abstract

Objective ·To investigate the expression and clinical significance of geranylgeranyl diphosphate synthase1 (GGPS1) in lung squamous cell carcinoma (LUSC) by bioinformatics and immunohistochemistry. Methods ·Firstly, the transcriptome data of LUSC tissues and paired normal tissues were downloaded from UCSC Xena platform. The data were standardized and differentially expressed by R language, and verified by UALCAN database. UALCAN and LinkedOmics databases were used to analyze the relationship between GGPS1 expression and clinicopathological features in LUSC patients. The Kaplan-Meier Plotter database was used to explore the effect of GGPS1 expression on prognosis in LUSC patients. The least absolute shrinkage and selection operator (LASSO) regression analyses were applied to screen gene correlation coefficients and risk scores. The diagnostic value of GGPS1 for LUSC was evaluated by nomogram and calibration curve. The protein-protein interaction (PPI) network of GGPS1 was constructed by using STRING and GeneMANIA databases. R language was used to select the differential genes related to GGPS1, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed. The expression of GGPS1 in LUSC patients was detected by immunohistochemistry, and its correlation with clinicopathological features and prognosis was analyzed. Results ·Through the TIMER2.0 database, it was found that GGPS1 expression was increased in most tumors and was highly expressed in LUSC. The expression of GGPS1 in LUSC was higher than that in adjacent tissues in UCSC Xena and UALCAN databases (both P<0.05). It was found that the expression level of GGPS1 was higher in patients with late stage in UALCAN and LinkedOmics databases, and the overall survival (OS) of LUSC patients with high expression of GGPS1 was shorter (P<0.05) in the Kaplan-Meier Plotter database. Assessment of LUSC patients based on LASSO regression had good risk prediction efficacy. Constructing an individualised prediction model for LUSC patients has the best prediction accuracy. The results of GO and KEGG showed that GGPS1-related genes were mainly related to protein metabolism, regulation of lipid and cholesterol metabolism, nicotine addiction, phosphatidylinositol3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), peroxisome proliferator-activated receptors (PPAR) signaling pathway and so on. The metabolic function of GGPS1 may promote tumorigenesis. The results of immunohistochemistry showed that GGPS1 was mainly located in the cytoplasm, and the expression of GGPS1 in LUSC tissues was higher than that in adjacent tissues (P<0.05). The high expression of GGPS1 was related to tumor size, lymph node metastasis and TNM stage of LUSC patients (all P<0.05), and the OS of patients with high expression of GGPS1 was significantly shorter than that of patients with low expression (P=0.000). Multivariate Cox regression analysis suggested that GGPS 1 could be used as an independent prognostic factor for LUSC. Conclusion ·Compared with normal lung tissue, the expression of GGPS1 in LUSC is significantly increased, especially in patients with large tumor volume, positive lymph node metastasis and advanced stage. GGPS1 overexpression is an independent predictor of poor prognosis in LUSC patients. GGPS1 is expected to become a new molecular target for the diagnosis, treatment and prevention of LUSC.

Key words： geranylgeranyl diphosphate synthase 1 (GGPS1); lung squamous cell carcinoma (LUSC); bioinformatics; immunohistochemistry; clinical significance

参考文献

1 SUNG H, FERLAY J, SIEGEL R L, 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 国家卫生健康委办公厅. 原发性肺癌诊疗指南(2022年版)[J]. 协和医学杂志, 2022, 13(4): 549-570.
2 General Office of National Health Commission. Guidelines for the diagnosis and treatment of primary lung cancer (2022 edition)[J]. Union Medical Journal, 2022, 13(4): 549-570.
3 LAZZARI C, KARACHALIOU N, GREGORC V, et al. Second-line therapy of squamous non-small cell lung cancer: an evolving landscape[J]. Expert Rev Respir Med, 2017, 11(6): 469-479.
4 ERICSSON J, GREENE J M, CARTER K C, et al. Human geranylgeranyl diphosphate synthase: isolation of the cDNA, chromosomal mapping and tissue expression[J]. J Lipid Res, 1998, 39(9): 1731-1739.
5 KUZUGUCHI T, MORITA Y, SAGAMI I, et al. Human geranylgeranyl diphosphate synthase. cDNA cloning and expression[J]. J Biol Chem, 1999, 274(9): 5888-5894.
6 王鑫, 许天祥, 李彦庆等. GGPPS及其抑制剂在肿瘤中的研究进展[J]. 生命的化学, 2023, 43(6): 831-840.
6 WANG X, XU T X, LI Y Q, et al. Research progress of GGPPS and its inhibitors in tumors[J]. Chemistry of Life, 2023, 43(6): 831-840.
7 LI T W, FU J X, ZENG Z X, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells[J]. Nucleic Acids Res, 2020, 48(W1): W509-W514.
8 CHANDRASHEKAR D S, KARTHIKEYAN S K, KORLA P K, et al. UALCAN: an update to the integrated cancer data analysis platform[J]. Neoplasia, 2022, 25: 18-27.
9 NAGY á, LáNCZKY A, MENYHáRT O, et al. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets[J]. Sci Rep, 2018, 8(1): 9227.
10 SZKLARCZYK D, KIRSCH R, KOUTROULI M, et al. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest[J]. Nucleic Acids Res, 2023, 51(D1): D638-D646.
11 FRANZ M, RODRIGUEZ H, LOPES C, et al. GeneMANIA update 2018[J]. Nucleic Acids Res, 2018, 46(W1): W60-W64.
12 BADE B C, DELA CRUZ C S. Lung cancer 2020: epidemiology, etiology, and prevention[J]. Clin Chest Med, 2020, 41(1): 1-24.
13 MANASWIYOUNGKUL P, DE ARAUJO E D, GUNNING P T. Targeting prenylation inhibition through the mevalonate pathway[J]. RSC Med Chem, 2020, 11(1): 51-71.
14 KAIYRZHANOV R, PERRY L, ROCCA C, et al. GGPS1-associated muscular dystrophy with and without hearing loss[J]. Ann Clin Transl Neurol, 2022, 9(9): 1465-1474.
15 YU D C, LIU J, CHEN J, et al. GGPPS1 predicts the biological character of hepatocellular carcinoma in patients with cirrhosis[J]. BMC Cancer, 2014, 14: 248.
16 ZHAO D D, YUAN J, CHENG Q, et al. Evidence for a role of geranylgeranylation in renal angiomyolipoma and renal epithelioid angiomyolipoma[J]. Oncol Lett, 2019, 17(2): 1523-1530.
17 WEISSENRIEDER J S, REILLY J E, NEIGHBORS J D, et al. Inhibiting geranylgeranyl diphosphate synthesis reduces nuclear androgen receptor signaling and neuroendocrine differentiation in prostate cancer cell models[J]. Prostate, 2019, 79(1): 21-30.
18 HUANG K, HAN L, XU H M, et al. The prognostic role and metabolic function of GGPS1 in oral squamous cell carcinoma[J]. Front Mol Biosci, 2023, 10: 1109403.
19 HANEY S L, VARNEY M L, CHHONKER Y S, et al. Inhibition of geranylgeranyl diphosphate synthase is a novel therapeutic strategy for pancreatic ductal adenocarcinoma[J]. Oncogene, 2019, 38(26): 5308-5320.
20 HANEY S L, VARNEY M L, WILLIAMS J T, et al. Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma[J]. Exp Hematol Oncol, 2022, 11(1): 5.
21 HANEY S L, FENG D, CHHONKER Y S, et al. Evaluation of geranylgeranyl diphosphate synthase inhibition as a novel strategy for the treatment of osteosarcoma and Ewing sarcoma[J]. Drug Dev Res, 2023, 84(1): 62-74.
22 WANG X X, XU W J, ZHAN P, et al. Overexpression of geranylgeranyl diphosphate synthase contributes to tumour metastasis and correlates with poor prognosis of lung adenocarcinoma[J]. J Cell Mol Med, 2018, 22(4): 2177-2189.
23 BIAN X L, LIU R, MENG Y, et al. Lipid metabolism and cancer[J]. J Exp Med, 2021, 218(1): e20201606.
24 ZHANG C J, ZHU N, LI H F, et al. New dawn for cancer cell death: emerging role of lipid metabolism[J]. Mol Metab, 2022, 63: 101529.
25 胡婵婵, 范毅, 徐源, 等. 脂质代谢在肺癌发生发展及诊疗领域中的研究进展[J]. 上海交通大学学报(医学版), 2022, 42(12): 1766-1771.
25 HU C C, FAN Y, XU Y, et al. Lipid metabolism and lung cancer: emerging roles in occurrence, progression, diagnosis and treatment[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(12): 1766-1771.
26 ERSHOV P, KALUZHSKIY L, MEZENTSEV Y, et al. Enzymes in the cholesterol synthesis pathway: interactomics in the cancer context[J]. Biomedicines, 2021, 9(8): 895.
27 XU H, WANG Q S, SUN Q, et al. In type 2 diabetes induced by cigarette smoking, activation of p38 MAPK is involved in pancreatic β-cell apoptosis[J]. Environ Sci Pollut Res Int, 2018, 25(10): 9817-9827.
28 SHEN N, GONG T, WANG J D, et al. Cigarette smoke-induced pulmonary inflammatory responses are mediated by EGR-1/GGPPS/MAPK signaling[J]. Am J Pathol, 2011, 178(1): 110-118.
29 CHANG W H, LAI A G. The pan-cancer mutational landscape of the PPAR pathway reveals universal patterns of dysregulated metabolism and interactions with tumor immunity and hypoxia[J]. Ann N Y Acad Sci, 2019, 1448(1): 65-82.
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