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Research Paper
Upregulation of stress-response genes with cell cycle arrest induced by carbon ion irradiation in multiple murine tumors models
Kaori Imadome, Mayumi Iwakawa, Kazunori Nojiri, Tomoaki Tamaki, Minako Sakai, Miyako Nakawatari, Takashi Moritake, Mitsuru Yanagisawa, Etsuko Nakamura, Hirohiko Tsujii and Takashi Imai
volume 7 | issue 2
February 2008Pages: 208 - 217
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Objective: To elucidate the in vivo biological effects induced by carbon-ion irradiation using comprehensive expression analysis.
Materials and Methods: We examined gene expression changes after carbon-ion (C-ion) irradiation (290 MeV/m, SOBP 6 cm middle, 50 kev/μm) with a single dose of 30 Gy in four mouse tumors (NR-S1, SCCVII, NFSa, and #8520) transplanted into the hind legs of C3H/HeNrs mice, using 44K single-color oligo-microarrays at 6 hours (h), 1 day, and 3 days after irradiation. Gamma rays of 30 Gy and 50 Gy were used as a reference beam. Identification of C-ion-responsive genes was based on a false discovery rate of < 5% using the Wilcoxon test (P < 0.001) and the Benjamini-Hochberg correction.
Results: In all tumors, the level of expression of several tens of genes, including Ccl3, Ccng1, Cd80, Cdkn1a, Cxcl2, IL7r, Lrdd, Mgmt, Mmp8, and Polk, was significantly altered 6 h and day 1 following C-ion irradiation. At day 3, several hundred genes, many of which are also classified as stress-response or cell-communication genes, including Tnfrsf5, Ikbke, and Icam1, were upregulated following C-ion irradiation. The expression level of the majority of these genes was similar following γ-ray treatment, although the change was not as extensive and intertumor variance was apparent. Several genes, including Ikbke, Serpina3n, and Saa3, responded differentially following C-ion irradiation than after γ-ray irradiation. Pathological investigation and immunohistochemical analysis of Cdkn1a revealed cell cycle arrest with mitotic catastrophe in tumors irradiated by C-ions.
Conclusions: This study revealed significant C-ion induced upregulation of stress-responsive and cell-communication genes common to different tumor types. These findings provide evidence for the efficacy of this modality for the treatment of local tumors.