Upregulation of stress-response genes with cell cycle arrest induced by carbon ion irradiation in multiple murine tumors models.
OBJECTIVE
To elucidate the in vivo biological effects induced by carbon-ion irradiation using comprehensive expression analysis.


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 gamma-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 gamma-ray irradiation. Pathological investigation and immunohistochemical analysis of Cdkn1a revealed cell cycle arrest with mitotic catastrophe in tumors irradiated by C-ions.


METHODS
We examined gene expression changes after carbon-ion (C-ion) irradiation (290 MeV/m, SOBP 6 cm middle, 50 kev/microm) 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 six hours (h), one day and three 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.


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.
Imadome
Kaori
K
RadGenomics Project, National Institute of Radiological Sciences, Inage, Chiba, Japan.
Iwakawa
Mayumi
M
Nojiri
Kazunori
K
Tamaki
Tomoaki
T
Sakai
Minako
M
Nakawatari
Miyako
M
Moritake
Takashi
T
Yanagisawa
Mitsuru
M
Nakamura
Etsuko
E
Tsujii
Hirohiko
H
Imai
Takashi
T
D000818:Animals; D002250:Carbon Radioisotopes / Q000627:therapeutic use*; D002453:Cell Cycle / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D019084:Fluorescent Antibody Technique, Indirect; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D020450:Heavy Ions; D018499:Linear Energy Transfer; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012015:Reference Standards; D017356:Synchrotrons; D013997:Time Factors; D047368:Tumor Burden
D002250:Carbon Radioisotopes; D012333:RNA, Messenger