Involvement of LKB1 in epithelial-mesenchymal transition (EMT) of human lung cancer cells.
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.
Roy
Badal C
BC
Biology Division, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
Kohno
Takashi
T
Iwakawa
Reika
R
Moriguchi
Tetsuo
T
Kiyono
Tohru
T
Morishita
Kazuhiro
K
Sanchez-Cespedes
Montse
M
Akiyama
Tetsu
T
Yokota
Jun
J
D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D018398:Homeodomain Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases