Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer
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Jin Li1, Lin Ye2, Xiaoshun Shi1, Jingyi Chen1, Fenglan Feng1, Yaoqi Chen1, Yiren Xiao3, Jianfei Shen1, Peng Li3, Wen G. Jiang2, Jianxing He1
1State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, National Clinical Research Center for Respiratory Disease, Guangzhou 510530, China
2Cardiff-China Medical Research Collaborative, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
3Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
Jianxing He, e-mail: Hejx@vip.163.com
Keywords: NSCLC, metastasis, RGMB
Received: June 23, 2015 Accepted: January 26, 2016 Published: February 17, 2016
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.
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