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Differential Network Analysis Reveals the Key Role of the ECM-receptor Pathway in α-Particle-induced Malignant Transformation

ABSTRACT: Space particle radiation is a major environmental factor in spaceflight, and it is known to cause body damage and even trigger cancer, but with unknown molecular etiologies. To examine these causes, we developed a systems biology analytical approach that included co-expression network analysis of transcriptomics profiles obtained using different α-particle radiation exposures of BEAS-2B human bronchial epithelial cells. These exposures employed either single high-dose irradiation of 0.5 Gy one time, or, multiple low-dose irradiations consisting of 25 exposures to 0.02 Gy once every three days. These exposures were then followed by differential network comparative analysis through the multiscale interactomes. Overall pathway analysis based on the global network and the core modules showed that genes in the multiple low-dose irradiation groups had higher significant enrichment for the extracellular matrix (ECM)-receptor interaction pathway. Then, collagen gene COL1A1 was screened as an important ECM-related gene in the multiple low-dose irradiation group assessed by network robustness parameters, and an expression study of lung adenocarcinoma samples from The Cancer Genome Atlas (TCGA) database and additional biological experiments was performed. COL1A1 was found to promote the emergence of the neoplastic characteristics of BEAS-2B cells by both in vitro experimental analyses and in vivo immunohistochemical staining. These findings suggested that the degree of malignant transformation of cells exposed to multiple low-dose irradiations was greater than that of a single high-dose irradiation, which may be caused by the dysregulation of the ECM-receptor pathway. This study provides information on the molecular mechanisms underlying multiple low-dose irradiations used to mimic spaceflight, with a combination of high-throughput RNA-seq-based transcriptomics and systems biology approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235882 | GEO | 2023/07/02

REPOSITORIES: GEO

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Project description:Alpha (α)-radiation is a ubiquitous environmental agent with epigenotoxic effects. Human exposure to α-radiation at potentially harmful levels can occur repetitively over the long term via inhalation of naturally occurring radon gas that accumulates in enclosed spaces, or as a result of a single exposure from a nuclear accident. Alterations in epigenetic DNA methylation (DNAm) have been implicated in normal aging and cancer pathogenesis. Nevertheless, the effects of aberrations in the methylome of human lung cells following exposure to single or multiple α-radiation events on these processes remain unexplored. Here, we performed genome-wide DNAm profiling of human embryonic lung fibroblasts from control and irradiated cells using americium-241 α-sources. Cells were α-irradiated in quadruplicates to seven doses using two exposure regimens, a single-fraction (SF) where the total dose was given at once, and a multi-fraction (MF) method, where the total dose was equally distributed over 14 consecutive days. Our results revealed that SF irradiations were prone to a decrease in methylation levels, while MF irradiations mostly increased methylation. The analysis also showed that the gene body (i.e. exons and introns) was the region mostly altered by both the SF hypomethylation and the MF hypermethylation. Additionally, the MF irradiations induced the highest number of differentially methylated regions in genes associated with DNAm biomarkers of aging, carcinogenesis, and cardiovascular disease. The DNAm profile of the oncogenes and tumour suppressor genes suggested that the fibroblasts elicited a defensive response to the MF α-irradiation. Key DNAm events of ionizing radiation exposure including changes in methyl levels in mitochondria dysfunction-related genes were mainly identified in the MF groups. However, these alterations were under-represented, indicating that the mitochondria undergo adaptive mechanisms, aside from methylation, in response to radiation-induced oxidative stress. In this study, we identified a contrasting methylomic profile in the lung fibroblasts α-irradiated to SF compared with MF exposures. These findings demonstrate that the methylome response of the lung cells to α-radiation is highly dependent on both the total dose and the exposure regimen. They also provide novel insights into potential biomarkers of α-radiation which may lead to the development of innovative approaches to detect, prevent and treat α-particle related diseases.

Project description:Genomic radiation signature illuminates low-dose effects with sharply reflected transcriptome in Ptch1-deficient medulloblastomas. Cancer risks of low-dose radiation are of great concern especially in relation to rapidly increasing medical exposures; however, their accurate assessments cope with many challenges and difficulties, partly due to the inability to distinguish radiation-induced tumors from spontaneous ones. Here, we analyzed the dose-dependent effect of radiation on medulloblastoma development in Ptch1 heterozygous mice on C3B6F1 background. The incidence and latency of medulloblastoma increased and shortened with increasing radiation dose, respectively. Amazingly, radiation contributed to tumorigenesis even at 50 mGy and 100% of mice got medulloblastoma with 1.5 Gy. Loss of heterozygosity (LOH) analysis on a total of 164 tumors indicated that spontaneous tumors showed LOH in broad regions on chromosome 13, including Ptch1 and distally-extending telomeric portion (S-type). In contrast, tumors developed after 3 Gy irradiation exhibited interstitial losses around Ptch1 (R-type). A clear dose-dependent increase in the proportion of R-type tumor at intermediate doses suggested R-type to be a reliable radiation signature. Array-CGH analysis indicated the R-type-specific copy-number reduction around Ptch1 and LOH-type-independent frequent gains of whole chromosome 6. Integrated expression microarray analysis indicated that expression levels of many genes within the altered genomic regions faithfully reflected the genomic copy-number changes. Furthermore, it was also suggested that these expression changes in turn influenced on many other genes, such as Tgfb2 and Tgfb3, on widespread genomic regions. This is the first demonstration that radiation-induced tumors developed after low-dose irradiation can be characterized quite precisely by interstitial deletion of Ptch1 and by associated gene expression profile. Gene expression in 3 normal cerebellum tissues and 12 medulloblastomas was measured.

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Differential Network Analysis Reveals the Key Role of the ECM-receptor Pathway in α-Particle-induced Malignant Transformation

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