Targeted deletion of MKK4 in cancer cells:: A detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss
Targeted deletion of MKK4 in cancer cells:: A detrimental phenotype manifests as decreased experimental metastasis and suggests a counterweight to the evolution of tumor-suppressor loss
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DOI：
10.1158/0008-5472.can-06-0555
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发表时间：
2006-06-01
期刊：
影响因子：
11.2
通讯作者：
Kern, Scott E.
中科院分区：
文献类型：
--
作者：
Cunningham, Steven C.;Gallmeier, Eike;Kern, Scott E.
肿瘤抑制基因因其在人类肿瘤中的失活突变而备受关注。然而，人们对相反的情况知之甚少，即肿瘤并不会选择很大比例的看似有利的肿瘤抑制基因突变。这可以用一种有害的表型来解释，这种表型是以细胞类型特有的方式积累到大多数经历双等位基因丧失的细胞中的。例如，MKK4是一种肿瘤抑制基因，其特点是在不同的肿瘤类型中具有非常一致的突变率和异常高的杂合性丢失率，其遗传失活率令人惊讶地低，仅为5%。为了探索这种不一致性，我们在人类癌细胞中设计了一种MKK4的体细胞基因敲除。尽管空细胞在塑料培养皿中的体外活性和增殖能力与野生型细胞相似，但在实验转移和肿瘤形成的更相关的体内模型上存在显著差异。静脉注射MKK4(-/-)克隆。与同基因MKK4活性细胞相比，MKK4诱导的肺转移较少(P=0.0034)。这些发现表明，细胞类型特定的有害表型如何提供一种自相矛盾但又关键的平衡，以对抗细胞在肿瘤形成过程中试验遗传零状态时获得的选择优势，所产生的平衡然后确定给定肿瘤抑制基因的观察到的双等位基因突变率。
Tumor-suppressors have commanded attention due to the selection for their inactivating mutations in human tumors. However, relatively little is understood about the inverse, namely, that tumors do not select for a large proportion of seemingly favorable mutations in tumor-suppressor genes. This could be explained by a detrimental phenotype accruing in a cell type-specific manner to most cells experiencing a biallelic loss. For example, MKK4, a tumor suppressor gene distinguished by a remarkably consistent mutational rate across diverse tumor types and an unusually high rate of loss of heterozygosity, has the surprisingly low rate of genetic inactivation of only similar to 5%. To explore this incongruity, we engineered a somatic gene knockout of MKK4 in human cancer cells. Although the null cells resembled the wild-type cells regarding in vitro viability and proliferation in plastic dishes, there was a marked difference in a more relevant in vivo model of experimental metastasis and tumorigenesis. MKK4(-/-) clones injected i.v. produced fewer lung metastases than syngeneic MKK4-competent cells (P = 0.0034). These findings show how cell type-specific detrimental phenotypes can offer a paradoxical and yet key counterweight to the selective advantage attained by cells as they experiment with genetic null states during tumorigenesis, the resultant balance then determining the observed biallelic mutation rate for a given tumor-suppressor gene.