Involvement of LKB1 in epithelial–mesenchymal transition (EMT) of human lung cancer cells

Roy, Badal C.; Kohno, Takashi; Iwakawa, Reika; Moriguchi, Tetsuo; Kiyono, Tohru; Morishita, Kazuhiro; Sanchez-Cespedes, Montse; Akiyama, Tetsu; Yokota, Jun

doi:10.1016/j.lungcan.2010.02.004

« Previous Next »Lung Cancer
Volume 70, Issue 2 , Pages 136-145, November 2010

Involvement of LKB1 in epithelial–mesenchymal transition (EMT) of human lung cancer cells

Badal C. Roy
- Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
Takashi Kohno
- Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
Reika Iwakawa
- Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
Tetsuo Moriguchi
- Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
Tohru Kiyono
- Virology Division, National Cancer Center Research Institute, Tokyo, 104-0045, Japan
Kazuhiro Morishita
- Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, University of Miyazaki, Miyazaki, Japan
Montse Sanchez-Cespedes
- Genes and Cancer Group, Programa de Epigenetica y Biologia del Cancer (PEBC), Institut d’Investigacions Biomediques Bellvitge (IDIBELL), Hospital Durant i Reynals, Avinguda Gran Via de I’Hospitalet, 199-203, 08907-L’Hospitalet de Llobregat, Barcelona, Spain
Tetsu Akiyama
- Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Bioscience, University of Tokyo, Tokyo, Japan
Jun Yokota
- Biology Division, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo, 104-0045, Japan
- Corresponding author. Tel.: +81 3 3547 5272; fax: +81 3 3542 0807.

Received 19 November 2009; received in revised form 5 February 2010; accepted 8 February 2010. published online 08 March 2010.

Abstract

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.

Keywords: LKB1, Epithelial–mesenchymal transition, ZEB1, Lung cancer, Invasion