Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse
Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse
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DOI：
10.1073/pnas.2235927100
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发表时间：
2003-11-25
影响因子：
11.1
通讯作者：
Pollard, HB
中科院分区：
文献类型：
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作者：
Srivastava, M;Montagna, C;Pollard, HB
膜联蛋白7（ANX 7）在前列腺癌中充当肿瘤抑制基因，其中杂合性丢失和ANX 7蛋白表达减少与侵袭性转移性肿瘤相关。为了研究该基因控制肿瘤发展的机制，我们开发了Anx 7（+/-）敲除小鼠。如假设的，Anx 7（+/-）小鼠具有癌症倾向表型。新出现的肿瘤表达低水平的Anx 7蛋白。尽管如此，野生型Anx 7等位基因在激光捕获显微切割衍生的肿瘤组织细胞中是可检测的。肝细胞癌组织的基因组阵列分析表明，Anx 7（+/-）基因型伴随着其他几个肿瘤抑制基因，DNA修复基因和凋亡相关基因的表达显著降低。通过原发性肿瘤中染色体的组织印迹原位分析和衍生细胞系的光谱核型分析鉴定染色体不稳定性和克隆性染色体畸变。此外，尽管23%的突变小鼠发生自发性肿瘤，但所有小鼠均表现出生长异常，包括性别特异性发育迟缓和器官肿大。我们的结论是，Anx 7表达的单倍不足似乎驱动疾病进展为癌症，因为基因组的不稳定性，通过一个离散的信号通路，涉及其他肿瘤抑制基因，DNA修复基因，和凋亡相关基因。
Annexin 7 (ANX7) acts as a tumor suppressor gene in prostate cancer, where loss of heterozygosity and reduction of ANX7 protein expression is associated with aggressive metastatic tumors. To investigate the mechanism by which this gene controls tumor development, we have developed an Anx7(+/-) knockout mouse. As hypothesized, the Anx7(+/-) mouse has a cancer-prone phenotype. The emerging tumors express low levels of Anx7 protein. Nonetheless, the wild-type Anx7 allele is detectable in laser-capture microdissection-derived tumor tissue cells. Genome array analysis of hepatocellular carcinoma tissue indicates that the Anx7(+/-) genotype is accompanied by profound reductions of expression of several other tumor suppressor genes, DNA repair genes, and apoptosis-related genes. In situ analysis by tissue imprinting from chromosomes in the primary tumor and spectral karyotyping analysis of derived cell lines identify chromosomal instability and clonal chromosomal aberrations. Furthermore, whereas 23% of the mutant mice develop spontaneous neoplasms, all mice exhibit growth anomalies, including gender-specific gigantism and organomegaly. We conclude that haploinsufficiency of Anx7 expression appears to drive disease progression to cancer because of genomic instability through a discrete signaling pathway involving other tumor suppressor genes, DNA-repair genes, and apoptosis-related genes.