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Original Article Prognostic Value and Interrelated Expression Profile of GINS Complex Subunits in Lung Adenocarcinoma

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Int J Clin Exp Med 2020;13(10):8068-8085 www.ijcem.com /ISSN:1940-5901/IJCEM0117492 Original Article Prognostic value and interrelated expression profile of GINS complex subunits in lung adenocarcinoma Fangyan Zhong1*, Jianxiong Deng1*, Xiaotong Duan2, Junming Lai3, Xin Long4, Ruoyan Shen5, Yi Zhong6, Hong Lin1, Hui Luo1 1Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang University, Nanchang 330006, Jiangxi, P. R. China; 2Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, P. R. China; 3Department of Radiation Oncology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, Zhejiang, P. R. China; 4Department of Radiation and Chemotherapy Oncology, Zhongnan Hospital, Wuhan University, Wuhan 430000, Hubei, P. R. China; 5Department of Second Institute of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310013, Zhejiang, P. R. China; 6Department of Acupuncture and Immune Rheumatism, First People’s Hospital of Tongxiang, Tongxiang 314500, Zhejiang, P. R. China. *Equal contributors. Received July 3, 2020; Accepted August 30, 2020; Epub October 15, 2020; Published October 30, 2020 Abstract: Lung adenocarcinoma (LUAD) is one of the common pathological types of lung cancer, it has a poor 5-year overall survival rate. The GINS complex was found to be a core component of replication helicases in eukaryotes, and its abnormal function may lead to the cause of human cancers and other diseases. However, few attempts have been made to find an association between GINS complex subunits (GINSs) and LUAD. Therefore, in this study, we will attempt to explore the prognostic value of GINSs in patients with LUAD and the interrelated expression profile. In this study, ONCOMINE database, UALCAN and Human Protein Atlas were used to investigate the role of GINSs in LUAD transcription expression profiles. KM-plotter and DriverDBv3 database were used to analyzed the correlation between GINSs gene expression and prognosis. By using LinkedOmics database, we screened GINSs-related dif- ferentially expressed genes and performed GO, KEGG analysis on these genes. We found that all GINS genes are highly expressed in LUAD and are associated with poor survival of patients with LUAD, especially those who have a smoking history. Additionally, we found that co-overexpression of two or more GINSs was associated with poor prognosis, suggesting the GINSs complex may co-operate to promote LUAD progression. We had also obtained some GINSs-related kinase targets and transcription factor targets, which may serve as a future research direction. We propose that individual GINSs or combinations of multiple GINS genes may be potential biomarkers for the progno- sis of LUAD. Keywords: Lung adenocarcinoma, GINS complex subunits, prognostic value, online databases, biomarker Introduction oncogenic drivers, Platinum-based chemother- apy was the most common treatment for ad- Lung cancer has the highest morbidity in the vanced LUAD. Recently, targeted drugs of on- world and is a leading cause of death [1, 2]. cogenic drivers are more widely used, and the Traditionally, it is classified into two primary prevailing oncogenic drivers in the field of lung groups, small cell versus non-small cell types. cancer are mutations in EGFR, BRAF, KRAS and The non-small cell lung carcinoma (NSCLC) ac- other important key drivers [5]. Nowadays, as counts for 80-85% of all cases of lung cancer research into the role of the immune system in and is mainly classified into two distinct pa- tumor immunosurveillance deepens, immuno- thological subtypes: squamous cell carcinoma therapy drugs are beginning to show their po- (LUSC) and the adenocarcinoma (LUAD) [3]. tential in lung cancer treatment [6]. However, Currently, LUAD is the most common subtype despite significant advances in treatment, the of lung cancer found in men and women [4]. prognosis for LUAD is not encouraging. Hence, Before the application of targeted therapies for it is urgent to discover valuable molecular tar- GINSs could be potential biomarkers for LUAD geted therapy through investigation and trials Material and methods so as to judge the prognosis or optimize the treatment efficacy of cancer treatment in pa- Oncomine database analysis tients. Oncomine (https://www.oncomine.org/) is a The GINS complex subunits (GINSs) consists of publicly accessible online database with plenti- 4 genes, namely GINS1, GINS2, GINS3, GINS4 ful information on cancer microarrays to help in the human genome, corresponding to Psf1, facilitate discovery from genome-wide expres- Psf2, Psf3, Sld5 proteins, respectively. The sion analyses [22]. In our study, we found tran- GINS complex, which was constituted by Psf1, scriptional expression of GINSs are over-ex- Psf2, Psf3, Sld5 proteins, is the basis for the pressed in distinct cancers and then compar- development of DNA replication forks and re- ed the transcriptional data between LUAD tis- plicators in eukaryotes, and it is one of the sues and normal lung tissues by Oncomine. core components of replication helicases in The difference of transcriptional expression eukaryotes (CMG complex, including Cdc45- was compared by student’s t-test. The cut-off MCM-GINS). The GINS complex initiates the of p-values and fold changes are listed as circular structure, regulates multifunctional follows: p-value: 1E-4, fold change: 1.5, gene proteins, growth factor signals and receptor rank: 10%, data type: mRNA. molecules at the beginning of DNA replication. The GINS also participates in the initiation of UALCAN analysis DNA replication and cell cycle progression [7- 9]. DNA helicases are necessary for genomic Ualcan (http://ualcan.path.uab.edu/) is a com- stability, and their abnormal function leads to prehensive, user-friendly, and interactive web the failure of faithful DNA replication inducing resource for analyzing cancer OMICS (The a loss of genome integrity, which may be the Cancer Genome Atlas, TCGA and MET500) cause of human cancers and other diseases data. It can provide graphs and plots depicting [10]. Hence, GINSs may be considered as po- gene expression [23]. We used Ualcan to ana- tential targets for human cancers. lyze mRNA expression of GINSs in LUAD tis- sues and their association with clinicopatho- In the past decade, a lot of studies have re- logic parameters. The difference of transcrip- ported on the role of GINSs in different can- tional expression was compared with student’s cers. It is shown that high expression of GINSs t-test and a p-value <0.05 was considered sta- indicates a poor prognosis in high-grade pros- tistically significant. tate cancer and hepatocellular carcinoma, and it can also promote the growth of breast can- Human protein atlas cer [11-13]. Over-expression of GINS2 promot- es tumor progression in early-stage cervical The Human Protein Atlas (HPA, https://www. cancer [14]. GINS3 may become a potential proteinatlas.org/) is a database which aims to prognostic biomarker for colorectal cancer and map all the human proteins in cells, tissues uterine endometrial carcinomas [15, 16]. Also, and organs using the integration of various GINS4 promotes the growth of gastric and omics technologies, including antibody-bas- colorectal cancer by distinct pathways [17, 18]. ed imaging, mass spectrometry-based pro- There are some studies reporting GINSs in teomics, transcriptomics and systems biology LUAD. However, research has mainly focused [24]. We compared protein expression patterns on the association between GINS3 and LUAD of each GINSs in patients with LUAD to normal [19-21]. In the current study, we extended the lung tissues. research field based on different databases in order to identify the prognostic values of GINSs Kaplan-Meier plotter analysis in LUAD. Some correlated genes of GINSs were also found, and their functional enrichments Kaplan-Meier plotter (KM-plotter, http://www. were discussed in combination with GINSs. We kmplot.com/) is an online tool mainly based also analyzed transcription factor targets and on the Gene Expression Omnibus (GEO) and kinase targets for GINSs and their related TCGA data sources for survival analysis bet- genes. ween gene expression and a variety of cancer 8069 Int J Clin Exp Med 2020;13(10):8068-8085 GINSs could be potential biomarkers for LUAD data [25]. The desired probe ID was determin- KEGG pathways, kinase-targets, miRNA-targets ed according to the file of probe sets provided and transcription factor-targets. Through wei- by KM-plotter. Patients with LUAD were divided ghted set coverage to reduce redundancy in into a low expression group and a high expres- the enrichment results. The rank criterion was sion group according to the median value as a an FDR <0.25, and 500 simulations were per- cut-off point of mRNA expression which were formed. analyzed by KM-plotter survival curves and Log-rank test. All the LUAD data are analyzed Results for overall survival (OS) in the KM-plotter. In addition, we analyzed OS by selecting for two Over-expression of GINSs in patients with subgroups: gender and smoking history. The LUAD number of at-risk cases, HRs, 95% CIs, and To begin our study, we first examined the ex- P-values were displayed accordingly. A p-value pression levels of GINSs in different cancer <0.05 was considered statistically significant. types by using Oncomine database. We discov- DriverDBv3 database analysis ered that GINSs are over-expressed in most cancer types, except leukemia, melanoma, DriverDBv3 is a cancer omics database whi- myeloma, and prostate cancer (Figure 1A). ch incorporates somatic mutations, RNA ex- Especially when comparing LUAD tissues ver- pression, miRNA expression, methylation, copy sus normal lung tissues, we found 14 datasets number variation and clinical data in addition with high expression of GINSs in patients with to annotation bases. There are three func- LUAD (Table 1). GINS1 mRNA expression sh- tions, ‘Cancer’, ‘Gene’, and ‘Customized-Analy- owed a 5.722-fold elevation from Hou lung sis’, to help researchers visualize the relation- (P=3.47e-18) [28], 3.861-fold elevation from ships between cancers and driver genes [26].
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  • Cell Cycle Arrest Through Indirect Transcriptional Repression by P53: I Have a DREAM

    Cell Cycle Arrest Through Indirect Transcriptional Repression by P53: I Have a DREAM

    Cell Death and Differentiation (2018) 25, 114–132 Official journal of the Cell Death Differentiation Association OPEN www.nature.com/cdd Review Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM Kurt Engeland1 Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53–p21–DREAM–E2F/CHR pathway (p53–DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements. However, because of its binding to E2F and CHR elements, DREAM regulates a larger set of target genes leading to regulatory functions distinct from pRB/E2F. The p53–DREAM pathway controls more than 250 mostly cell cycle-associated genes. The functional spectrum of these pathway targets spans from the G1 phase to the end of mitosis. Consequently, through downregulating the expression of gene products which are essential for progression through the cell cycle, the p53–DREAM pathway participates in the control of all checkpoints from DNA synthesis to cytokinesis including G1/S, G2/M and spindle assembly checkpoints. Therefore, defects in the p53–DREAM pathway contribute to a general loss of checkpoint control. Furthermore, deregulation of DREAM target genes promotes chromosomal instability and aneuploidy of cancer cells. Also, DREAM regulation is abrogated by the human papilloma virus HPV E7 protein linking the p53–DREAM pathway to carcinogenesis by HPV.Another feature of the pathway is that it downregulates many genes involved in DNA repair and telomere maintenance as well as Fanconi anemia.