Frequent down-regulation of hRAB37 in metastatic tumor by genetic and epigenetic mechanisms in lung cancer

We looked for the involvement tumor suppressor gene (TSG) in lung cancer in 17q25 region by loss of heterozygosity analysis and 5′/3′ RACE and identified a candidate gene named human RAB37 (hRAB37), which encodes a small GTPase. The Ras-GTPase superfamily functions as important regulators including membrane trafficking and cytoskeletal organization. Therefore, we further examined the mRNA expression and promoter/exon1 hypermethylation of hRAB37 gene in paired normal and tumor lung tissue from 71 non-small cell lung cancer (NSCLC) patients. Low hRAB37 mRNA expression occurred in 47.9% (34/71) of patient and promoter/exon1 hypermethylation of hRAB37 was found in 57.7% (41/71) of patients. Low mRNA expression of hRAB37 was significantly associated with their promoter/exon1 hypermethylation. Importantly, a reduction in hRAB37 mRNA expression and promoter/exon1 hypermethylation was found to be significantly associated with lung metastatic patients as compared to non-metastatic patients. 5-Aza-2-deoxycytidine treatment of a highly metastatic cell line showed demethylation and re-expression of the hRAB37 gene and coincided with reduced migration. Knockdown of hRAB37 in low metastasis cell line led to a significant increase in cell migration. Our findings demonstrated that hRAB37 small GTPase and acts as a metastasis-related TSG in lung cancer. Promoter/exon1 methylation is the predominant mechanism in down-regulation of the hRAB37, and can serve as a potential prediction biomarker of NSCLC progression.