Allemand I, Grimber G, Kornprobst M, Bennoun M, Molina T, Briand P, Joulin V
INSERM U-380, Institut Cochin de Génétique Moléculaire, Paris, France.
Oncogene. 1995 Dec 21;11(12):2583-90.
Transgenesis allows the in vivo determination of the effects of oncogene expression in normal tissues. In an attempt to understand the mechanism underlying liver transformation, we have previously created transgenic mice carrying the SV40 early gene sequences, which developed hepatocarcinoma in a reproducible way. In the present study, we show that constant expression of the transgene was directly correlated to an abnormally increased hepatocyte proliferation, even at the adult stage. We further demonstrate in this model that the preneoplastic stage of hepatocarcinoma is characterized by marked ploidy alterations as early as 1 month, including the emergence of aneuploid and hyperpolyploid cells, and the persistence of an important diploid cell population. We show that this elevated proliferation is early and transiently counterbalanced by a mechanism of apoptosis, which maintains liver homeostasis. The disappearance of this programmed cell death response effective during preneoplasia might signal the commitment of the liver to neoplasia.
转基因技术能够在体内确定癌基因在正常组织中表达所产生的影响。为了试图理解肝脏转化的潜在机制，我们之前构建了携带SV40早期基因序列的转基因小鼠，这些小鼠会以可重复的方式发生肝癌。在本研究中，我们发现，即使在成年阶段，转基因的持续表达也与肝细胞异常增殖增加直接相关。我们在该模型中进一步证明，肝癌的癌前阶段早在1个月时就以明显的倍性改变为特征，包括非整倍体和超倍体细胞的出现，以及重要的二倍体细胞群体的持续存在。我们表明，这种增殖升高在早期会被一种凋亡机制短暂抵消，该机制维持着肝脏的稳态。这种在癌前阶段有效的程序性细胞死亡反应的消失可能预示着肝脏向肿瘤的转变。
