Restoration of fragile histidine triad expression restores Chk2 activity in response to ionizing radiation in oral squamous cell carcinoma cells
Restoration of fragile histidine triad expression restores Chk2 activity in response to ionizing radiation in oral squamous cell carcinoma cells
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DOI：
10.1111/j.1349-7006.2007.00707.x
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发表时间：
2008-03
期刊：
影响因子：
5.7
通讯作者：
H. Yutori;S. Semba;T. Komori;H. Yokozaki
中科院分区：
文献类型：
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作者：
H. Yutori;S. Semba;T. Komori;H. Yokozaki
在肿瘤发生的早期，DNA损伤反应网络在肿瘤前细胞中被激活，从而延迟或预防癌症。Chk 2 G2/M检查点激酶的激活和脆性组氨酸三联体（Fhit）肿瘤抑制因子表达的缺失增加了细胞对DNA损伤“致癌”应激因子的易感性，特别是在前体或癌前病变中。为了了解口腔癌的发生机制，我们评估了磷酸化Chk 2（pChk 2）和Fhit表达在口腔鳞状细胞癌中的相关性。Fhit表达的丧失是口腔癌发生过程中的早期事件，而pChk 2阳性细胞数量的减少与肿瘤进展相关。虽然酪氨酸114对Fhit的肿瘤抑制活性至关重要，但野生型和酪氨酸114突变型Fhit均增加了含有subG 1 DNA的HSC-3 OSCC细胞的数量，pChk 2水平升高。特别是，当细胞暴露于电离辐射时，pChk 2水平显著上调，其下游靶点Cdc 25 C也是如此。用FHIT小干扰RNA敲低Fhit可减少HEK 293细胞中电离辐射诱导的Chk 2磷酸化。此外，Fhit缺陷小鼠不仅在发育异常病变中，而且在N-亚硝基苄胺诱导的前胃乳头状瘤中，pChk 2阳性细胞的数量也减少，这表明Fhit表达的缺乏和共济失调毛细血管扩张突变-Chk 2途径的缺陷可能导致N-亚硝基苄胺诱导的前胃病变发生率的差异。这些结果表明，Fhit在调节共济失调毛细血管扩张症突变的Chk 2 DNA损伤反应在口腔癌的发生过程中起着关键作用。（Cancer Sci 2008; 99：524-530）
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)