RPA1 downregulation enhances nasopharyngeal cancer radiosensitivity via blocking RAD51 to the DNA damage site

Zhang, Zixin; Huo, Haifeng; Liao, Kui; Wang, Zhihai; Gong, Zhongying; Li, Yanshi; Liu, Chuan; Hu, Guohua

doi:10.1016/j.yexcr.2018.08.025

Cited by 19 publications

(16 citation statements)

References 37 publications

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“…[ 23 ] Our data confirm that RPA1 plays a role in modulating the radiosensitivity of NPC cells, whereby overexpression of RPA1 leads to radioresistance. This is consistent with a very recent finding in another NPC cell line, [ 24 ] as well as the finding in esophageal cancer. [ 25 ] The correlation of RPA1 to the genes involved in crucial DNA repair pathways as revealed by transcriptome analysis would suggest that NPC tumors with higher expression or activation of RPA1 might result in a higher repair fidelity of radiation‐induced DNA damage leading to radioresistance.…”

Section: Discussionsupporting

confidence: 94%

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome‐Wide Association Study in Multiple Cohorts

et al. 2020

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Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3′-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10 −8 ). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

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Section: Discussionsupporting

confidence: 94%

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome‐Wide Association Study in Multiple Cohorts

et al. 2020

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“…High RAD51 expression enhances cancer progression through the p38/Akt/Snail signaling pathway (Chiu et al, 2019). RAD51 may lead to increased drug resistance in triple-negative breast cancer patients (Zhao et al, 2019) and is also associated with the radiosensitivity of some tumors, such as nasopharyngeal cancer (Zhang Z. et al, 2018) and prostate cancer (Maranto et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

2020

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Background: Tumor stem cells play important roles in the survival, proliferation, metastasis and recurrence of tumors. We aimed to identify new prognostic biomarkers for lung squamous cell carcinoma (LUSC) based on the cancer stem cell theory. Methods: RNA-seq data and relevant clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Weighted gene coexpression network analysis (WGCNA) was applied to identify significant modules and hub genes, and prognostic signatures were constructed with the prognostic hub genes. Results: LUSC patients in the TCGA database have higher mRNA expression-based stemness index (mRNAsi) in tumor tissue than in adjacent normal tissue. In addition, some clinical features and outcomes were highly correlated with the mRNAsi. WGCNA revealed that the pink and yellow modules were the most significant modules related to the mRNAsi; the top 10 hub genes in the pink module were enriched mostly in epidermal development, the secretory granule membrane, receptor regulator activity and the cytokine-cytokine receptor interaction. The protein-protein interaction (PPI) network revealed that the top 10 hub genes were significantly correlated with each other at the transcriptional level. In addition, the top 10 hub genes were all highly expressed in LUSC, and some were differentially expressed in different TNM stages. Regarding the survival analysis, the nomogram of a prognostic signature with three hub genes showed high predictive value. Conclusion: mRNAsi-related hub genes could be a potential biomarker of LUSC.

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“…Thus, modulating RPA availability may be a useful strategy particularly when drug resistance occurs. Similarly, downregulation of RPA affects RAD51 recruitment to DSBs and enhances the radiosensitivity of nasopharyngeal cancer cells ( 342 ). These studies in aggregate provide an explanation as to why overexpression of RPA in various cancers is predictive for unfavorable outcome ( 322–332 ).…”

Section: Targeting Rpa For Effective Cancer Therapymentioning

confidence: 99%

Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

Dueva

Iliakis

2020

NAR Cancer

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Single-stranded DNA (ssDNA) forms continuously during DNA replication and is an important intermediate during recombination-mediated repair of damaged DNA. Replication protein A (RPA) is the major eukaryotic ssDNA-binding protein. As such, RPA protects the transiently formed ssDNA from nucleolytic degradation and serves as a physical platform for the recruitment of DNA damage response factors. Prominent and well-studied RPA-interacting partners are the tumor suppressor protein p53, the RAD51 recombinase and the ATR-interacting proteins ATRIP and ETAA1. RPA interactions are also documented with the helicases BLM, WRN and SMARCAL1/HARP, as well as the nucleotide excision repair proteins XPA, XPG and XPF–ERCC1. Besides its well-studied roles in DNA replication (restart) and repair, accumulating evidence shows that RPA is engaged in DNA activities in a broader biological context, including nucleosome assembly on nascent chromatin, regulation of gene expression, telomere maintenance and numerous other aspects of nucleic acid metabolism. In addition, novel RPA inhibitors show promising effects in cancer treatment, as single agents or in combination with chemotherapeutics. Since the biochemical properties of RPA and its roles in DNA repair have been extensively reviewed, here we focus on recent discoveries describing several non-canonical functions.

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RPA1 downregulation enhances nasopharyngeal cancer radiosensitivity via blocking RAD51 to the DNA damage site

Cited by 19 publications

References 37 publications

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome‐Wide Association Study in Multiple Cohorts

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome‐Wide Association Study in Multiple Cohorts

Bioinformatics Analysis Reveals Biomarkers With Cancer Stem Cell Characteristics in Lung Squamous Cell Carcinoma

Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

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