論文 - 詳細
| RRC ID | 63782 |
|---|---|
| 著者 | Nagaoka K, Ogawa K, Ji C, Cao KY, Bai X, Mulla J, Cheng Z, Wands JR, Huang CK. |
| タイトル | Targeting Aspartate Beta-Hydroxylase with the Small Molecule Inhibitor MO-I-1182 Suppresses Cholangiocarcinoma Metastasis. |
| ジャーナル | Dig Dis Sci |
| Abstract |
BACKGROUND:Cholangiocarcinoma is a devastating disease with a 2% 5-year survival if the disease has spread outside the liver. The enzyme aspartate beta-hydroxylase (ASPH) has been demonstrated to be highly expressed in cholangiocarcinoma but not in normal bile ducts and found to stimulate tumor cell migration. In addition, it was found that targeting ASPH inhibits cholangiocarcinoma malignant progression. However, it is not clear whether targeting ASPH with the small molecule inhibitor MO-I-1182 suppresses cholangiocarcinoma metastasis. The current study aims to study the efficacy of MO-I-1182 in suppressing cholangiocarcinoma metastasis. METHODS:The analysis was performed in vitro and in vivo with a preclinical animal model by using molecular and biochemical strategies to regulate ASPH expression and function. RESULTS:Knockdown of ASPH substantially inhibited cell migration and invasion in two human cholangiocarcinoma cell lines. Targeting ASPH with a small molecule inhibitor suppressed cholangiocarcinoma progression. Molecular mechanism studies demonstrated that knockdown of ASPH subsequently suppressed protein levels of the matrix metalloproteinases. The ASPH knockdown experiments suggest that this enzyme may modulate cholangiocarcinoma metastasis by regulating matrix metalloproteinases expression. Furthermore, using an ASPH inhibitor in a rat cholangiocarcinoma intrahepatic model established with BED-Neu-CL#24 cholangiocarcinoma cells, it was found that targeting ASPH inhibited intrahepatic cholangiocarcinoma metastasis and downstream expression of the matrix metalloproteinases. CONCLUSION:ASPH may modulate cholangiocarcinoma metastasis via matrix metalloproteinases expression. Taken together, targeting ASPH function may inhibit intrahepatic cholangiocarcinoma metastasis and improve survival. |
| 巻・号 | 66(4) |
| ページ | 1080-1089 |
| 公開日 | 2021-4-1 |
| DOI | 10.1007/s10620-020-06330-2 |
| PII | 10.1007/s10620-020-06330-2 |
| PMID | 32445050 |
| MeSH | Animals Bile Ducts, Intrahepatic / metabolism Bile Ducts, Intrahepatic / pathology Calcium-Binding Proteins* / antagonists & inhibitors Calcium-Binding Proteins* / metabolism Cell Line, Tumor Cell Movement / drug effects Cholangiocarcinoma* / drug therapy Cholangiocarcinoma* / metabolism Cholangiocarcinoma* / pathology Enzyme Inhibitors / pharmacology* Gene Expression Gene Knockdown Techniques Humans Liver Neoplasms* / drug therapy Liver Neoplasms* / metabolism Liver Neoplasms* / pathology Matrix Metalloproteinases / metabolism Membrane Proteins* / antagonists & inhibitors Membrane Proteins* / metabolism Mixed Function Oxygenases* / antagonists & inhibitors Mixed Function Oxygenases* / metabolism Muscle Proteins* / antagonists & inhibitors Muscle Proteins* / metabolism Neoplasm Metastasis / prevention & control* Rats |
| IF | 2.751 |
| リソース情報 | |
| ヒト・動物細胞 | HuCCT1(RCB1960) RBE(RCB1292) SSP25(RCB1293) |