Exogenous expression of synaptotagmin XIII suppresses the neoplastic phenotype of a rat liver tumor cell line through molecular pathways related to mesenchymal to epithelial transition
Exogenous expression of synaptotagmin XIII suppresses the neoplastic phenotype of a rat liver tumor cell line through molecular pathways related to mesenchymal to epithelial transition
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DOI：
10.1016/j.yexmp.2010.09.001
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发表时间：
2010-12-01
影响因子：
3.6
通讯作者：
Coleman, William B.
中科院分区：
文献类型：
--
作者：
Jahn, Jennifer E.;Best, D. Hunter;Coleman, William B.
肝细胞癌的分子发病机制已被充分研究，但尚未完全了解。我们利用大鼠肝肿瘤细胞的肿瘤抑制的微细胞杂交模型，以促进位于人类11号染色体上的肝肿瘤抑制基因的鉴定。这些研究证实了在人类11p11.2的肝脏肿瘤抑制基因座，确定WO作为11p11.2介导的肿瘤抑制的潜在效应子，并且随后确定人类SYT 13作为11p11.2肝脏肿瘤抑制基因的强有力的候选者。在这里介绍的研究中，我们将SYT 13引入GN 6 TF大鼠肝肿瘤细胞系中，以表征SYT 13在该模型系统中的功能作用。表达SDS抗性二聚体形式的SYT 13蛋白的转染克隆显示诱导Wt 1基因表达和由亲本肿瘤细胞系表现出的肿瘤表型的显著减弱。SYT 13二聚体阳性细胞系的饱和密度和非贴壁依赖性生长在体外降低，在体内同基因宿主大鼠中的致瘤性显著降低或消融。此外，在正常肝上皮细胞中观察到的接触抑制的上皮样形态的恢复伴随SYT 13蛋白二聚体的异位表达，表明SYT 13可能介导这些细胞中与肿瘤抑制协调的上皮分化。因此，与亲本肿瘤细胞相比，SYT 13二聚体阳性细胞系中E-钙粘蛋白（Cdh 1）mRNA的表达增加>100倍，而Cdh 1转录抑制因子Snail在这些细胞中降低>3倍。这些研究联合收割机表明SYT 13是一种肝脏肿瘤抑制基因，其功能可能通过间充质向上皮转化的途径介导。(C)2010年爱思唯尔公司All rights reserved.
The molecular pathogenesis of hepatocellular carcinoma is well-studied but not completely understood. We utilized a microcell-hybrid model of tumor suppression in rat liver tumor cells to facilitate the identification of liver tumor suppressor genes located on human chromosome 11. These investigations confirmed a liver tumor suppressor locus at human 11p11.2, identified WO as a potential effector of 11p11.2-mediated tumor suppression, and subsequently identified human SYT13 as a strong candidate for the 11p11.2 liver tumor suppressor gene. In the studies presented here, we introduced SYT13 into the GN6TF rat liver tumor cell line to characterize a functional role for SYT13 in this model system. Transfected clones expressing an SDS-resistant dimer form of the SYT13 protein displayed induction of Wt1 gene expression and a significant attenuation of the neoplastic phenotype exhibited by the parental tumor cell line. Saturation densities and anchorage-independent growth of SYT13 dimer-positive cell lines were reduced in vitro, and tumorigenicity was significantly decreased or ablated in syngeneic host rats in vivo. In addition, restoration of the contact-inhibited, epithelioid morphology observed in normal liver epithelial cells accompanied ectopic expression of the SYT13 protein dimer, suggesting that SYT13 may be mediating an epithelial differentiation coordinate with tumor suppression in these cells. Accordingly, the expression of E-cadherin (Cdh1) mRNA was increased >100-fold in SYT13-dimer-positive cell lines and the Cdh1 transcriptional repressor Snail was decreased >3-fold in these cells compared to the parental tumor cells. These studies combine to suggest that SYT13 is a liver tumor suppressor gene and that its function may be mediated through pathways implicated in mesenchymal to epithelial transition. (C) 2010 Elsevier Inc. All rights reserved.