Authors: Yutori, Hirokazu¹; Semba, Shuho; Komori, Takahide²; Yokozaki, Hiroshi¹

Source: Cancer Science, Volume 99, Number 3, March 2008 , pp. 524-530(7)

Publisher: Wiley-Blackwell

Abstract:

Early in tumorigenesis, a DNA damage-response network is activated in preneoplastic cells that delays or prevents cancer. Activation of the Chk2 G₂/M checkpoint kinase and loss of fragile histidine triad (Fhit) tumor suppressor expression increase cellular susceptibility to DNA-damaging `oncogenic' stressors, particularly in precursor or precancerous lesions. To understand the mechanism of oral carcinogenesis, we assessed the association between phosphorylated Chk2 (pChk2) and Fhit expression in oral squamous cell carcinoma. Loss of Fhit expression was an early event during oral carcinogenesis, whereas a decrease in the number of pChk2-positive cells was associated with tumor progression. Although tyrosine 114 is known to be essential to Fhit's tumor-suppressing activity, both wild-type and tyrosine 114 mutant Fhit increased the population of subG₁ DNA-containing HSC-3 OSCC cells with elevated pChk2 levels. In particular, when cells were exposed to ionizing radiation, pChk2 levels were upregulated dramatically, as were those of its downstream target Cdc25C. Knockdown of Fhit with FHIT small interfering RNA diminished the ionizing radiation-induced Chk2 phosphorylation in HEK293 cells. Furthermore, Fhit-deficient mice demonstrated a decrease in the number of pChk2-positive cells not only in dysplastic lesions but also in N-nitrosobenzylamine-induced papilloma of the forestomach, suggesting that lack of Fhit expression and the resultant defects of the ataxia telangiectasia mutated-Chk2 pathway can cause a difference in the incidence of N-nitrosobenzylamine-induced forestomach lesions. These findings suggest that Fhit plays a key role in the regulation of the ataxia telangiectasia mutated-Chk2 DNA damage response during oral carcinogenesis. (Cancer Sci 2008; 99: 524-530)

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1349-7006.2007.00707.x

Affiliations: 1: Division of Pathology, Department of Pathology and Microbiology and 2: Division of Oral and Maxillofacial Surgery, Surgery Department, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Publication date: 2008-03-01

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