Kas K
Laboratorium voor Moleculaire Oncologie Centrum Menselijke Erfelijkheid V.I.B.-KULeuven, Herestraat 49-B 3000 Leuven.
Verh K Acad Geneeskd Belg. 2001;63(1):35-40.
Pleomorphic adenomas are the most common type of salivary gland tumours. Activation of the PLAG1 gene on chromosome 8q12 is the most frequent mutation found in these tumours. This results from chromosomal translocations leading to promoter substitution between PLAG1, mainly expressed in fetal tissue, and more broadly expressed genes. The replacement of the PLAG1 promoter, inactive in adult salivary glands, by a strong promoter derived from the translocation partner, leads to ectopic expression of PLAG1 in the tumor cells. This abnormal PLAG1 expression results in deregulation of PLAG1 target genes causing salivary gland tumorigenesis. PLAG1 binds to promoter 3 of the Insulin-like growth factor 2 gene (IGF2) and stimulates its activity. IGF2 is highly expressed in salivary gland adenomas overexpressing PLAG1 while no IGF2 expression is found in adenoma without abnormal PLAG1 expression nor in normal salivary gland tissue, indicating a perfect correlation between PLAG1 and IGF2 expression. These results provide us with the first clue for understanding the role of PLAG1 in salivary gland tumor development. IGF2 perfectly fits in the picture of a restarted developmental program with concomitant loss of differentiation, the typical hallmark for any tumour. Salivary gland genesis provides a system for studying the development of glandular organs having many basic features in common with the salivary gland, such as breast, kidney, lung, pancreas and prostate. With a unique salivary gland organ culture system we now can study principles of epitheliogenesis, tubulogenesis and branching morphogenesis. Genes expressed at the spot where during tumourigenesis proliferation overrules differentiation constitute new targets for reverting the proliferative, tumour-specific stage. By elucidating molecular mechanisms involved in human cancer, we will hence contribute at the level of fundamental cancer research (oncogenesis) and normal organ development (organogenesis).
多形性腺瘤是唾液腺肿瘤中最常见的类型。8号染色体q12上PLAG1基因的激活是这些肿瘤中最常见的突变。这是由染色体易位导致的，易位使得主要在胎儿组织中表达的PLAG1与更广泛表达的基因之间发生启动子替换。在成年唾液腺中无活性的PLAG1启动子被来自易位伙伴的强启动子所取代，导致PLAG1在肿瘤细胞中异位表达。这种异常的PLAG1表达导致PLAG1靶基因失调，从而引发唾液腺肿瘤发生。PLAG1与胰岛素样生长因子2基因（IGF2）的启动子3结合并刺激其活性。IGF2在过表达PLAG1的唾液腺腺瘤中高度表达，而在无异常PLAG1表达的腺瘤以及正常唾液腺组织中未发现IGF2表达，这表明PLAG1与IGF2表达之间存在完美的相关性。这些结果为我们理解PLAG1在唾液腺肿瘤发展中的作用提供了首个线索。IGF2完全符合重新启动的发育程序的情况，同时伴有分化丧失，这是任何肿瘤的典型特征。唾液腺发生为研究与唾液腺具有许多共同基本特征的腺器官的发育提供了一个系统，如乳腺、肾脏、肺、胰腺和前列腺。借助独特的唾液腺器官培养系统，我们现在可以研究上皮发生、管状发生和分支形态发生的原理。在肿瘤发生过程中增殖超过分化的部位表达的基因构成了逆转增殖性肿瘤特异性阶段的新靶点。通过阐明人类癌症所涉及的分子机制，我们将因此在基础癌症研究（肿瘤发生）和正常器官发育（器官发生）层面做出贡献。
