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Rad51 in regulating the radiosensitivity of non-small cell lung cancer with different epidermal growth factor receptor mutation status.

ABSTRACT: Non-small cell lung cancer (NSCLC) harboring kinase-domain mutations in epidermal growth factor receptors (EGFR) has been observed to be sensitive to ionizing radiation (IR). We explore Rad51-dependent homologous recombination (HR) DNA repair in regulating radiosensitivity in two NSCLC cell lines with different EGFR mutation status.NSCLC cell lines, wild-type EGFR A549 and mutant EGFR H820 with an in-frame deletion in exon 19 of EGFR (?E746-E750), were cultured. Radiosensitivity was estimated by colony forming assay. Rad51 expression was evaluated by quantitative real time-polymerase chain reaction and Western-blot. Lentiviral small hairpin ribonucleic acid-Rad51 and ?E746-E750 deletion mutant EGFR were constructed and transfected into cells. Flowcytometry assay was used to analyze DNA double strand breaks, cell cycle alterations, and apoptosis.A549 had a higher survival factor (SF)2 (0.66 vs. 0.44) and lower ?/? value (4.07 vs. 9.01). Compared with the A549 cell, the H820 cell exhibited defective arrest in the S-phase, a higher rate of G2/M accumulation, early apoptosis, and residual ?-H2AX. Downregulated Rad51 expression decreased SF2 (0.42 vs. 0.31) and increased the ?/? ratio (7.51 vs. 10.5), G2/M accumulation, early apoptosis, and ?-H2AX in two cell lines. H820 had a low IR-induced Rad51 expression and nuclear translocation. Exogenous expression of the ?E746-E750 deletion mutant EGFR caused the A549 cell to become more radiosensitive.An EGFR mutated NSCLC cell line is sensitive to IR , which is correlated with reduced IR-induced Rad51 expression and nuclear translocation. The signaling pathway of EGFR maintaining Rad51 protein levels maybe a novel lung cancer therapeutic target to overcome radioresistance.

SUBMITTER: Zhong X

PROVIDER: S-EPMC4718133 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Rad51 in regulating the radiosensitivity of non-small cell lung cancer with different epidermal growth factor receptor mutation status.

Zhong Xing X Luo Guomin G Zhou Xiaojuan X Luo Wen W Wu Xia X Zhong Renming R Wang Yanping Y Xu Feng F Wang Jin J

Thoracic cancer 20150519 1

<h4>Background</h4>Non-small cell lung cancer (NSCLC) harboring kinase-domain mutations in epidermal growth factor receptors (EGFR) has been observed to be sensitive to ionizing radiation (IR). We explore Rad51-dependent homologous recombination (HR) DNA repair in regulating radiosensitivity in two NSCLC cell lines with different EGFR mutation status.<h4>Methods</h4>NSCLC cell lines, wild-type EGFR A549 and mutant EGFR H820 with an in-frame deletion in exon 19 of EGFR (ΔE746-E750), were cultured ...[more]

PMID: 26816539

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Project description:Purpose To retrospectively identify the relationship between epidermal growth factor receptor (EGFR) mutation status, predominant histologic subtype, and computed tomographic (CT) characteristics in surgically resected lung adenocarcinomas in a cohort of Asian patients. materials and Methods This study was approved by the institutional review board, with waiver of informed consent. Preoperative chest CT findings were retrospectively evaluated in 385 surgically resected lung adenocarcinomas. A total of 30 CT descriptors were assessed. EGFR mutations at exons 18-21 were determined by using the amplification refractory mutation system. Multiple logistic regression analyses were performed to identify independent factors of harboring EGFR mutation status. The final model was selected by using the backward elimination method, and two areas under the receiver operating characteristic curve (ROC) were compared with the nonparametric approach of DeLong, DeLong, and Clarke-Pearson. Results EGFR mutations were found in 168 (43.6%) of 385 patients. Mutations were found more frequently in (a) female patients (P < .001); (b)those who had never smoked (P < .001); (c)those with lepidic predominant adenocarcinomas (P = .001) or intermediate pathologic grade (P < .001); (e) smaller tumors (P < .001); (f)tumors with spiculation (P = .019), ground-glass opacity (GGO) or mixed GGO (P < .001), air bronchogram (P = .006), bubblelike lucency (P < .001), vascular convergence (P = .024), thickened adjacent bronchovascular bundles (P = .027), or pleural retraction (P < .001); and (g) tumors without pleural attachment (P = .004), a well-defined margin (P = .010), marked heterogeneous enhancement (P = .001), severe peripheral emphysema (P = .002), severe peripheral fibrosis (P = .013), or lymphadenopathy (P = .028). The most important and significantly independent prognostic factors of harboring EGFR-activating mutation for the model with both clinical variables and CT features were those who had never smoked and those with smaller tumors, bubblelike lucency, homogeneous enhancement, or pleural retraction when adjusting for histologic subtype, pathologic grade, or thickened adjacent bronchovascular bundles. ROC curve analysis showed that use of clinical variables combined with CT features (area under the ROC curve = 0.778) was superior to use of clinical variables alone (area under the ROC curve = 0.690). Conclusion CT imaging features of lung adenocarcinomas in combination with clinical variables can be used to prognosticate EGFR mutation status better than use of clinical variables alone. (©) RSNA, 2016 Online supplemental material is available for this article.

Dataset Information

Rad51 in regulating the radiosensitivity of non-small cell lung cancer with different epidermal growth factor receptor mutation status.

Publications

Rad51 in regulating the radiosensitivity of non-small cell lung cancer with different epidermal growth factor receptor mutation status.

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