論文 - 詳細
| RRC ID | 51927 |
|---|---|
| 著者 | Aoki S, Mizuma M, Takahashi Y, Haji Y, Okada R, Abe T, Karasawa H, Tamai K, Okada T, Morikawa T, Hayashi H, Nakagawa K, Motoi F, Naitoh T, Katayose Y, Unno M. |
| タイトル | Aberrant activation of Notch signaling in extrahepatic cholangiocarcinoma: clinicopathological features and therapeutic potential for cancer stem cell-like properties. |
| ジャーナル | BMC Cancer |
| Abstract |
BACKGROUND:Little is known about the roles of Notch signaling in cholangiocarcinoma (CC). The expression of hairy and enhancer of split 1 (Hes-1) has not been investigated yet in resected specimens of CC. Notch signaling has been reported to be related to cancer stem cell (CSC) like properties in some malignancies. Our aim is to investigate the participation of Notch signaling in resected specimens of extrahepatic CC (EHCC) and to evaluate the efficacy of CC cells with CSC-like properties by Notch signaling blockade. METHODS:First, the expression of Notch1, 2, 3, 4 and Hes-1 was examined by immunohistochemistry in 132 resected EHCC specimens. The clinicopathological characteristics in the expression of Notch receptors and Hes-1 were investigated. Second, GSI IX, which is a γ-secretase-inhibitor, was used for Notch signaling blockade in the following experiment. Alterations of the subpopulation of CD24+CD44+ cells, which are surface markers of CSCs in EHCC, after exposure with GSI IX, gemcitabine (GEM), and the combination of GSI IX plus GEM were assessed by flow cytometry using the human CC cell lines, RBE, HuCCT1 and TFK-1. Also, anchorage-independent growth and mice tumorigenicity in the cells recovered by regular culture media after GSI IX exposure were assessed. RESULTS:Notch1, 2, 3, 4 and Hes-1 in the resected EHCC specimens were expressed in 50.0, 56.1, 42.4, 6.1, and 81.8 % of the total cohort, respectively. Notch1 and 3 expressions were associated with poorer histological differentiation (P = 0.008 and 0.053). The patients with the expression of at least any one of Notch1-3 receptors, who were in 80.3 % of the total, exhibited poorer survival (P = 0.050). Similarly, the expression of Hes-1 tended to show poor survival (P = 0.093). In all of the examined CC cell lines, GSI IX treatment significantly diminished the subpopulation of CD24+CD44+ cells. Although GEM monotherapy relatively increased the subpopulation of CD24+CD44+ cells in all lines, GSI IX plus GEM attenuated it. Anchorage-independent growth and mice tumorigenicity were inhibited in GSI IX-pretreated cells in RBE and TFK-1 (P < 0.05). CONCLUSION:Aberrant Notch signaling is involved with EHCC. Inhibition of Notch signaling is a novel therapeutic strategy for targeting cells with CSC-like properties. |
| 巻・号 | 16(1) |
| ページ | 854 |
| 公開日 | 2016-11-7 |
| DOI | 10.1186/s12885-016-2919-4 |
| PII | 10.1186/s12885-016-2919-4 |
| PMID | 27821106 |
| PMC | PMC5100105 |
| MeSH | Adolescent Adult Aged Aged, 80 and over Animals Bile Duct Neoplasms / diagnosis Bile Duct Neoplasms / metabolism* Bile Duct Neoplasms / therapy Biomarkers Cell Line, Tumor Cell Proliferation Cholangiocarcinoma / diagnosis Cholangiocarcinoma / metabolism* Cholangiocarcinoma / therapy Disease Models, Animal Female Gene Expression Heterografts Humans Immunohistochemistry Immunophenotyping Male Middle Aged Neoplasm Grading Neoplasm Metastasis Neoplasm Staging Neoplastic Stem Cells / metabolism Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction* Transcription Factor HES-1 / metabolism Young Adult |
| IF | 3.15 |
| 引用数 | 10 |
| リソース情報 | |
| ヒト・動物細胞 | RBE(RCB1292) |