Van Dyck Frederik, Scroyen Ilse, Declercq Jeroen, Sciot Raf, Kahn Barbara, Lijnen Roger, Van de Ven Wim J M
Laboratory for Molecular Oncology, Department for Human Genetics, University of Leuven, B-3000 Leuven, Belgium.
Int J Oncol. 2008 Jan;32(1):33-40.
The developmentally regulated PLAG1 proto-oncogene has been implicated in the development of various human tumor types, such as pleomorphic salivary gland adenomas, lipoblastomas, hepatoblastomas and AML. In previous studies, we generated two independent PLAG1 transgenic founder strains, PTMS1 and PTMS2, in which PLAG1 could be activated via Cre-mediated excision of a stop cassette. With these founders, PLAG1-induced tumor formation in salivary and mammary glands of mice was studied. To further delineate the oncogenic spectrum of PLAG1 in mice, we induced aP2-Cre-mediated overexpression of PLAG1 in offspring from crossbreeding PTMS1 mice with aP2-Cre transgenic mice. More than 80% of aP2-Cre(+/-)/PLAG1(+/-) (P1-ACre) mice developed a vascular tumor type within one year, which could be classified histopathologically as cavernous angiomatosis. The lesions occurred in various regions of the mouse body but almost exclusively in the immediate surrounding of fat cells. Validation of available PLAG1-induced gene expression profiling data, using targeted tissues, revealed that expression activation of PLAG1 is functional because it leads to elevated levels of PLAG1 target gene transcripts in those tissues, such as for instance those of H19, Dlk1, and Igf-2, similarly as observed in PLAG1-induced salivary and mammary gland tumors. In conclusion, we present the first evidence that links PLAG1 to the molecular pathogenesis of vascular tumorigenesis, known as cavernous angiomatosis, with the possible involvement of Igf signaling and, moreover, further delineate the oncogenic spectrum of PLAG1 in mice, increasing the potential of this transgenic mouse tumor model system for research and therapeutic drug testing.
发育调控的PLAG1原癌基因与多种人类肿瘤类型的发生发展有关，如多形性涎腺腺瘤、脂肪母细胞瘤、肝母细胞瘤和急性髓细胞白血病。在先前的研究中，我们构建了两个独立的PLAG1转基因奠基鼠品系PTMS1和PTMS2，其中PLAG1可通过Cre介导的终止盒切除而被激活。利用这些奠基鼠，研究了PLAG1诱导的小鼠唾液腺和乳腺肿瘤形成。为了进一步明确PLAG1在小鼠中的致癌谱，我们通过将PTMS1小鼠与aP2-Cre转基因小鼠杂交，诱导后代中aP2-Cre介导的PLAG1过表达。超过80%的aP2-Cre(+/-)/PLAG1(+/-)（P1-ACre）小鼠在一年内发生了一种血管肿瘤类型，经组织病理学分类为海绵状血管瘤病。病变发生在小鼠身体的各个部位，但几乎只出现在脂肪细胞的紧邻区域。使用靶向组织对现有的PLAG1诱导的基因表达谱数据进行验证，结果显示PLAG1的表达激活具有功能，因为它导致这些组织中PLAG1靶基因转录本水平升高，例如H19、Dlk1和Igf-2的转录本，这与在PLAG1诱导的唾液腺和乳腺肿瘤中观察到的情况类似。总之，我们首次提供了证据，将PLAG1与血管肿瘤发生的分子发病机制（即海绵状血管瘤病）联系起来，可能涉及Igf信号传导，此外，进一步明确了PLAG1在小鼠中的致癌谱，增加了这种转基因小鼠肿瘤模型系统用于研究和治疗药物测试的潜力。
