Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer.
HOP homeobox (HOPX) is an unusual homeobox gene encoding three spliced transcript variants, among which the only HOPX-beta promoter harbors CpG islands. The characteristics of its promoter methylation was analyzed using bisulfite sequencing and quantitative-methylation-specific polymerase chain reaction (Q-MSP), and the effects of HOPX expression were also examined. HOPX-beta expression was silenced in all gastric cancer cell lines tested; its expression could be restored by treatment with demethylating agent. On Q-MSP, HOPX-beta hypermethylation (cut-off value of 3.55) was found in 84% (67 out of 80) of primary tumor tissues and 10% (8 out of 80) of the corresponding normal tissues and could discriminate normal from tumor tissues (P<0.0001). The prognosis of the advanced cases with HOPX-beta hypermethylation was as poor as those with stage IV disease when cut-off value was set at 11.28. This finding was validated in an independent cohort of 90 advanced gastric cancers. The HOPX-beta hypermethylation was also an independent prognostic factor (P=0.029) on multivariate analysis. Exogenous HOPX expression significantly inhibited cell proliferation, colony formation and invasion as well as enhanced apoptosis. Taken together, HOPX-beta promoter methylation is a frequent and cancer-specific event in gastric cancer. Quantitative assessment of HOPX-beta methylation has great clinical potential as a marker of tumor aggressiveness.
Department of Surgery, Kitasato University Hospital, Sagamihara, Kanagawa, Japan. sp9y9tq9@piano.ocn.ne.jp
A
A
Ooki
K
K
Yamashita
S
S
Kikuchi
S
S
Sakuramoto
N
N
Katada
K
K
Kokubo
H
H
Kobayashi
M S
MS
Kim
D
D
Sidransky
M
M
Watanabe
D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
C476884:HOPX protein, human; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins