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摘要/Abstract

摘要： 背景与目的：低密度脂蛋白受体相关蛋白8（low-density lipoprotein receptor-related protein 8，LRP8）在肝癌、肺癌、乳腺癌、结直肠癌等多种肿瘤发生中起重要作用，分析LRP8在胃癌中的表达及其意义，探讨LRP8作为胃癌生物治疗新靶点的可能性。方法：利用人类癌症基因组图谱（The Cancer Genome Atlas，TCGA）和基因表达汇编（Gene Expression Omnibus，GEO）数据库分析LRP8在胃癌组织中的表达；对胃癌中与LRP8共表达的基因进行基因本体（Gene Ontology，GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）分析；利用RNA干扰技术及细胞功能实验，测定LRP8表达对胃癌细胞系AGS增殖和迁移能力的影响，并检测LRP8敲低对Wnt信号通路活性的影响。利用Kaplan-Meier plotter数据库分析LRP8高低表达与胃癌患者预后的相关性；分析TCGA数据库中240例和郑州大学第五附属医院2018年8月—2019年7月行全胃切除术或部分切除术的25例胃癌患者LRP8表达及其与临床病理学特征之间的关系。结果：TCGA数据库中胃癌组织中LRP8表达高于正常胃黏膜，差异有统计学意义（P<0.000 1），GEO数据库中3项研究结果一致（P<0.05）。细胞功能实验表明，AGS细胞系中沉默LRP8表达后，相比对照组，si-LRP8组AGS细胞在体外增殖率和迁移率下降（P<0.05），且Wnt通路下游关键靶点β-catenin、LRP5、POU5F1、CCND1、AXIN2表达下调（P<0.05）；Kaplan-Meier plotter数据库中两项芯片的生存分析显示，LRP8高表达患者预后不良（均P<0.05）；TCGA数据库中分析显示，LRP8高表达与胃癌患者年龄呈正相关（P<0.001）；回顾性分析显示LRP8高表达与胃癌分期正相关（P=0.034）。结论：LRP8在胃癌中高表达，并通过影响Wnt/β-catenin信号转导通路促进胃癌细胞恶性行为。LRP8的高表达与胃癌患者的远期生存率下降相关，有望成为胃癌患者治疗或预后的生物学标志物。

关键词: 胃癌, 低密度脂蛋白受体相关蛋白8, 人类癌症基因组图谱, 基因表达汇编, Kaplan-Meier plotter, 细胞功能实验, Wnt信号通路

Abstract: Background and purpose: Low-density lipoprotein receptor-related protein 8 (LRP8) plays an important role in the development of liver cancer, lung cancer, breast cancer, colorectal cancer and other tumors. This study aimed to explore the expression and prognostic role of LRP8 in gastric cancer, and evaluate the possibility of a new target for gastric cancer biotherapy. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were used to analyze the expression of LRP8 in gastric cancer tissues. The co-expressed gene with LRP8 in gastric cancer was analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RNA interference (RNAi) was used for silencing the expression of LRP8 in AGS cell line, and functional assays were performed to evaluate the effects of LRP8 knockdown on the proliferation ability, invasiveness and the Wnt signaling pathway of AGS cell line in vitro. The relationship between LRP8 expression and prognosis of patients with gastric cancer was assessed by using Kaplan-Meier plotter database. To validate the 240 gastric cancer patients from TCGA database results, retrospective immunohistochemical analysis was performed to classify the relationship between the expression of LRP8 and clinical pathological features of 25 gastric cancer patients who underwent total or subtotal gastrectomy from August 2018 to July 2019 in the Fifth Affiliated Hospital of Zhengzhou University. Results: Data from the TCGA database showed LRP8 was overexpressed in gastric cancer tissues compared with normal gastric mucosa (P<0.000 1), and three studies from GEO database gave consistent results (P<0.05). Functional cell-based assays demonstrated that compared with the control group, proliferation ability and invasiveness of si-LRP8 AGS cell line were reduced in vitro, and the expressions of β-catenin, LRP5, POU5F1, CCND1 and AXIN2 were downregulated (all P<0.05). Survival analysis results of the two probes from Kaplan-Meier plotter database displayed the poor prognosis in patients with high expression of LRP8 (P<0.05). TCGA data containing 240 gastric cancer patients demonstrated a positive correlation between high expression of LRP8 and patient’s age (P<0.001), while the results from 25 patients showed a positive association with tumor stage (P=0.034). Conclusion: LRP8 is overexpressed in gastric cancer, which may promote the malignant transformation of gastric cancer cells by regulating Wnt/β-catenin signaling pathway activity and may be a new molecular mechanism of gastric tumorigenesis. Gastric cancer patients with high expression of LRP8 have decreased long-term survival, and LRP8 is expected to become a treatment or prognostic biomarker of gastric cancer.

Key words: Gastric cancer, Low-density lipoprotein receptor-related protein 8, The Cancer Genome Atlas, Gene Expression Omnibus, Kaplan-Meier plotter, Functional cell-based assays, Wnt signaling pathway

刘　斌, 郑鹏远, 米　阳, 任飞飞, 高　爽, 刘　传, 李发展 . LRP8在胃癌中的表达及其在胃癌发生过程中的作用[J]. 中国癌症杂志, 2021, 31(4): 285-293.

LIU Bin , ZHENG Pengyuan , MI Yang , REN Feifei , GAO Shuang , LIU Chuan , LI Fazhan . Expression of LRP8 in gastric cancer and its significance in tumorigenesis[J]. China Oncology, 2021, 31(4): 285-293.

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链接本文: http://www.china-oncology.com/CN/10.19401/j.cnki.1007-3639.2021.04.007

http://www.china-oncology.com/CN/Y2021/V31/I4/285

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LRP8在胃癌中的表达及其在胃癌发生过程中的作用

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