MRPL12在肺腺癌中的表达和预后分析

doi:10.3969/j.issn.1674-8115.2021.08.006

摘要/Abstract

摘要：

目的·分析线粒体核糖体蛋白L12（mitochondrial ribosomal protein L12，MRPL12）在肺腺癌（lung adenocarcinoma，LUAD）和正常组织中的表达差异和对患者预后的影响，以及预测其生物学功能。方法·利用肿瘤浸润性免疫细胞分析数据库TIMER和GEPIA（gene expression profiling and interactive analyses）交互式网站服务器分析癌症基因组图谱（The Cancer Genome Atlas，TCGA）中MRPL12在不同癌组织中的表达情况的影响。利用Sangerbox生物信息分析平台对MRPL12差异表达的癌症类型进行Cox回归和Kaplan-Meier生存分析，评估风险比（hazard ratio，HR）、95%置信区间（confidence interval，CI）和Log-rank P值。采用UALCAN数据分析平台评估MRPL12蛋白表达与临床病理参数的关系。使用LinkedOmics数据库筛选与MRPL12表达相关的基因。采用DAVID数据库进行京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）通路富集分析。定量聚合酶链反应验证MRPL12在细胞中的转录水平。结果·MRPL12在多种癌组织中显著高表达，但只有在LUAD中MRPL12的高表达与患者较差的总体生存期（overall suivival，OS）和疾病特异性生存期（disease-specific survival，DSS）相关；肿瘤分级程度越高的LUAD患者MRPL12蛋白表达水平越高；在LUAD基因表达数据集中与MRPL12负相关的基因富集到癌症通路（P=0.000）、癌症蛋白聚糖（P=0.000）、非小细胞肺癌（P=0.000）等癌症相关的通路。MRPL12在LUAD细胞（H1395、H1975和HCC827）中的mRNA表达水平高于正常细胞（Beas-2B），差异有统计学意义（P<0.05）。结论·MRPL12高表达的LUAD患者可能预后较差；MRPL12可以作为LUAD预后不良的潜在生物标志物和潜在的治疗新靶点。

关键词: 肺腺癌, 线粒体核糖体蛋白L12, 生存分析, 预后, 生物标志物, 治疗靶点

Abstract:

Objective·To analyze the difference of expression of mitochondrial ribosomal protein L12 (MRPL12) in lung adenocarcinoma (LUAD) and normal tissues and its influence on the prognosis of patients, and predict its biological function.

Methods·The expressions of MRPL12 in different cancer tissues were analyzed by The Cancer Genome Atlas (TCGA) using the tumor-infiltrating immune cell analysis database TIMER and GEPIA (gene expression profiling and interactive analyses) server. The expressions of MRPL12 in different types of cancer were analyzed by Sangerbox bioinformatics platform. Cox regression and Kaplan-Meier survival analysis were used and the hazard ratios (HR), the 95% confidence intervals (CI) and the Log-rank P values were evaluated. The LinkedOmics database was used to identify the genes associated with MRPL12 expression. The DAVID database was used for the enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The transcription levels of MRPL12 in cells were verified by quantitative PCR (qPCR).

Results·MRPL12 was highly expressed in many cancer types. But only the LUAD patients with high MRPL12 expression had lower overall survival (OS) and disease-specific survival (DSS). The expression of MRPL12 protein increased with tumor stage and individual tumor grade. The genes negatively related to MRPL12 were enriched into several cancer-related pathways in LUAD gene expression data set, including pathways in cancer (P=0.000), proteoglycans in cancer (P=0.000) and non-small cell lung cancer (P=0.000). The mRNA expression levels of MRPL12 in the LUAD cells (H1395, H1975 and HCC827) were higher than that in the normal cell (Beas-2B), and the difference was statistically significant (P<0.05).

Conclusion·The LUAD patients with high expression of MRPL12 may have poor prognosis, and thus MRPL12 can be a potential biomarker and potential therapeutic target for LUAD.

Key words: lung adenocarcinoma (LUAD), mitochondrial ribosomal protein L12 (MRPL12), survival analysis, prognosis, biomarker, therapeutic target

中图分类号:

R734.2

熊雷, 易茜, 许明芳, 陈健. MRPL12在肺腺癌中的表达和预后分析[J]. 上海交通大学学报(医学版), 2021, 41(8): 1033-1040.

Lei XIONG, Qian YI, Ming-fang XU, Jian CHEN. Expression and prognosis analysis of MRPL12 in lung adenocarcinoma[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1033-1040.

图/表 6

图1 MRPL12在不同癌症中的转录水平Note：A. MRPL12 expression levels of different tumor types in the TCGA database detected by TIMER database. ACC—adrenocortical carcinoma; BRCA—breast carcinoma; CHOL—cholangiocarcinoma; DLBC—diffuse large B-cell lymphoma; ESCA—esophageal carcinoma; GBM—glioblastoma multiforme; HNSC—head and neck squamous cell carcinoma; HPV—human papillomavirus; 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; MESO—mesothelioma; 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; TGCT—testicular germ cell tumor; THCA—thyroid carcinoma; THYM—thymoma; UCS—uterine carcinosarcoma; UVM—uveal melanoma. B. MRPL12 in different cancers compared to normal tissues in the GEPIA. TPM—transcripts per millon; T—tumor; N— normal. *P<0.05, **P<0.01, ***P<0.001.

Fig1 Expression levels of MRPL12 in different cancers

图2 LUAD患者MRPL12表达与OS和DSS的关系Note：A/B. Forest plot displaying univariate Cox analysis of MRPL12 expression. C/D. Kaplan-Meier survival curves comparing the high and low expression of MRPL12 in LUAD. A/C. OS. B/D. DSS.

Fig 2 Relationship between MRPL12 expression and OS and DSS in LUAD patients

图3 LUAD组织中MRPL12的蛋白表达水平与临床病理参数的关系Note： A. The difference of expression of MRPL12 in normal tissues and LUAD tissues. B. The difference of expression of MRPL12 in LUAD tissues with different tumor grades. C. The difference of expression of MRPL12 in LUAD tissues with different tumor stages. ①P=0.000, compared with the normal group; ②P=0.040, compared with the grade 1 group; ③P=0.000, compared with the grade 2 group.

Fig 3 Relationship between protein expression of MRPL12 and clinicopathological parameters in LUAD tissues

图4 基于LinkedOmics数据库的LUAD组织MRPL12相关基因分析Note：A. The global MRPL12-highly-correlated genes identified by Pearson test in LUAD cohort. B/C. Heat maps showing top 50 genes negatively (B) and positively (C) correlated with MRPL12 in LUAD tissues.

Fig 4 MRPL12 co-expression genes in LUAD tissues based on LinkedOmics database

图5 LUAD组织中与MRPL12负相关基因的KEGG通路富集分析Note： cGMP-PKG—cyclic guanosine monophosphate-protein kinase G; PI3K—phosphatidylinositol 3-kinase; JAK-STAT—Janus kinase-signal transducer and activator of transcription. Circle size represents the ratio of the number of genes enriched into a certain pathway to the total number of the related genes.

Fig 5 KEGG enrichment analysis of MRPL12-negatively-correlated genes in LUAD tissues

图6 MRPL12在细胞系中的mRNA表达水平Note：①P=0.040, ②P=0.010, ③P=0.009, compared with the Beas-2B cell.

Fig 6 The mRNA expression levels of MRPL12 in cell lines

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