Focal Exposure of Limited Lung Volumes to High-dose Irradiation Down-regulated Organ Development-related Functions and Up-regulated the Immune Response in Mouse Pulmonary Tissues

Overview

Journal BMC Genet

Publisher Biomed Central

Specialties Biotechnology
Molecular Biology

Date 2016 Jan 29

PMID 26818610

Citations 3

Authors

Bu-Yeo Kim

Hee Jin

Yoon-Jin Lee

Ga-Young Kang

Jaeho Cho

Yun-Sil Lee

Affiliations

Soon will be listed here.

Abstract

Background: Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT.

Results: Central areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions.

Conclusions: Focal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non-irradiated neighboring areas of lung tissue, indicating a global lung response to focal high-dose irradiation.

Citing Articles

GTSE1-driven ZEB1 stabilization promotes pulmonary fibrosis through the epithelial-to-mesenchymal transition.

Jin H, Park S, Lee J, Park H, Jeong M, Lee H Mol Ther. 2024; 32(11):4138-4157.

PMID: 39342428 PMC: 11573610. DOI: 10.1016/j.ymthe.2024.09.029.

LXA-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling.

Kim H, Park S, Han S, Lee Y, Cho J, Kim J Cell Death Dis. 2020; 11(8):653.

PMID: 32811815 PMC: 7434774. DOI: 10.1038/s41419-020-02846-7.

Minimally invasive surgery is best treatment for early lung cancer.

Swanson S J Thorac Dis. 2018; 10(Suppl 17):S1998-S1999.

PMID: 30023102 PMC: 6036013. DOI: 10.21037/jtd.2018.04.171.

References

Lee S, Lee H, Moon J, Kim J, Park J, Lee J . Transcriptional regulation of Zic3 by heterodimeric AP-1(c-Jun/c-Fos) during Xenopus development. Exp Mol Med. 2004; 36(5):468-75. DOI: 10.1038/emm.2004.59. View

Baril M, Es-Saad S, Chatel-Chaix L, Fink K, Pham T, Raymond V . Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses. PLoS Pathog. 2013; 9(6):e1003416. PMC: 3681753. DOI: 10.1371/journal.ppat.1003416. View

Baker R, Han G, Sarangkasiri S, DeMarco M, Turke C, Stevens C . Clinical and dosimetric predictors of radiation pneumonitis in a large series of patients treated with stereotactic body radiation therapy to the lung. Int J Radiat Oncol Biol Phys. 2012; 85(1):190-5. DOI: 10.1016/j.ijrobp.2012.03.041. View

Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J . Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010; 303(11):1070-6. PMC: 2907644. DOI: 10.1001/jama.2010.261. View

Tarca A, Draghici S, Khatri P, Hassan S, Mittal P, Kim J . A novel signaling pathway impact analysis. Bioinformatics. 2008; 25(1):75-82. PMC: 2732297. DOI: 10.1093/bioinformatics/btn577. View

Komarova Y, Malik A . Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol. 2010; 72:463-93. DOI: 10.1146/annurev-physiol-021909-135833. View

Pao L, Lam K, Henderson J, Kutok J, Alimzhanov M, Nitschke L . B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity. 2007; 27(1):35-48. DOI: 10.1016/j.immuni.2007.04.016. View

Wagner E . Bone development and inflammatory disease is regulated by AP-1 (Fos/Jun). Ann Rheum Dis. 2009; 69 Suppl 1:i86-88. DOI: 10.1136/ard.2009.119396. View

Wu G, Feng X, Stein L . A human functional protein interaction network and its application to cancer data analysis. Genome Biol. 2010; 11(5):R53. PMC: 2898064. DOI: 10.1186/gb-2010-11-5-r53. View

10.

Willis B, duBois R, Borok Z . Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc. 2006; 3(4):377-82. PMC: 2658689. DOI: 10.1513/pats.200601-004TK. View

11.

Hong Z, Lee H, Choi W, Lee Y, Eun S, Lee J . A preclinical rodent model of acute radiation-induced lung injury after ablative focal irradiation reflecting clinical stereotactic body radiotherapy. Radiat Res. 2014; 182(1):83-91. DOI: 10.1667/RR13535.1. View

12.

Rubin P, Johnston C, Williams J, McDonald S, Finkelstein J . A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys. 1995; 33(1):99-109. DOI: 10.1016/0360-3016(95)00095-G. View

13.

Kim K, Kugler M, Wolters P, Robillard L, Galvez M, Brumwell A . Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A. 2006; 103(35):13180-5. PMC: 1551904. DOI: 10.1073/pnas.0605669103. View

14.

Zhang R, Ghosh S, Zhu D, North P, Fish B, Morrow N . Structural and functional alterations in the rat lung following whole thoracic irradiation with moderate doses: injury and recovery. Int J Radiat Biol. 2008; 84(6):487-97. PMC: 2435093. DOI: 10.1080/09553000802078396. View

15.

Kelly G, Saijoh Y, Finkielsztein A, Mangos S . Mouse G-protein gamma3 expression in the developing CNS and neural crest cell derivatives. Int J Dev Biol. 2008; 52(8):1143-50. DOI: 10.1387/ijdb.072561gk. View

16.

Bolstad B, Irizarry R, Astrand M, Speed T . A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics. 2003; 19(2):185-93. DOI: 10.1093/bioinformatics/19.2.185. View

17.

Ernst J, Bar-Joseph Z . STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics. 2006; 7:191. PMC: 1456994. DOI: 10.1186/1471-2105-7-191. View

18.

Mohamet L, Hawkins K, Ward C . Loss of function of e-cadherin in embryonic stem cells and the relevance to models of tumorigenesis. J Oncol. 2011; 2011:352616. PMC: 3005858. DOI: 10.1155/2011/352616. View

19.

Kim S, Choe C, Shin Y, Jeon M, Choi S, Lee J . Human lung cancer-associated fibroblasts enhance motility of non-small cell lung cancer cells in co-culture. Anticancer Res. 2013; 33(5):2001-9. View

20.

Bang J, Jeon W, Lee I, Han J, Kim B . Biphasic functional regulation in hippocampus of rat with chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid artery. PLoS One. 2013; 8(7):e70093. PMC: 3728362. DOI: 10.1371/journal.pone.0070093. View