title: Aberrant hypermethylation and reduced expression of disabled-2 promote the development of lung cancers.
abstract: Disabled-2 (Dab2) is considered a tumor suppressor and is downregulated in cancers. We examined the promoter methylation status and expression levels of Dab2, and investigated their roles in the development of lung cancers. Methylation-specific PCR was employed to analyze the methylation status of Dab2 in 100 lung cancer tissues. The cytoplasmic and nuclear expression of the Dab2 protein was determined using western blot analysis. Demethylation treatment using 5-Aza-2-deoxycytidine (5-Aza-dC) was performed in three lung cancer cell lines. Dab2 expression was upregulated by Dab2 transfection or interrupted by Dab2 siRNA in lung cancer cells. Proliferative and invasive ability tests were performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) and a Matrigel invasion assay, respectively. The methylation rate of Dab2 was significantly higher in lung cancer tissues compared to normal lung tissues. Dab2 methylation correlated with the reduced nuclear and cytoplasmic expression of Dab2, as well as the TNM stage and lymphatic metastasis of lung cancers. Treatment with 5-Aza-dC was able to eliminate the hypermethylation of Dab2, enhance Dab2 expression, and inhibit β-catenin expression, and the proliferative and invasive ability of lung cancer cells. Upregulation of Dab2 expression reduced β-catenin expression and proliferation and invasiveness of lung cancer cells. However, interruption of Dab2 expression induced the opposite results. Dab2 methylation is common in lung cancers, and is one of the most important factors responsible for the reduced expression of Dab2. Aberrant hypermethylation and reduced expression of Dab2 promote the development of lung cancers.
authors.affiliation: Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang 110001, P.R. China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Xie
authors.forename: Zi-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Lian-He
authors.initials: LH
authors.lastname: Yang
authors.forename: Da-Lei
authors.initials: DL
authors.lastname: Yang
authors.forename: Na
authors.initials: N
authors.lastname: Tang
authors.forename: Huan-Yu
authors.initials: HY
authors.lastname: Zhao
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Xu
authors.forename: Qing-Chang
authors.initials: QC
authors.lastname: Li
authors.forename: En-Hua
authors.initials: EH
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C102885:DAB2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D051176:beta Catenin