PARP1表达在预测结直肠癌总体生存中的作用

doi:10.3969/j.issn.1009-976X.2022.05.007

摘要/Abstract

摘要： 目的探讨PARP1的表达水平与结直肠癌预后的关系。方法从基因表达综合数据库（GEO）和癌症基因图谱（TCGA）数据库下载PARP1基因的RNA-Seq数据,使用R软件绘制散点图并分析PARP1在结直肠癌和癌旁组织中的表达水平,将PARP1分为高、低表达组并进行生存分析、亚组生存分析和GSEA基因富集分析,筛选与PARP1相关的基因并进行GO、KEGG富集分析,鉴定与PARP1共表达的基因。结果在GSE184093、GSE100179、GSE44076、GSE110225和TCGA数据集中,PARP1在肿瘤样本中的mRNA表达显著高于其在非肿瘤样本中的表达（P<0.05）;以6.93作为阈值,分为PARP1高、低表达组,PARP1高表达组患者的总体生存期（OS）、无病生存期（DFS）、疾病特异性生存期（DSS）和无进展生存期（PFS）较PARP1低表达组显著缩短（P<0.05）。在结直肠癌和癌旁组织中共筛出差异表达基因2629个,其中有765个基因与PARP1显著相关,GO分析显示PARP1相关基因与DNA聚合酶结合、组蛋白激酶活性、血小板衍生生长因子结合、卡哈尔体蛋白定位、端粒蛋白定位等有关;KEGG分析显示PARP1相关基因与DNA复制、细胞周期、错配修复等通路有关。结论 PARP1在结肠癌中表达上调,并与结直肠癌患者不良预后有关。

关键词: 结肠癌, PARP1, GEO, TCGA, 预后

Abstract: Objective To investigate the relationship between the expression of PARP1 and the prognosis of colorectal cancer. Methods the RNA SEQ data of PARP1 gene were downloaded from the Gene Expression Omnibus （GEO） and the Cancer Gene Atlas （TCGA） database. The scatter plot was drawn by R software to analyze the expression level of PARP1 in colorectal cancer and adjacent tissues. The data was divided according to the expression level of PARP1 as high and low expression groups to analyze for survival, subgroup survival and GSEA gene enrichment. The PARP1-related genes were screened and analyzed for GO and KEGG enrichment,and the PARP1 co-expressed genes were identified. Results The mRNA expression of PARP1 in tumor samples was significantly higher than that in non-tumor samples（P<; 0.05）in GSE184093, GSE100179, GSE44076, GSE110225 and TCGA data sets. Taking 6.93 as the threshold, the patients were divided into high and low PARP1 expression groups. The overall survival （OS）, disease-free survival （DFS）, disease-specific survival （DSS） and progression free survival （PFS） of patients with high PARP1 expression group were significantly shorter than those with low PARP1 expression group（P<; 0.05）. A total of 2629 differentially expressed genes were screened from colorectal cancer and adjacent tissues, of which 765 genes were significantly related to PARP1. GO analysis showed that PARP1-related genes were related to DNA polymerase binding, histone kinase activity, platelet-derived growth factor binding, Cajal body protein localization, telomere protein localization, etc; KEGG analysis showed that PARP1-related genes were related to DNA replication, cell cycle, mismatch repair and other pathways. Conclusion The expression of PARP1 is up-regulated in colorectal cancer and is related to the poor prognosis of colorectal cancer patients.

Key words: Colon cancer, PARP1, GEO, TCGA, prognosis

中图分类号:

R735.3+5

叶臻, 林㼆. PARP1表达在预测结直肠癌总体生存中的作用[J]. 岭南现代临床外科, 2022, 22(05): 466-474.

YE Zhen, LIN Ying. Role of PARP1 expression in predicting survival of colorectal cancer[J]. Lingnan Modern Clinics In Surgery, 2022, 22(05): 466-474.

参考文献

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33.
[2] Bray F, Ferlay J, Soerjomataram I, et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424.
[3] 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. doi: 10.3322/caac.21660.
[4] Zheng R, Zhang S, Zeng H, et al.Cancer incidence and mortality in China, 2016[J]. J Natl Cancer Cent, 2022, 2(1): 1-9.
[5] Siegel RL, Miller KD, Goding Sauer A, et al.Colorectal cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(3): 145-164.
[6] Jubin T, Kadam A, Jariwala M, et al.The PARP family: insights into functional aspects of poly (ADP-ribose) polymerase-1 in cell growth and survival[J]. Cell Prolif, 2016, 49(4): 421-437.
[7] Matveeva EA, Al-Tinawi QMH, Rouchka EC, Fondufe-Mittendorf YN.Coupling of PARP1-mediated chromatin structural changes to transcriptional RNA polymerase II elongation and cotranscriptional splicing[J]. Epigenetics Chromatin, 2019, 12(1): 15.
[8] Ke Y, Wang C, Zhang J, et al.The Role of PARPs in Inflammation-and Metabolic-Related Diseases: Molecular Mechanisms and Beyond[J]. Cells, 2019, 8(9).
[9] Alshammari AH, Shalaby MA, Alanazi MS, Saeed HM.Novel mutations of the PARP-1 gene associated with colorectal cancer in the Saudi population[J]. Asian Pac J Cancer Prev, 2014, 15(8): 3667-3673.
[10] Ha HC, Snyder SH.Poly(ADP-ribose) polymerase-1 in the nervous system[J]. Neurobiol Dis, 2000, 7(4): 225-239.
[11] Deng L, Lei Q, Wang Y, et al.Downregulation of miR-221-3p and upregulation of its target gene PARP1 are prognostic biomarkers for triple negative breast cancer patients and associated with poor prognosis[J]. Oncotarget, 2017, 8(65): 108712-108725.
[12] Bertucci F, Finetti P, Monneur A, et al.PARP1 expression in soft tissue sarcomas is a poor-prognosis factor and a new potential therapeutic target[J]. Mol Oncol, 2019, 13(7): 1577-1588.
[13] Afzal H, Yousaf S, Rahman F, et al.PARP1: A potential biomarker for gastric cancer[J]. Pathol Res Pract, 2019, 215(8): 152472.
[14] Nosho K, Yamamoto H, Mikami M, et al.Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis[J]. Eur J Cancer, 2006, 42(14): 2374-2381.
[15] Manic G, Musella M, Corradi F, et al.Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51[J]. Cell Death Differ, 2021, 28(7): 2060-2082.
[16] Li YJ, Yang CN, Kuo MY, et al.ATMIN Suppresses Metastasis by Altering the WNT-Signaling Pathway via PARP1 in MSI-High Colorectal Cancer[J]. Ann Surg Oncol, 2021, 28(13): 8544-8554.
[17] Sakthianandeswaren A, Parsons MJ, Mouradov D, et al.MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors[J]. Cancer Discov, 2018, 8(8): 988-1005.
[18] Dorsam B, Seiwert N, Foersch S, et al.PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression[J]. Proc Natl Acad Sci U S A, 2018, 115(17): E4061-E4070.
[19] Gautier L, Cope L, Bolstad BM, Irizarry RA. affy--analysis of Affymetrix GeneChip data at the probe level[J]. Bioinformatics, 2004, 20(3): 307-315.
[20] Huambachano O, Herrera F, Rancourt A, Satoh MS.Double-stranded DNA binding domain of poly(ADP-ribose) polymerase-1 and molecular insight into the regulation of its activity[J]. J Biol Chem, 2011, 286(9): 7149-7160.
[21] Jungmichel S, Rosenthal F, Altmeyer M, et al.Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses[J]. Mol Cell, 2013, 52(2): 272-285.
[22] Zhou Z, Huang F, Shrivastava I, et al.New insight into the significance of KLF4 PARylation in genome stability, carcinogenesis, and therapy[J]. EMBO Mol Med, 2020, 12(12): e12391.
[23] Zhao X, Li D, Huang D, et al.Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF[J]. Mol Ther, 2018, 26(3): 755-773.
[24] Xu M, Zhao X, Zhao S, et al.Landscape analysis of lncRNAs shows that DDX11-AS1 promotes cell-cycle progression in liver cancer through the PARP1/p53 axis[J]. Cancer Lett, 2021, 520: 282-294.
[25] Chen K, Li Y, Xu H, et al.An analysis of the gene interaction networks identifying the role of PARP1 in metastasis of non-small cell lung cancer[J]. Oncotarget, 2017, 8(50): 87263-87275.
[26] Gao Z, Man X, Li Z, et al.PLK1 promotes proliferation and suppresses apoptosis of renal cell carcinoma cells by phosphorylating MCM3[J]. Cancer Gene Ther, 2020, 27(6): 412-423.
[27] Xing X, Gu F, Hua L, et al.TIMELESS Promotes Tumor Progression by Enhancing Macrophages Recruitment in Ovarian Cancer[J]. Front Oncol, 2021, 11: 732058.
[28] Zhou Y, Yong H, Cui W, et al.Long noncoding RNA SH3PXD2A-AS1 promotes NSCLC proliferation and accelerates cell cycle progression by interacting with DHX9[J]. Cell Death Discov, 2022, 8(1): 192.
[29] Neska-Dlugosz I, Buchholz K, Durslewicz J, et al.Prognostic Impact and Functional Annotations of KIF11 and KIF14 Expression in Patients with Colorectal Cancer[J]. Int J Mol Sci, 2021, 22(18).
[30] Hu S, Molina L, Tao J, et al.NOTCH-YAP1/TEAD-DNMT1 Axis Drives Hepatocyte Reprogramming into Intrahepatic Cholangiocarcinoma[J]. Gastroenterology, 2022, 10.1053/j.gastro.2022.05.007.
[31] Qin C, Ji Z, Zhai E, et al.PARP inhibitor olaparib enhances the efficacy of radiotherapy on XRCC2-deficient colorectal cancer cells[J]. Cell Death Dis, 2022, 13(5): 505.
[32] Lew ZX, Zhou HM, Fang YY, et al.Transgelin interacts with PARP1 in human colon cancer cells[J]. Cancer Cell Int, 2020, 20: 366.