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

doi:10.3969/j.issn.1674-8115.2024.03.003

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (3): 312-324.doi: 10.3969/j.issn.1674-8115.2024.03.003

• 论著 · 基础研究 • 上一篇

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¹^,²(), 王晓霞³(), 李彦庆¹^,², 郑永鑫¹^,², 乌杰²^,⁴, 任猛², 贾向东², 许天祥²()

^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

收稿日期:2023-09-13 接受日期:2023-12-28 出版日期:2024-03-28 发布日期:2024-04-29
通讯作者: 许天祥 E-mail:1363166062@qq.com;xiaoxiawang_2012@163.com;122784509@qq.com
作者简介: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）
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)

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

WANG Xin¹^,²(), WANG Xiaoxia³(), LI Yanqing¹^,², ZHENG Yongxin¹^,², WU Jie²^,⁴, REN Meng², JIA Xiangdong², XU Tianxiang²()

^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

Received:2023-09-13 Accepted:2023-12-28 Online:2024-03-28 Published:2024-04-29
Contact: XU Tianxiang E-mail:1363166062@qq.com;xiaoxiawang_2012@163.com;122784509@qq.com
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)

摘要/Abstract

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

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

中图分类号:

R734.2

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.

WANG Xin, WANG Xiaoxia, LI Yanqing, ZHENG Yongxin, WU Jie, REN Meng, JIA Xiangdong, XU Tianxiang. Expression and clinical significance of geranylgeranyl diphosphate synthase1 (GGPS1) in lung squamous cell carcinoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(3): 312-324.

图/表 13

图1 GGPS1 在泛癌中的表达Note： ACC—adrenocortical carcinoma; BLCA—bladder urothelial carcinoma; BRCA—breast invasive carcinoma; CESC—cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL—cholangiocarcinoma; COAD—colon adenocarcinoma; DLBC—diffuse large B cell lymphoma; ESCA—esophageal carcinoma; GBM—glioblastoma multiforme; HNSC—head and neck squamous cell carcinoma; KICH—kidney chromophobe; KIRC—kidney renal clear cell carcinoma; KIRP—kidney renal papillary cell carcinoma; LAML—acute myeloid leukemia; LGG—brain lower grade glioma; LIHC—liver hepatocellular carcinoma; LUAD—lung adenocarcinoma; LUSC—lung squamous cell carcinoma; OV—ovarian serous cystadenocarcinoma; PAAD—pancreatic adenocarcinoma; PCPG—pheochromocytoma and paraganglioma; PRAD—prostate adenocarcinoma; READ—rectum adenocarcinoma; SARC—sarcoma; SKCM—skin cutaneous melanoma; STAD—stomach adenocarcinoma; THCA—thyroid carcinoma; THYM—thymoma; UCEC—uterine corpus endometrial carcinoma; UCS—uterine carcinosarcoma. Blue represents normal tissue and red represents tumor tissue. **P<0.01, ***P<0.001.

Fig 1 The expression of GGPS1 in pan-carcinoma

图2 UCSC Xena和UALCAN数据库中 GGPS1 在LUSC和癌旁正常组织的差异表达Note： A. GGPS1 expression in the tumors and normal tissues. B. GGPS1 expression in the 49 pairs of tumors and normal tissues. C. The expression of GGPS1 in LUSC in UALCAN database. ①P=0.000, ②P=0.003.

Fig 2 Differential expression of GGPS1 in the LUSC and paracancerous normal tissues in the UCSC Xena and UALCAN databases

图3 UALCAN数据库中 GGPS1 表达与LUSC患者临床病理特征的关系Note： A. Comparison of GGPS1 expression between different stages of patients. B. Comparison of GGPS1 expression between different N stages of patients. ①P=0.000, ②P=0.001, ③P=0.027.

Fig 3 Relationship between GGPS1 expression and clinicopathological characteristics of LUSC patients in UALCAN database

图4 LinkedOmics数据库中 GGPS1 表达与LUSC患者临床病理特征的关系Note： A. Expression level of GGPS1 of different ages. B. Expression level of GGPS1 in different tumor purity. C. Expression level of GGPS1 in different pathological grades. D. Expression level of GGPS1 in different T stages. E. Expression level of GGPS1 in different N stages. F. Expression level of GGPS1 in different M stages.

Fig 4 Relationship between GGPS1 expression and clinicopathological characteristics of LUSC patients in LinkedOmics database

图5 Kaplan-Meier Plotter 数据库中 GGPS1 表达与LUSC患者预后的关系Note： A. Relationship between GGPS1 expression and overall survival. B. Relationship between GGPS1 expression and post progression survival.

Fig 5 Relationship between GGPS1 expression and prognosis of LUSC patients in Kaplan-Meier Plotter database

图6 LUSC 患者LASSO回归分析与列线图的建立Note： A. Screening of candidate genes by LASSO-COX analysis. B. Relationship between risk score and overall survival. C. Effect of risk scores on survival outcomes. D. A nomogram for assessing the survival probability of 1-,2-, 3-,5- and 10-year for LUSC. E. Calibration curve of the prognostic risk model.

Fig 6 LASSO regression analyses and establishment of nomogram for LUSC patients

图7 GGPS1的PPI网络及GO、KEGG分析Note： A/B. PPI network analysis of STRING database (A) and GeneMANIA database (B). C/D. Bubble plot of GO enrichment analysis (C) and KEGG enrichment analysis (D). MVD—mevalonate diphosphate decarboxylase; DHDDS—dehydrodolichyl diphosphate synthase subunit; PDSS1—decaprenyl diphosphate dynthase subunit 1; FNTA—farnesyltransferase, CAAX box, α; FNTB—farnesyltransferase, CAAX box, β; MVK—mevalonate kinase; PARS2—prolyl-TRNA synthetase 2, mitochondrial; SNRPE—small nuclear ribonucleoprotein polypeptide E; OMA1—OMA1 zinc metallopeptidase; HMBS—hydroxymethylbilane synthase; ZMPSTE24—zinc metallopeptidase STE24; GCH1—GTP cyclohydrolase 1; NFYA—nuclear transcription factor Y subunit α; NFYB—nuclear transcription factor Y subunit β; NFYC—nuclear transcription factor Y subunit γ; SP1—Sp1 transcription factor; NDUFAF6—NADH:ubiquinone oxidoreductase complex assembly factor 6; KCTD5—potassium channel tetramerization domain containing 5; TUSC1—tumor suppressor candidate 1.

Fig 7 PPI network and GO and KEGG analysis of GGPS1

图8 LUSC及癌旁组织中GGPS1免疫组化染色(×200)Note： A/B. High expression (A) and low expression (B) of GGPS1 in cancer tissues. C/D. High expression (A) and low expression (B) of GGPS1 in adjacent tissues.

Fig 8 Immunohistochemical staining of GGPS1 in LUSC and adjacent tissues (×200)

表1 GGPS1在中LUSC组织与癌旁正常肺组织表达差异

Tab 1 Differential expression of GGPS1 in LUSC and adjacent normal lung tissues

Expression	LUSC (n=90)	Normal (n=90)	χ²	P value
GGPS1/n(%)			8.193	0.004
Low	42 (46.7)	61 (67.8)
High	48 (53.3)	29 (32.2)

表2 GGPS1表达水平与LUSC临床病理特征的相关性

Tab 2 Correlation between GGPS1 expression level and clinicopathological characteristics of LUSC

Characteristic	Total/n	GGPS1/n(%)		χ² value	P value
Characteristic	Total/n	Low expression	High expression	χ² value	P value
Gender				1.213	0.271
Male	84	41 (48.8)	43 (51.2)
Female	6	1 (16.7)	5 (83.3)
Age				0.003	0.955
≤64 years old	49	23 (46.9)	26 (53.1)
>64 years old	41	19 (46.3)	22 (53.7)
History of smoking				2.691	0.101
No	41	23 (56.1)	18 (43.9)
Yes	49	19 (38.8)	30 (61.2)
Tumor location				0.984	0.321
Left	40	21 (52.5)	19 (47.5)
Right	50	21 (42.0)	29 (58.0)
Tumor size				10.247	0.001
≤3 cm	26	19 (73.1)	7 (26.9)
>3 cm	64	23 (35.9)	41 (64.1)
Lymph node metastasis				7.626	0.006
No	46	28 (60.9)	18 (39.1)
Yes	44	14 (31.8)	30 (68.2)
TNM stage				8.935	0.003
Ⅰ~Ⅱ	47	29 (61.7)	18 (38.3)
Ⅲ~Ⅳ	43	13 (30.2)	30 (69.8)

图9 GGPS1不同表达水平LUSC患者OS的生存曲线

Fig 9 Survival curves of OS in LUSC patients with different GGPS1 expression levels

表3 影响LUSC患者OS的Cox回归模型

Tab 3 Cox regression model affecting OS of LUSC patients

Variable	Univariate analysis			Multivariate analysis
Variable	HR	95%CI	P value	HR	95%CI	P value
Gender	0.652	0.232‒1.837	0.419
Age	0.631	0.336‒1.185	0.152
History of smoking	2.054	1.054‒4.003	0.034	2.045	1.024‒4.086	0.043
Tumor location	0.878	0.468‒1.648	0.686
Tumor size	2.751	1.151‒6.574	0.023	1.621	0.639‒4.114	0.309
Lymph node metastasis	3.116	1.577‒6.157	0.001	4.039	1.257‒12.983	0.019
TNM stage	2.399	1.246‒4.619	0.009	0.473	0.147‒1.523	0.210
GGPS1 expression	3.872	1.834‒8.176	0.000	2.867	1.316‒6.242	0.008

图10 Cox回归分析森林图

Fig 10 Forest plot of Cox regression analysisNote: A. Univariate Cox regression analysis tree diagram. B. Multivariate Cox regression analysis tree diagram. HR>1 indicates disadvantageous factors.

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