title: Homeobox D10 gene, a candidate tumor suppressor, is downregulated through promoter hypermethylation and associated with gastric carcinogenesis.
abstract: Homeobox D10 (HoxD10 ) gene plays a critical role in cell differentiation and morphogenesis during development. However, the function of HoxD10 in tumor progression remains largely unknown. We demonstrate that the expression of HoxD10 is commonly downregulated in gastric cancer tissues (n = 33) and cell lines (n = 8) relative to normal stomach tissues. Functionally, reexpression of HoxD10 results in significant inhibition of cell survival, induction of cell apoptosis, and impairment of cell migration and invasion. Moreover, ectopic expression of HoxD10 suppresses gastric tumor growth in a mouse xenograft model. To identify target candidates of HoxD10, we performed cDNA microarray and showed that HoxD10 regulates multiple downstream genes including IGFBP3. Reintroduction of HoxD10 transcriptionally upregulates IGFBP3, activates caspase 3 and caspase 8, and subsequently induces cell apoptosis. Methylation specific PCR revealed that HoxD10 promoter DNA was hypermethylated in gastric cancer cell lines. Additionally, 5-aza demethylation treatment could transiently reactivate the expression of HoxD10 in gastric cancer cells. HoxD10 promoter methylation frequently was detected in gastric cancer tissues obtained from endoscopic biopsies (85.7%, 24/28) and surgically resected samples (82.6%, 57/69). Intestinal metaplasia tissues showed a 60% methylation rate (18/30), but no detectable methylation in normal stomach tissues (0%, 0/10). Taken together, our results suggest that HoxD10 functions as a candidate tumor suppressor in gastric cancer, which is inactivated through promoter hypermethylation.
authors.affiliation: Laboratory of Digestive Disease, Sir Run Run Shaw Clinical Medicine Institution of Zhejiang University, Hangzhou, China.
authors.forename: Liangjing
authors.initials: L
authors.lastname: Wang
authors.forename: Shujie
authors.initials: S
authors.lastname: Chen
authors.forename: Meng
authors.initials: M
authors.lastname: Xue
authors.forename: Jing
authors.initials: J
authors.lastname: Zhong
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.forename: Lihong
authors.initials: L
authors.lastname: Gan
authors.forename: Emily K Y
authors.initials: EK
authors.lastname: Lam
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Jianbin
authors.initials: J
authors.lastname: Zhang
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
authors.forename: Jianmin
authors.initials: J
authors.lastname: Si
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D047368:Tumor Burden
chemical_list: D018398:Homeodomain Proteins; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D014157:Transcription Factors; C072064:HOXD10 protein, human