Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats

作者：Yafune Atsunori; Taniai Eriko; Morita Reiko; Hayashi Hitomi; Suzuki Kazuhiko; Mitsumori Kunitoshi; Shibutani Makoto^*

来源：Toxicology Letters, 2013, 219(3): 203-210.

DOI：10.1016/j.toxlet.2013.03.012

• Carcinogen
• M phase
• Cell proliferation
• Immunohistochemical analysis

We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G(1) checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1 alpha (HP1 alpha)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[ 4,5-b] pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B+ carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1 alpha responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs.

• 出版日期2013-6-7