Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma
Tumor-specific mutation and downregulation of ING5 detected in oral squamous cell carcinoma
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DOI：
10.1002/ijc.25224
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发表时间：
2010-11-01
影响因子：
6.4
通讯作者：
Nagatsuka, Hitoshi
中科院分区：
文献类型：
--
作者：
Cengiz, Beyhan;Gunduz, Esra;Nagatsuka, Hitoshi
我们前期的研究表明，口腔癌患者在染色体2q37区域的等位基因丢失频率较高。该位置包含几个候选肿瘤抑制基因，如PPP1R7、ILKAP、DTYMK和ING5。我们之前发现生长抑制因子（ING）家族的3个成员，ING1， ING3和ING4在头颈癌中作为肿瘤抑制基因。由于ING5与ING基因的其他成员具有高度的同源性，包括高度保守的羧基末端植物同源结构域和核定位信号，我们首先发现了ING5并将其作为可能的肿瘤抑制因子在口腔癌中进行了研究。为此，我们采用逆转录聚合酶链反应（RT-PCR）和测序技术检测了ING5在正常和口腔鳞状细胞癌配对样本中的突变和mRNA表达情况。在ING5蛋白的亮氨酸拉链样（LZL）指和新保守区（NCR）结构域检测到3个错义突变，可能使其丧失了正常功能。我们还发现了ING5的5种不同的备选剪接变体。然后，我们通过定量实时反转录聚合酶链反应（qRT-PCR）分析检测了ING5 mRNA的水平，结果表明，与匹配的正常样本相比，61%的原发肿瘤中ING5 mRNA的表达降低。综上所述，ing5mrna的肿瘤特异性突变和下调提示其在口腔鳞状细胞癌中可能是肿瘤抑制基因。
Our previous study showed high frequency of allelic loss at chromosome 2q37 region in oral cancer. This location contains several candidate tumor suppressor genes such as PPP1R7, ILKAP, DTYMK and ING5. We previously showed 3 members of inhibitor of growth (ING) family, ING1, ING3 and ING4 as tumor suppressor gene in head and neck cancer. As ING5 shows high homology with other members of ING genes including highly conserved carboxy-terminal plant homeodomain and nuclear localization signal, we first picked up ING5 and examined it as a possible tumor suppressor in oral cancer. For this aim, mutation and mRNA expression status of ING5 in paired normal and oral squamous cell carcinoma samples were examined by reverse transcription polymerase chain reaction (RT-PCR) and sequencing. Three missense mutations located within leucine zipper like (LZL) finger and novel conserved region (NCR) domains in ING5 protein were detected, probably abrogating its normal function. We also found 5 different alternative splicing variants of ING5. Then, we examined mRNA level of ING5 by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) analysis, which demonstrated decreased expression of ING5 mRNA in 61% of the primary tumors as compared to the matched normal samples. In conclusion, tumor-specific mutation and downregulation of ING5 mRNA suggested it as a tumor suppressor gene in oral squamous cell carcinoma.