| RRC ID |
43657
|
| 著者 |
Yamakawa N, Kaneda K, Saito Y, Ichihara E, Morishita K.
|
| タイトル |
The increased expression of integrin α6 (ITGA6) enhances drug resistance in EVI1(high) leukemia.
|
| ジャーナル |
PLoS One
|
| Abstract |
Ecotropic viral integration site-1 (EVI1) is one of the candidate oncogenes for human acute myeloid leukemia (AML) with chromosomal alterations at 3q26. High EVI1 expression (EVI1(high)) is a risk factor for AML with poor outcome. Using DNA microarray analysis, we previously identified that integrin α6 (ITGA6) was upregulated over 10-fold in EVI1(high) leukemia cells. In this study, we determined whether the increased expression of ITGA6 is associated with drug-resistance and increased cell adhesion, resulting in poor prognosis. To this end, we first confirmed the expression pattern of a series of integrin genes using semi-quantitative PCR and fluorescence-activated cell sorter (FACS) analysis and determined the cell adhesion ability in EVI1(high) leukemia cells. We found that the adhesion ability of EVI1(high) leukemia cells to laminin increased with the increased expression of ITGA6 and integrin β4 (ITGB4). The introduction of small-hairpin RNA against EVI1 (shEVI1) into EVI1(high) leukemia cells reduced the cell adhesion ability and downregulated the expression of ITGA6 and ITGB4. In addition, the overexpression of EVI1 in EVI1(low) leukemia cells enhanced their cell adhesion ability and increased the expression of ITGA6 and ITGB4. In a subsequent experiment, the introduction of shRNA against ITGA6 or ITGB4 into EVI1(high) AML cells downregulated their cell adhesion ability; however, the EVI1(high) AML cells transfected with shRNA against ITGA6 could not be maintained in culture. Moreover, treating EVI1(high) leukemia cells with neutralizing antibodies against ITGA6 or ITGB4 resulted in an enhanced responsiveness to anti-cancer drugs and a reduction of their cell adhesion ability. The expression of ITGA6 is significantly elevated in cells from relapsed and EVI1(high) AML cases; therefore, ITGA6 might represent an important therapeutic target for both refractory and EVI1(high) AML.
|
| 巻・号 |
7(1)
|
| ページ |
e30706
|
| 公開日 |
2012-1-1
|
| DOI |
10.1371/journal.pone.0030706
|
| PII |
PONE-D-11-14771
|
| PMID |
22295105
|
| PMC |
PMC3266272
|
| MeSH |
3T3 Cells
Animals
Antibodies, Neutralizing / immunology
Cattle
Cell Adhesion
Cell Adhesion Molecules / metabolism
Cell Cycle
Cell Line, Tumor
Collagen / metabolism
DNA-Binding Proteins / metabolism*
Down-Regulation
Drug Combinations
Drug Resistance, Neoplasm*
Gene Expression Regulation, Neoplastic*
Gene Silencing
Humans
Integrin alpha6 / genetics*
Integrin alpha6 / immunology
Integrin alpha6 / metabolism*
Integrin beta4 / genetics
Integrin beta4 / immunology
Integrin beta4 / metabolism
Laminin / metabolism
Leukemia, Myeloid, Acute / genetics
Leukemia, Myeloid, Acute / pathology*
MDS1 and EVI1 Complex Locus Protein
Mice
Osteoblasts / cytology
Osteoblasts / metabolism
Proteoglycans / metabolism
Proto-Oncogenes
RNA, Small Interfering / genetics
Recurrence
Transcription Factors / metabolism*
|
| IF |
2.74
|
| 引用数 |
33
|
|
WOS 分野
|
HEMATOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
MC3T3-E1(RCB1126)
HNT-34(RCB1296) |
