| Non-small cell lung cancer(NSCLC)accounts for the highest mobility and mortality among cancer patients all over the world.Although radiotherapy plays a major role in non-small cell lung cancer(NSCLC)treatment,the curative efficacy is unsatisfactory which mainly attributed to the radio-resistance to conventional radiotherapy.In addition,gadolinium-based nanoparticles(GBNPs)have been used as theranostic sensitizers in clinical radiotherapy studies;however,the biomechanisms underlying the radiosensitizing effects of Gd NPs have yet to be determined.In this study,some radio-responsive biomarkers to X-ray and carbon ions were discovered by proteomics.NSCLC cell lines with acquired radio-resistance to X-rays were obtained through fractionated irradiation.Differentially expressed proteins(DEPs)between A549-R11 and parallel control(A549-CK)were measured using the TMT(tandem mass tages)labeling in combination with high-resolution mass spectrometry(MS).Forty-eight DEPs from 5224 ones were found in A549-R11 basing on p<0.05 and fold changes>2 or <1/2 compared with control.CRIP2,ARHGDIB and PADI3 were validated to be up-regulated in A549-R11 compared with control both in m RNA and protein levels.Further analysis of bioinformatics deciphered that CRIP2,as a potential biomarker for diagnosis and a key biomarker for predicting the prognosis,may impact the X-ray radiosensitivity of NSCLC by regulating the occurrence of apoptosis and cell cycle arrest;as such,it may serve as a potent therapeutic target to facilitate NSCLC radiotherapy.In addition,NSCLC with the higher CRIP2 expression may be selected as candidates for heavy ion or proton radiotherapy.CRIP2 and other DEPs may throw new light on the recognition of complex factors associated with radiation-responsive and finally be beneficial in the advancement of personalized therapies and precision medical treatment.On the other hand,ultra-small gadolinium oxide nanocrystals(GONs)which synthesized using the polyol method were employed to investigate their radiosensitizing effects and biological mechanisms in non-small cell lung cancer(NSCLC)cells under X-ray and carbon ion irradiation.GONs induced hydroxyl radical production and oxidative stress in a dose-and concentration-dependent manner in NSCLC cells after irradiation.The sensitizer enhancement ratios(SER)of GONs ranged between 19.3%~26.3% for the NSCLC cells under investigation with a 10% survival rate compared with that of cells treated with X-ray irradiation alone.Similarly,the SERSF10 of GON ranges from 10.12% to 19.6% after carbon ion irradiation.The addition of 3-methyladenine(3-MA)to the cell medium decreased the incidence rate of autophagy and increased cell survival,supporting the idea that the GONs promoted cytostatic autophagy in NSCLC cells under X-ray and carbon ion irradiation in the same way.Apoptosis were also enhanced by GON in A549 and NH1650 cells but not in NH1299 cells after irradiation.Compared with the cytoplasmic damage induced by cotreatment of GON and X-ray irradiation,carbon ion radiation mainly led to nuclei damages like DSB.Our finding may pave way for the clinically useage of the theranostic materials.Basing on the biomarkers associated with radioresistance and the mechnisms related to radiosensitivity both studied in this thesis,our findings benefical for the choice of therapeutical strategies,as well as promote the efficiency of targeted radiotherapy and the optimization of diagnosis and treatment. |
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