| RRC ID |
43899
|
| 著者 |
Asada K, Ando T, Niwa T, Nanjo S, Watanabe N, Okochi-Takada E, Yoshida T, Miyamoto K, Enomoto S, Ichinose M, Tsukamoto T, Ito S, Tatematsu M, Sugiyama T, Ushijima T.
|
| タイトル |
FHL1 on chromosome X is a single-hit gastrointestinal tumor-suppressor gene and contributes to the formation of an epigenetic field defect.
|
| ジャーナル |
Oncogene
|
| Abstract |
Tumor-suppressor genes on chromosome X can be inactivated by a single hit, any of the point mutations, chromosomal loss and aberrant DNA methylation. As aberrant DNA methylation can be induced frequently, we here aimed to identify a tumor-suppressor gene on chromosome X inactivated by promoter DNA methylation. Of 69 genes on chromosome X upregulated by treatment of a gastric cancer cell line with a DNA-demethylating agent, 5-aza-2'-deoxycytidine, 11 genes had low or no expression in the cell line and abundant expression in normal gastric mucosae. Among them, FHL1 was frequently methylation-silenced in gastric and colon cancer cell lines, and methylated in primary gastric (21/80) and colon (5/50) cancers. Knockdown of the endogenous FHL1 in two cell lines by two kinds of shRNAs significantly increased cell growth in vitro and sizes of xenografts in nude mice. Expression of exogenous FHL1 in a non-expressing cell line significantly reduced its migration, invasion and growth. Notably, a somatic mutation (G642T; Lys214Asn) was identified in one of 144 colon cancer specimens, and the mutant FHL1 was shown to lack its inhibitory effects on migration, invasion and growth. FHL1 methylation was associated with Helicobacter pylori infection and accumulated in normal-appearing gastric mucosae of gastric cancer patients. These data showed that FHL1 is a methylation-silenced tumor-suppressor gene on chromosome X in gastrointestinal cancers, and that its silencing contributes to the formation of an epigenetic field for cancerization.
|
| 巻・号 |
32(17)
|
| ページ |
2140-9
|
| 公開日 |
2013-4-25
|
| DOI |
10.1038/onc.2012.228
|
| PII |
onc2012228
|
| PMID |
22689052
|
| MeSH |
Adult
Aged
Aged, 80 and over
Animals
Base Sequence
Colonic Neoplasms / genetics*
Colonic Neoplasms / metabolism
CpG Islands
DNA Methylation
DNA Mutational Analysis
Epigenesis, Genetic
Female
Gastric Mucosa / metabolism
Gene Silencing*
Genes, Tumor Suppressor*
HCT116 Cells
Humans
Intracellular Signaling Peptides and Proteins / genetics*
LIM Domain Proteins / genetics*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Muscle Proteins / genetics*
Neoplasm Transplantation
Promoter Regions, Genetic
Stomach Neoplasms / genetics*
Stomach Neoplasms / metabolism
X Chromosome
|
| IF |
7.971
|
| 引用数 |
26
|
|
WOS 分野
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
ONCOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
MKN28(RCB1000)
MKN45(RCB1001)
MKN74(RCB1002) |
