Abstract
Immune inhibitory receptors expressed on various types of immune cells deliver inhibitory signals that maintain the homeostasis of the immune system. Recently we demonstrated that leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) and its murine homolog, paired immunoglobulin-like receptor B (PIRB), are expressed on hematopoietic stem cells and acute myeloid leukemia stem cells and function in maintenance of stemness. Herein, we determined that both LILRB2 and its soluble ligand ANGPTL2 are highly expressed in non-small cell lung cancer (NSCLC) samples, and levels are adversely related to patient prognosis. Inhibition of LILRB2 expression in NSCLC cell lines, such as A549 cells, resulted in a dramatic decrease in proliferation, colony formation, and migration. Mechanistic analyses indicated that ANGPTL2 binds LILRB2 to support the growth of lung cancer cells and that the SHP2/CaMK1/CREB axis controls the proliferation of lung cancer cell lines. Our results suggest that signaling involving ANGPTL2 and LILRB2 is important for lung cancer development and represents a novel target for treatment of this type of cancer.
Highlights
According to data from American Cancer Society (2000-2014), lung cancer is the second most common type of tumor and the leading cause of cancer deaths worldwide [1]
We recently demonstrated that calcium/calmodulindependent protein kinase (CaMK) signaling is increased upon ANGPTL stimulation in hematopoietic cells, suggesting that CaMK is a mediator of the ANGPTL/ leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) signaling [19]
ANGPTL2 and LILRB2 are highly expressed on human non-small cell lung cancer (NSCLC) cell lines and human lung cancer samples and expression levels reversely correlate with the survival of lung cancer patients
Summary
According to data from American Cancer Society (2000-2014), lung cancer is the second most common type of tumor and the leading cause of cancer deaths worldwide [1]. About 40% of lung cancers are adenocarcinomas, and the incidence of this subtype is tightly correlated with smoking [3, 4]. Mutations or abnormal expression of a number of molecules, including EGFR, KRAS, TITF1, B7-H1, and epigenetic regulators, are correlated with initiation and development of lung cancers [5,6,7,8,9]. EGFR inhibitors, angiogenesis inhibitors, and monoclonal antibodies have been analyzed in clinic trials with www.impactjournals.com/oncotarget promising results in some subtypes of lung cancer [10, 11]. The mechanisms underlying lung cancer initiation, progression, and metastasis remain largely unknown and patients will benefit from a better understanding of this disease
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