Abstract
Repulsive guidance molecules (RGMs) are co-receptors of bone morphogenetic proteins (BMPs) and programmed death ligand 2 (PD-L2), and might be involved in lung and other cancers. We evaluated repulsive guidance molecule B (RGMB) expression in 165 non-small cell lung cancer (NSCLC) tumors and 22 normal lung tissue samples, and validated the results in an independent series of 131 samples. RGMB was downregulated in NSCLC (P ≤ 0.001), possibly through promoter hypermethylation. Reduced RGMB expression was observed in advanced-stage tumors (P = 0.017) and in tumors with vascular invasion (P < 0.01), and was significantly associated with poor overall survival (39 vs. 62 months, P < 0.001) and with disease-associated patient mortality (P = 0.015). RGMB knockdown promoted cell adhesion, invasion and migration, in both NSCLC cell lines and an in vivo mouse model, which enhanced metastatic potential. Conversely, RGMB overexpression and secretion suppressed cancer progression. The tumor-suppressing effect of RGMB was exerted through inhibition of the Smad1/5/8 pathway. Our results demonstrate that RGMB is an important inhibitor of NSCLC metastasis and that low RGMB expression is a novel predictor or a poor prognosis.
Highlights
Lung cancer is one of the most commonly diagnosed malignancies and accounted for approximately 13% of the total cancer diagnoses in 2012
Reduced Repulsive guidance molecule B (RGMB) expression is associated with disease progression and poor prognosis Lower RGMB transcript levels were observed in more advanced-stage tumors and tumors with vascular invasion (Figure 1D)
The present study revealed that RGMB is downregulated in lung cancer and that downregulation of RGMB is correlated with poor prognosis and shorter OS
Summary
Lung cancer is one of the most commonly diagnosed malignancies and accounted for approximately 13% of the total cancer diagnoses in 2012. It is the leading cause of cancer death in males and second leading cause in females worldwide [1]. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases and includes adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma [2]. Repulsive guidance molecules (RGMs) are glycosylphosphatidylinisotol (GPI)-linked membrane proteins consisting of three family members (RGMA, RGMB, and RGMC). Repulsive guidance molecule B (RGMB), known as Dragon (‘turned on in DRG’), was the first RGM family member identified. RGMB, which is transcriptionally regulated by DRG11 [3], is a myelin-derived inhibitor of axon growth in the central nervous system [4] and a co-receptor for bone morphogenetic proteins (BMPs) [5]
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