Dataset Information

Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma.

ABSTRACT:

Objective

The current study aims to identify the dysregulated pathway involved in carcinogenesis and the essential survival-related dysregulated genes among this pathway in the early stage of lung adenocarcinoma (LUAD).

Patients and methods

Data from The Cancer Genome Atlas (TCGA) including 526 tumor tissues of LUAD and 59 healthy lung tissues were analyzed to gain differentially expressed genes (DEGs). Gene ontology (GO) analysis was conducted with DAVID, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs was performed, followed by gene set enrichment analysis (GSEA) methods. Survival analysis was implemented in TCGA dataset and validated in Gene Expression Omnibus (GEO) cohort GSE50081, which includes 127 patients with stage I LUAD.

Results

GSEA enrichment analysis suggested that homologous recombination repair (HRR) pathway was significantly enriched. Subsequent KEGG pathway enrichment analysis indicated the significant up-regulation of HRR pathway in patients with T1 stage LUAD. Retrieved in Gene database, RAD54L is involved in HRR pathway and were recognized to be significantly differentially expressed in T1 stage LUAD in our study. The survival analysis indicated that high expression of RAD54L was significantly related to worse overall survival in patients with T1 stage LUAD (TCGA cohort: HR=2.10, 95% CI [1.47-2.98], P = 0.001; GSE50081 validation cohort: HR = 2.61, 95% CI [1.51-4.52], P = 0.002). Multivariate cox regression analysis indicated that RAD54L is an independent prognostic factor in the early-stage LUAD.

Conclusion

HRR pathway is up-regulated in LUAD, among which the expression of RAD54L was found to be significantly differentially expressed in T1 stage tumor tissue. Patients with high expression of RAD54L were associated with worse overall survival in the TCGA cohort and validation cohort. This study suggests a potential mechanism of lung cancer progression and provide a budding prognostic factor and treatment target in early-stage LUAD.

SUBMITTER: Zheng S

PROVIDER: S-EPMC7894105 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma.

Zheng Shaopeng S Yao Lintong L Li Fasheng F Huang Luyu L Yu Yunfang Y Lin Zenan Z Li Hao H Xia Jin J Lanuti Michael M Zhou Haiyu H

PeerJ 20210216

<h4>Objective</h4>The current study aims to identify the dysregulated pathway involved in carcinogenesis and the essential survival-related dysregulated genes among this pathway in the early stage of lung adenocarcinoma (LUAD).<h4>Patients and methods</h4>Data from The Cancer Genome Atlas (TCGA) including 526 tumor tissues of LUAD and 59 healthy lung tissues were analyzed to gain differentially expressed genes (DEGs). Gene ontology (GO) analysis was conducted with DAVID, while the Kyoto Encyclop ...[more]

PMID: 33628633

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Project description:ObjectiveEsophageal adenocarcinoma (EAC) continues to be a disease associated with high mortality. Among the factors leading to poor outcomes are innate resistance to currently available therapies, advanced stage at diagnosis, and complex biology. Platinum and ionizing radiation form the backbone of treatment for the majority of patients with EAC. Of the multiple processes involved in response to platinum chemotherapy or ionizing radiation, deoxyribonucleic acid (DNA) repair has been a major player in cancer sensitivity to these agents. DNA repair defects have been described in various malignancies. The purpose of this study was to determine whether alterations in DNA repair are present in EAC compared with normal gastroesophageal tissues.MethodsWe analyzed the expression of genes involved in homologous recombination (HR), nonhomologous end-joining, and nucleotide excision repair (NER) pathways in 12 EAC tumor samples with their matched normal counterparts. These pathways were chosen because they are the main pathways involved in the repair of platinum- or ionizing-radiation-induced damage. In addition, abnormalities in these pathways have not been well characterized in EAC.ResultsWe identified increased expression of at least one HR gene in eight of the EAC tumor samples. Alterations in the expression of EME1, a structure-specific endonuclease involved in HR, were the most prevalent, with messenger (m)RNA overexpression in six of the EAC samples. In addition, all EAC samples revealed decreased expression of at least one of numerous NER genes including XPC, XPA, DDB2, XPF, and XPG.ConclusionOur study identified DNA repair dysregulation in EAC involving two critical pathways, HR and NER, and is the first demonstration of EME1 upregulation in any cancer. These DNA repair abnormalities have the potential to affect a number of processes such as genomic instability and therapy response, and the consequences of these defects deserve further study in EAC.

Project description:BackgroundRadiation therapy is one of the most common treatments for non-small cell lung cancer (NSCLC). However, the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients, and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge. This study aimed to identify the molecules associated with radioresistance in lung adenocarcinoma (LUAD), identified thyroid hormone receptor interactor 13 (TRIP13) as the main target initially, and explored whether TRIP13 is related to radioresistance in LUAD and the specific mechanism, with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic.MethodsThree datasets, GSE18842, GSE19188 and GSE33532, were selected from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (|log FC|>1.5, P<0.05) in each of the three datasets using the R 4.1.3 software, and then Venn diagram was used to find out the differentially expressed genes common to the three datasets. The screened differential genes were then subjected to protein-protein interaction (PPI) analysis and module analysis with the help of STRING online tool and Cytoscape software, and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database, and the TRIP13 gene was identified as the main molecule for subsequent studies. Subsequently, the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line, H292DR. The radioresistance of H292DR cells was verified using cell counting kit-8 (CCK-8) assay and clone formation assay. The expression levels of TRIP13 in H292 and H292DR cells were measured by Western blot. Small interfering RNA (siRNA) was used to silence the expression of TRIP13 in H292DR cells and Western blot assay was performed. The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing, followed by the detection of changes in the expression levels of proteins closely related to homologous recombination, such as ataxia telangiectasia mutated (ATM) protein.ResultsScreening of multiple GEO datasets, validation of external datasets and survival analysis revealed that TRIP13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy. And the results of gene set enrichment analysis (GSEA) of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy. Experimentally, TRIP13 expression was found to be upregulated in H292DR, and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation.ConclusionsTRIP13 is associated with poor prognosis in LUAD patients treated with radiation, possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

Dataset Information

Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma.

Objective

Patients and methods

Results

Conclusion

Publications

Homologous recombination repair rathway and RAD54L in early-stage lung adenocarcinoma.

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