Biology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Lung Cancer. 2010 Nov;70(2):136-45. doi: 10.1016/j.lungcan.2010.02.004. Epub 2010 Mar 5.
Epithelial-mesenchymal transition (EMT) is a critical phenotypic alteration of cancer cells that triggers invasion and metastasis. Lung cancer cells often show mesenchymal phenotypes; however, a causative genetic alteration for the induction of EMT in lung cancer cells remains unknown. Recent studies have shown that the LKB1 gene is mutated in up to one-third of lung adenocarcinomas. Therefore, to pursue the possible involvement of LKB1 inactivation in the induction of EMT in lung carcinogenesis, we generated immortalized lung epithelial cells and lung adenocarcinoma cells with stable or transient LKB1 knockdown. LKB1 knockdown increased cell motility and invasiveness, and induced the expression of several mesenchymal marker proteins accompanied by the expression of ZEB1, a transcriptional repressor for E-cadherin and an EMT inducer. In agreement with the recent findings, expression of miR-200a/c was inversely correlated with that of ZEB1 in LKB1 knockdown clones with mesenchymal phenotype. Furthermore, transient knockdown of LKB1 induced ZEB1 mRNA and increased cell motility, and this motility was suppressed by ZEB1 repression. These results strongly indicate that LKB1 inactivation triggers EMT in lung cancer cells through the induction of ZEB1.
上皮-间充质转化（EMT）是癌症细胞的一种关键表型改变，可触发侵袭和转移。肺癌细胞常表现出间充质表型；然而，肺癌细胞中 EMT 诱导的致病变异仍不清楚。最近的研究表明，LKB1 基因在多达三分之一的肺腺癌中发生突变。因此，为了探讨 LKB1 失活在肺肿瘤发生中诱导 EMT 中的可能参与，我们生成了稳定或瞬时敲低 LKB1 的永生化肺上皮细胞和肺腺癌细胞。LKB1 敲低增加了细胞迁移和侵袭性，并诱导了几个间充质标记蛋白的表达，同时表达了 ZEB1，它是 E-钙粘蛋白的转录抑制因子和 EMT 诱导因子。与最近的发现一致，在具有间充质表型的 LKB1 敲低克隆中，miR-200a/c 的表达与 ZEB1 的表达呈负相关。此外，瞬时敲低 LKB1 诱导 ZEB1 mRNA 的表达并增加细胞迁移性，而这种迁移性被 ZEB1 抑制所抑制。这些结果强烈表明，LKB1 失活通过诱导 ZEB1 触发肺癌细胞中的 EMT。
