| RRC ID |
55966
|
| 著者 |
Pan B, Yang J, Wang X, Xu K, Ikezoe T.
|
| タイトル |
miR-217 sensitizes chronic myelogenous leukemia cells to tyrosine kinase inhibitors by targeting pro-oncogenic anterior gradient 2.
|
| ジャーナル |
Exp Hematol
|
| Abstract |
BCR-ABL1-independent mechanisms had been thought to mediate drug resistance to tyrosine kinase inhibitors (TKIs) in patients with chronic myelogenous leukemia (CML). The pro-oncogenic anterior gradient 2 (AGR2) mediates drug resistance of cancer cells. In this study, we observed an increased level of AGR2 in TKI-resistant CML cells. Silence of AGR2 in dasatinib-resistant K562 (K562DR) cells led to restored sensitivity to dasatinib both in vitro and in vivo. Exposure to dasatinib induced upregulation of AGR2 in K562 cells, which indicated a probable treatment-related drug resistance. We further investigated the potential interaction between microRNA (miRNA) and AGR2 in K562DR cells and found that downregulation of miR-217 was associated with overexpression of AGR2 in K562DR cells. Luciferase reporter assay identified that miR-217 negatively regulated expression of AGR2 through binding the 3'-untranslated region of AGR2. Hypermethylation of the CpG island on the promoter region of the MIR217 gene is a probable reason for the downregulation of miR-217 in dasatinib-treated K562 cells. Forced expression of miR-217 led to decreased expression of AGR2 as well as compromised TKI-resistant potential of K562DR cells. Similarly, overexpression of miR-217 resensitized K562DR cells to dasatinib treatment in a murine xenograft transplantation model. TKI treatment-induced drug resistance is correlated with a decrease of miR-217 and upregulation of AGR2. The miR-217/AGR2 interaction might be a potential therapeutic target in treating CML patients with TKI resistance.
|
| 巻・号 |
68
|
| ページ |
80-88.e2
|
| 公開日 |
2018-12-1
|
| DOI |
10.1016/j.exphem.2018.09.001
|
| PII |
S0301-472X(18)30798-7
|
| PMID |
30195077
|
| MeSH |
3' Untranslated Regions
Animals
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
DNA Methylation
Dasatinib / pharmacology
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Leukemic* / drug effects
Gene Expression Regulation, Leukemic* / genetics
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
Mice
Mice, Inbred NOD
MicroRNAs / biosynthesis
MicroRNAs / genetics
MicroRNAs / physiology*
Mucoproteins
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Oncogene Proteins
Promoter Regions, Genetic
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors
Proteins / genetics*
Proteins / metabolism
RNA / metabolism
RNA Interference
RNA, Neoplasm / genetics
RNA, Neoplasm / physiology*
RNA, Small Interfering / genetics
RNA, Small Interfering / pharmacology
Specific Pathogen-Free Organisms
Xenograft Model Antitumor Assays
|
| IF |
2.462
|
| 引用数 |
7
|
| リソース情報 |
| ヒト・動物細胞 |
EoL-1 cell(RCB0641) |
