LKB1 modulates lung cancer differentiation and metastasis
LKB1 modulates lung cancer differentiation and metastasis
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DOI：
10.1038/nature06030
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发表时间：
2007-08-16
期刊：
影响因子：
64.8
通讯作者：
Wong, Kwok-Kin
中科院分区：
文献类型：
--
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
丝氨酸/苏氨酸激酶11(STK11，也称为LKB1)的种系突变导致Peutz-Jeghers综合征，其特征是肠道错构瘤和上皮性癌发病率增加(1)。虽然LKB1在大多数散发性癌症中不常见(2)，但在原发人类肺腺癌及其衍生细胞系(3-5)中已有报道LKB1的失活体细胞突变。在这里，我们使用了一种身体可激活的突变Kras驱动的小鼠肺癌模型，以比较Lkb1与其他肿瘤抑制因子在肺癌中的作用。虽然在这个系统中，Kras突变与P53或Ink4a/Arf(也称为CDKN2a)的丢失是协同作用的，但与Lkb1纯合失活的协同作用最强。与缺乏P53或Ink4a/Arf的肿瘤相比，LKB1缺失的肿瘤表现出更短的潜伏期、更广泛的组织学谱(腺癌、鳞癌和大细胞癌)和更频繁的转移。Lkb1基因的半合子失活也加速了肺肿瘤的发生。与这些发现一致的是，在分析的144例人肺腺癌和鳞癌中，分别有34%和19%的人发现LKB1失活。在人肺癌细胞系和小鼠肺癌中的表达谱表明，多种促进转移的基因，如NEDD9，VEGFC和CD24，是肺癌中LKB1抑制的靶点。这些研究证实，LKB1是肺肿瘤发生的关键屏障，控制着肿瘤的起始、分化和转移。
Germline mutation in serine/ threonine kinase 11 ( STK11, also called LKB1) results in Peutz - Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers(1). Although uncommon in most sporadic cancers(2), inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines(3-5). Here we used a somatically activatable mutant Kras- driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/ Arf ( also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1- deficient tumours demonstrated shorter latency, an expanded histological spectrum ( adeno-, squamous and large- cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/ Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.