Molecularbaological study of craniofacial dysmorphology in transgenic mice bearing Apert type mutant Fgfr2 gene

携带Apert型突变Fgfr2基因的转基因小鼠颅面畸形的分子生物学研究

• 批准号: 14370664
• 负责人: TAKAGI Rituo
• 金额: $ 8万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370664/
• 关键词: oral squamous cell carcinoma; Individual diagnosis; gene expression; real time PCR; MMP; lymph node metastasis; MMP-1

We surveyed the expression of 557 cancer-related genes in 15 cases of histologically well-differentiated oral squamous cell carcinoma(OSCC) by cDNA microarray analysis. U values and results of SAM(significance analysis of microarray) suggested significance of MMP genes and integrin a3 as the biomarker of lymph node metastasis(LNM). We have collected 140 OSCC samples by collaboration of the four institutes. Real time PCR with TaqMan probes are used for the quantification of gene expression levels in OSCC tissues that were incised at biopsy or operation. We have analyzed the 16 genes of MMPs and MMP inhibitors as the possible clinical biomarkers for the cervical LNM. High expression level of MMP-1,MMP-7,MMP-11 and MMP-13 were significantly correlated with existence of the LNM in the 40 cases of tangue OSCC(20 SCC with LNM and 20 without LNM ; Mann-Whitney test, p<0.05). To identify accurate biomarker system for predicting the risk of lymph node metastasis in OSCC, we further analyzed the expression ratios of MMPs to MMP inhibitors(MMPs/TIMP1 or TIMP2 or RECK). As a consequence, only MMP-1 or MMP-7/TIMP1 or TIMP2 exhibited significance, however, the high level of those expression ratio reflected poor prognosis such as multiple LNM, delayed LNM in small T1 cases, and death by uncontrollable tumor including the case of T1-T4. Whereas gene expression analysis by whole tumor tissue involves biases due to the sampling condition, the consistent clinical significance of MMP-1 and MMP-7 indicates the usefulness of these genes as biomarkers for aggressive characteristics of the OSCC.

应用基因芯片技术检测了15例组织学分化良好的口腔鳞状细胞癌（OSCC）中557个癌相关基因的表达。U值和SAM（微阵列显著性分析）结果表明MMP基因和整合素a3作为淋巴结转移（LNM）生物标志物的意义。我们与四间研究所合作，共收集了140个口腔鳞状细胞癌样本。使用TaqMan探针的真实的PCR用于定量活检或手术时切割的OSCC组织中的基因表达水平。我们分析了MMP及其抑制剂的16个基因作为宫颈淋巴结转移的可能临床生物标志物。40例舌鳞癌中MMP-1、MMP-7、MMP-11和MMP-13的高表达与舌鳞癌中存在淋巴结转移（20例有淋巴结转移，20例无淋巴结转移; Mann-Whitney检验，p<0.05）相关。为了确定准确的预测OSCC淋巴结转移风险的生物标志物系统，我们进一步分析了MMPs与MMP抑制剂（MMPs/TIMP 1或TIMP 2或RECK）的表达比率。因此，只有MMP-1或MMP-7/TIMP 1或TIMP 2表现出显著性，然而，这些表达比率的高水平反映了预后不良，例如多发性LNM，小T1病例中的延迟LNM，以及不可控制的肿瘤（包括T1-T4病例）导致的死亡。而整个肿瘤组织的基因表达分析涉及由于采样条件的偏差，MMP-1和MMP-7的一致的临床意义表明这些基因作为OSCC侵袭性特征的生物标志物的有用性。

项目成果

Nagata M, et al.: "Identification of potential biomarkers of lymph node metastasis in oral squamous cell carcinoma by cDNA microarray analysis."Int J Cancer 106:683-9,2003.. 106. 683-689 (2003)

Nagata M 等人：“通过 cDNA 微阵列分析鉴定口腔鳞状细胞癌淋巴结转移的潜在生物标志物。”Int J Cancer 106：683-9,2003.. 106. 683-689 (2003)

Nagashima, K, et al.: "Effect of local hyperthermia on metastases in oral squamous cell carcinoma."Int.J.Oral Maxillofac.Surg.. 31. 84-89 (2002)

Nagashima, K, et al.：“局部热疗对口腔鳞状细胞癌转移的影响。”Int.J.Oral Maxillofac.Surg.. 31. 84-89 (2002)

Nagashima, K., Takagi, R., Hoshina, H.: "Effect of local hyperthermia on metastases in oral squamous cell carcinoma."Int.J.Oral Maxillofac.Surg.. 31. 84-89 (2002)

Nagashima, K.、Takagi, R.、Hoshina, H.：“局部热疗对口腔鳞状细胞癌转移的影响。”Int.J.Oral Maxillofac.Surg.. 31. 84-89 (2002)

Maruyama, S., Takagi, R., Saku, T., et al.: "Sebaceous lymphadenoma of the lip : report of a case of minor salivary gland origin"J. Oral Pathol. Med.. 31. 75-79 (2002)

Maruyama, S., Takagi, R., Saku, T., et al.：“唇部皮脂腺淋巴腺瘤：小唾液腺起源病例的报告”J.

Lai, W., Takagi, R., et al.: "Postoperative mandibular stability after orthognathic surgery in patients with mandibular protrusion and mandibular deviation"Int. J. Adult Orthod. Orthognath. Surg.. 7. 13-22 (2002)

Lai，W.，Takagi，R.，等人：“下颌前突和下颌偏斜患者正颌手术后的术后下颌稳定性”Int。