Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer
Genetic Ablation of Bcl-x Attenuates Invasiveness without Affecting Apoptosis or Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Cancer
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DOI：
10.1371/journal.pone.0004455
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发表时间：
2009-02-11
期刊：
影响因子：
3.7
通讯作者：
Hanahan, Douglas
中科院分区：
文献类型：
--
作者：
Hager, Jeffrey H.;Ulanet, Danielle B.;Hanahan, Douglas
肿瘤细胞死亡是由Bcl-2家族的促凋亡和抗凋亡成员控制的内在细胞死亡途径调节的。抗凋亡Bcl-2家族成员的上调在人类癌症临床前模型中已被证明可以抑制细胞死亡，并与人类肿瘤进展有关。先前在胰岛癌RIP1-Tag2模型中的功能获得性研究，涉及Bcl-x(L)的均匀或局灶性/暂时性过表达，表明肿瘤形成和生长加速。为了在该模型中明确评估内源性Bcl-x在调节细胞凋亡和肿瘤进展中的作用，我们利用同源重组的Cre-LoxP系统设计了胰腺β细胞特异性敲除Bcl-x的两个等位基因。令人惊讶的是，在Bcl-x基因敲除小鼠中，对肿瘤细胞凋亡率或肿瘤生长没有明显的影响。其他抗凋亡的Bcl-2家族成员在bcl -x缺失的肿瘤中表达，但在mRNA水平上没有实质性改变，提示存在冗余，但没有代偿性的转录上调。有趣的是，在模拟缺氧条件下，侵袭性癌的发生率降低，缺乏Bcl-x的肿瘤细胞在侵袭中受损。因此，虽然Bcl-x在抑制细胞凋亡从而促进肿瘤生长方面的功能显然是多余的，但基因消融暗示Bcl-x有选择性地促进侵袭，这与最近报道的Bcl-x(L)在外源性过表达时的促侵袭能力相一致。
Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro-and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L), demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L) upon exogenous over-expression.