Gunduz Mehmet, Nagatsuka Hitoshi, Demircan Kadir, Gunduz Esra, Cengiz Beyhan, Ouchida Mamoru, Tsujigiwa Hidetsugu, Yamachika Eiki, Fukushima Kunihiro, Beder Levent, Hirohata Satoshi, Ninomiya Yoshifumi, Nishizaki Kazunori, Shimizu Kenji, Nagai Noriyuki
Department of Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, 2-5-1 Shikatacho, Okayama 700-8525, Japan.
Gene. 2005 Aug 15;356:109-17. doi: 10.1016/j.gene.2005.02.014.
We previously showed two members of the ING family, ING1 and ING3 as a tumor suppressor gene in head and neck cancer. Progress in human genome sequencing provided additional information of the new members of the ING family genes. ING4 is localized to chromosome 12p13.31 region and harbors the PHD domain highly homologous among ING family proteins. We analyzed loss of heterozygosity at 12p12-13 region in 50 head and neck squamous cell carcinomas by using six highly polymorphic microsatellite markers and found allelic loss in 66% (33/50) of the informative cases. To clarify the role of ING4 in head and neck carcinogenesis, we first checked mutation status in tumor samples. As mutation of the ING4 gene was not found in head and neck cancers, we examined the mRNA expression level. Quantitative real-time RT-PCR analysis demonstrated decreased expression of ING4 mRNA in 76% of primary tumors as compared with that of matched normal samples. Since p53 dependent pathways of other ING family members have been shown, we examined p53 mutation status and compared with ING4 mRNA expression in tumor samples. However, no such direct relationship has been detected. In conclusion, frequent deletion and decreased mRNA expression of ING4 suggested it as a class two tumor suppressor gene and may play an important role in head and neck cancer.
我们之前已表明，ING家族的两个成员ING1和ING3在头颈癌中作为肿瘤抑制基因发挥作用。人类基因组测序的进展为ING家族基因的新成员提供了更多信息。ING4定位于染色体12p13.31区域，且含有在ING家族蛋白中高度同源的PHD结构域。我们使用六个高度多态性的微卫星标记分析了50例头颈鳞状细胞癌中12p12 - 13区域的杂合性缺失情况，发现在66%（33/50）的信息性病例中存在等位基因缺失。为阐明ING4在头颈癌发生中的作用，我们首先检测了肿瘤样本中的突变状态。由于在头颈癌中未发现ING4基因的突变，我们检测了其mRNA表达水平。定量实时RT-PCR分析表明，与配对的正常样本相比，76%的原发性肿瘤中ING4 mRNA表达降低。鉴于其他ING家族成员的p53依赖途径已被证实，我们检测了p53突变状态，并将其与肿瘤样本中的ING4 mRNA表达进行比较。然而，未检测到这种直接关系。总之，ING4的频繁缺失和mRNA表达降低表明它是一种二类肿瘤抑制基因，可能在头颈癌中发挥重要作用。
