Oral Carcinogenesis: Studies With Human Gingival Kerocyt

癌的发生是一个多步骤的过程，涉及细胞原癌基因的激活和肿瘤抑制基因的失活。上皮细胞经历不同阶段的表型和基因型改变，并逐渐获得恶性生长特征。尽管口腔癌的发病率相对较高，但对导致疾病发生和进展的分子事件知之甚少。本研究的目的是建立一种永生化人牙龈角质形成细胞（IHGK）体外口腔癌发生模型，并研究正常人牙龈角质形成细胞（NHGK）、IHGK和一些头颈部鳞状细胞癌（HNSCC）细胞系的生长和分化特性，以及表型变化与基因表达谱的关系。 还使用正常人牙龈角质形成细胞（NHGK）作为参照进行了22个HNSCC系的基因表达谱分析。聚类数据的分析揭示了两个不同的亚型的基因表达模式之间的HNSCC线表明HNSCC的基因表达谱之间的异质性程度。在HNSCC中也有一组与NHGK相关的基因表达上调或下调。在HNSCC中上调的基因包括癌基因如ECT 2（上皮细胞转化序列2癌蛋白）、STMN 1（stathmin/癌蛋白18）、DEK癌基因、RACGAP 1、生长调节因子如复制因子C、复制蛋白A3、CKS 2（CDC 28蛋白激酶2）、PCNA（增殖细胞核抗原）、CDC 20（CDC 20细胞分裂周期20同系物）和角蛋白8。HNSCC中通常下调的基因包括许多角蛋白，（角蛋白1、2A、6A、7、14、15、16、17、B1和B3），分化标志物，（小脯氨酸丰富蛋白3（SPR 3）和1B（SPR 1B），和转氨酶3），生长停滞或肿瘤抑制基因（GADD 45 A和FAT），细胞表面和细胞外基质蛋白（膜联蛋白A1、A2和A3，层粘连蛋白α和γ 2，整联蛋白β 1，包斑蛋白，包斑蛋白，角桥蛋白和桥粒糖蛋白3）和各种蛋白酶抑制剂蛋白（SERPINB 1、SERPINB 5、SKALP和SLPI）。HNSCC基因表达谱的深入分析应该提供潜在的分子标志物，可以用于诊断和/或治疗目的。

Carcinogenesis is a multi-step process involving the activation of cellular proto-oncogenes and inactivation of tumor suppressor genes. Epithelial cells undergo different stages of phenotypic and genotypic alterations and gradually acquire malignant growth characteristics. In spite of the relatively high frequency of oral cancers, little is known about the molecular events that lead to disease initiation and progression. The goals of our study are to develop an in vitro model of oral carcinogenesis using immortalized human gingival keratinocytes (IHGK) and to characterize the growth and differentiation properties of normal human gingival keratinocytes (NHGK), IHGK and a number of head and neck squamous cell carcinoma (HNSCC) lines and to relate the changes in phenotype with the gene expression profiles. Gene expression profiling of 22 HNSCC lines was also carried out using normal human gingival keratinocytes (NHGK) as a reference. Analysis of the clustered data revealed two distinctive subtypes of gene-expression patterns among the HNSCC lines suggesting a degree of heterogeneity among the gene-expression profiles of HNSCC. There were also a group of genes upregulated or down regulated in HNSCCs with respect to NHGK. The genes upregulated in HNSCC include oncogenes such as ECT2 (epithelial cell transforming sequence 2 oncoprotein), STMN1 (stathmin/oncoprotein 18), DEK oncogene, RACGAP1, growth regulatory factors such as replication factor C, replication protein A3, CKS2 (CDC28 protein kinase2), PCNA (proliferating cell nuclear antigen), CDC20 (CDC20 cell division cycle 20 homolog and keratin 8. The genes commonly downregulated in HNSCC include many keratins, (keratins 1, 2A, 6A, 7, 14, 15, 16, 17, B1 and B3), differentiation markers, (small proline rich protein 3 (SPR3) and 1B (SPR1B), and transglutaminase 3), growth arrest or tumor suppressor gene (GADD45A and FAT), cell surface and extracellular matrix proteins (annexins A1, A2 and A3, laminins alpha and gamma2, integrin beta1, envoplakin, periplakin, corneodesmosin and desmoglein3) and various protease inhibitor proteins (SERPINB1, SERPINB5, SKALP, and SLPI). The in-depth analysis of the gene expression profile of HNSCC should provide potential molecular markers that can be useful for diagnostic and/or therapeutic purposes.