L1 cell adhesion molecule promotes tumorigenicity and metastatic potential in non-small cell lung cancer.
OBJECTIVE
Non-small cell lung cancer (NSCLC) is a highly metastatic cancer with limited treatment options, thus requiring development of novel targeted therapies. Our group previously identified L1 cell adhesion molecule (L1CAM) expression as a member of a prognostic multigene expression signature for NSCLC patients. However, there is little information on the biologic function of L1CAM in lung cancer cells. This study investigates the functional and prognostic role of L1CAM in NSCLC.


METHODS
Cox proportional hazards regression analysis was done on four independent published mRNA expression datasets of primary NSCLCs. L1CAM expression was suppressed by short-hairpin RNA (shRNA)-mediated silencing in human NSCLC cell lines. Effects were assessed by examining in vitro migration and invasion, in vivo tumorigenicity in mice, and metastatic potential using an orthotopic xenograft rat model of lung cancer.


RESULTS
L1CAM is an independent prognostic marker in resected NSCLC patients, with overexpression strongly associated with worse prognosis. L1CAM downregulation significantly decreased cell motility and invasiveness in lung cancer cells and reduced tumor formation and growth in mice. Cells with L1CAM downregulation were deficient in constitutive extracellular signal-regulated kinase (Erk) activation. Orthotopic studies showed that L1CAM suppression in highly metastatic lung cancer cells significantly decreases spread to distant organs, including bone and kidney.


CONCLUSIONS
L1CAM is a novel prometastatic gene in NSCLC, and its downregulation may effectively suppress NSCLC tumor growth and metastasis. Targeted inhibition of L1CAM may be a novel therapy for NSCLC.
Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
Josephine
J
Hai
Chang-Qi
CQ
Zhu
Bizhan
B
Bandarchi
Yu-Hui
YH
Wang
Roya
R
Navab
Frances A
FA
Shepherd
Igor
I
Jurisica
Ming-Sound
MS
Tsao
D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D034622:RNA Interference; D051381:Rats; D011923:Rats, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
D039842:Neural Cell Adhesion Molecule L1; D048049:Extracellular Signal-Regulated MAP Kinases