Abstract
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. 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. 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. 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.
Highlights
Lung cancer is one of the most lethal cancers with an estimated 1.3 million deaths per year worldwide [1]
L1 cell adhesion molecule (L1CAM) is an independent prognostic marker in resected Non– small cell lung cancer (NSCLC) patients, with overexpression strongly associated with worse prognosis
Cells with L1CAM downregulation were deficient in constitutive extracellular signal–regulated kinase (Erk) activation
Summary
Lung cancer is one of the most lethal cancers with an estimated 1.3 million deaths per year worldwide [1]. Non– small cell lung cancer (NSCLC) comprises approximately 85% of all lung cancers. Despite recent identification of many oncogenes and tumor suppressor genes important for the development and treatment of NSCLC, overall 5-year survival remains poor at 15% [2,3,4,5,6]. Early-stage patients potentially are curable by surgery, approximately 30% to 60% recur postoperatively and die Authors' Affiliations: 1Ontario Cancer Institute/Princess Margaret Hospital, University Health Network; and Departments of 2Medical Biophysics, 3Medicine, 4Computer Science, and 5Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Factors contributing to early progression and metastasis in NSCLC remain largely unknown.
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