The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice
The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor essential for chromosome stability in mice
复制标题
DOI：
10.1172/jci43452
复制
发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Lu, Kun Ping
中科院分区：
文献类型：
--
作者：
Zhou, Xiao Zhen;Huang, Pengyu;Lu, Kun Ping
端粒酶在大多数人类癌症中被激活，对癌细胞生长至关重要。然而，人们对端粒酶激活在染色体不稳定和癌症发生中的重要性知之甚少。编码有效内源性端粒酶抑制剂 PinX1（PIN2/TRF1 相互作用，端粒酶抑制剂 1）的基因位于人类染色体 8p23，该区域在许多常见人类癌症中经常表现出杂合性，但 PinX1 在发育和肿瘤发生中的功能尚不清楚。在这里，我们证明了 PinX1 是一种单倍体不足的肿瘤抑制基因，对于小鼠染色体的稳定性至关重要。我们发现 PinX1 表达在大多数人类乳腺癌组织和细胞系中降低。此外，小鼠胚胎成纤维细胞中的 PinX1 杂合性和 PinX1 敲低可激活端粒酶并导致伴随的端粒酶依赖性染色体不稳定。此外，虽然 PinX1 缺失小鼠胚胎死亡，但大多数 PinX1(+/-) 小鼠自发发展出恶性肿瘤，并有染色体不稳定的证据。值得注意的是，大多数 PinX1 突变肿瘤都是癌，并且与 8p23 相关的人类癌症类型共享起源组织。 PinX1 敲除还将 p53 突变小鼠的肿瘤谱从淋巴瘤转变为上皮癌。因此，PinX1 是一种主要的单倍体不足的肿瘤抑制因子，对于维持端粒酶活性和染色体稳定性至关重要。这些发现揭示了我们认为 PinX1 和端粒酶在染色体不稳定和癌症发生中的新作用，并表明端粒酶抑制可能可用于治疗过度表达端粒酶的癌症。
Telomerase is activated in most human cancers and is critical for cancer cell growth. However, little is known about the significance of telomerase activation in chromosome instability and cancer initiation. The gene encoding the potent endogenous telomerase inhibitor PinX1 (PIN2/TRF1-interacting, telomerase inhibitor 1) is located at human chromosome 8p23, a region frequently exhibiting heterozygosity in many common human cancers, but the function or functions of PinX1 in development and tumorigenesis are unknown. Here we have shown that PinX1 is a haploinsufficient tumor suppressor essential for chromosome stability in mice. We found that PinX1 expression was reduced in most human breast cancer tissues and cell lines. Furthermore, PinX1 heterozygosity and PinX1 knockdown in mouse embryonic fibroblasts activated telomerase and led to concomitant telomerase-dependent chromosomal instability. Moreover, while PinX1-null mice were embryonic lethal, most PinX1(+/-) mice spontaneously developed malignant tumors with evidence of chromosome instability. Notably, most PinX1 mutant tumors were carcinomas and shared tissues of origin with human cancer types linked to 8p23. PinX1 knockout also shifted the tumor spectrum of p53 mutant mice from lymphoma toward epithelial carcinomas. Thus, PinX1 is a major haploinsufficient tumor suppressor essential for maintaining telomerase activity and chromosome stability. These findings uncover what we believe to be a novel role for PinX1 and telomerase in chromosome instability and cancer initiation and suggest that telomerase inhibition may be potentially used to treat cancers that overexpress telomerase.