Establishment of a Choriocarcinoma Model from Immortalized Normal Extravillous Trophoblast Cells Transduced with HRASV12
Establishment of a Choriocarcinoma Model from Immortalized Normal Extravillous Trophoblast Cells Transduced with HRASV12
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DOI：
10.1016/j.ajpath.2011.05.019
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发表时间：
2011-09-01
影响因子：
6
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Kobayashi, Yusuke;Shimizu, Takatsune;Saya, Hideyuki
绒毛膜癌是一种恶性滋养细胞肿瘤。为了降低目前多药化疗的毒副作用，成功治疗耐药病例，需要开发新的分子靶向治疗。绒毛膜癌turnorigenesis的分子机制仍然没有特点，但是，适当的绒毛膜癌动物模型尚未开发。在本研究中，我们用诱导的绒毛膜癌细胞-1（iC（3）-1）细胞建立了绒毛膜癌模型，所述诱导的绒毛膜癌细胞-1（iC（3）-1）细胞来自视网膜转导活化的H-RAS（HRASV 12）的HTR 8/SVneo人滋养层细胞。iC（3）-1细胞表现出丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇3-激酶（PI 3 K）途径的组成性激活，并在所有接种小鼠中发展成致死性肿瘤。组织学分析显示，肿瘤由两种不同类型的细胞组成，使人联想到合体滋养细胞和细胞滋养细胞，如在人绒毛膜癌中所见。肿瘤表达HLA-G和细胞角蛋白（滋养层标志物）和hCG（绒毛膜癌标志物）。对iC（3）-1细胞和亲代HTR 8/SVneo细胞之间基因表达谱的比较分析显示，iC（3）-1细胞表达的基质金属蛋白酶、上皮-间质转化相关基因和SOX 3的水平高于亲代滋养层细胞。给予SOX 3特异性短发夹RNA可降低SOX 3的表达并减弱iC（3）-1细胞的致瘤活性，表明SOX 3过表达可能与绒毛膜癌的发病机制密切相关。我们的小鼠模型代表了一个强有力的新工具，研究绒毛膜癌的发病机制和治疗。(Am J Pathol 2011，179：1471-1482; DOI：10.1016/j.ajpath.2011.05.019）
Gestational choriocarcinoma is a malignant trophoblastic tunor. The development of novel molecular-targeted therapies is needed to reduce the toxicity of current multiagent chemotherapy and to treat successfully the chemoresistant cases. The molecular mechanisms underlying choriocarcinoma turnorigenesis remain uncharacterized, however, and appropriate choriocarcinoma animal models have not yet been developed. In this study, we established a choriocarcinoma model by inoculating mice with induced-choriocarcinoma cell-1 (iC(3)-1) cells, generated from HTR8/SVneo human trophoblastic cells retnwirally transduced with activated H-RAS (HRASV12). The iC(3)-1 cells exhibited constitutive activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways and developed into lethal tumors in all inoculated mice. Histopathological analysis revealed that the tumors consisted of two distinct types of cells, reminiscent of syncytiotrophoblasts and cytotrophoblasts, as seen in the human choriocarcinoma. The tumors expressed HLA-G and cytokeratin (trophoblast markers) and hCG (a choriocarcinoma marker). Comparative analysis of gene expression profiles between iC(3)-1 cells and parental HTR8/SVneo cells revealed that iC(3)-1 cells expressed matrix metalloproteinases, epithelial-mesenchymal transition-related genes, and SOX3 at higher levels than parental trophoblastic cells. Administration of SOX3-specific short-hairpin RNA decreased SOX3 expression and attenuated the tumorigenic activity of iC(3)-1 cells, suggesting that SOX3 overexpression might be critically involved in the pathogenesis of choriocarcimmia. Our murine model represents a potent new tool for studying the pathogenesis and treatment of choriocarcinoma. (Am J Pathol 2011, 179:1471-1482; DOI: 10.1016/j.ajpath.2011.05.019)