論文 - 詳細
| RRC ID | 43852 |
|---|---|
| 著者 | Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N, Watanabe T, Sakurai T. |
| タイトル | Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. |
| ジャーナル | Br J Cancer |
| Abstract |
BACKGROUND:Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. While sorafenib, a multikinase inhibitor targeting the Raf/extracellular signal-regulated protein kinase (ERK) pathway, has been shown recently to provide a survival advantage to patients with advanced HCC, a predictive biomarker has not been developed. We studied whether c-Jun N-terminal kinase (JNK), which promotes liver carcinogenesis in mice, affects therapeutic response to sorafenib in HCC patients. METHODS:We collected pathological specimens from 39 patients with advanced HCC before starting sorafenib treatment, and measured JNK activity in HCCs. RESULTS:In patients treated with sorafenib, the expression of phospho-c-Jun in HCC, as a read out of JNK activity, was significantly higher (P<0.001) in the non-responder group than in the responder group. c-Jun N-terminal kinase activation in HCC was associated with a decreased time to progression and a poor overall survival (P=0.0028 and P=0.0008, respectively). CONCLUSION:In addition, JNK activity was significantly correlated with CD133 expression level. Correspondingly, high expression level of CD133 was linked to a poor response to sorafenib. Furthermore, D-JNKi, a specific JNK inhibitor, reduced the growth of xenografted CD133(+) cells in athymic mice. In conclusion, JNK activation was positively correlated with CD133 expression level and inversely correlated with the therapeutic response to sorafenib, suggesting that JNK activity may be considered as a new predictive biomarker for response to sorafenib treatment. |
| 巻・号 | 106(12) |
| ページ | 1997-2003 |
| 公開日 | 2012-6-5 |
| DOI | 10.1038/bjc.2012.145 |
| PII | bjc2012145 |
| PMID | 22596232 |
| PMC | PMC3388555 |
| MeSH | AC133 Antigen Adult Aged Animals Antigens, CD / metabolism* Benzenesulfonates / therapeutic use* Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / metabolism* Cell Line, Tumor Female Glycoproteins / metabolism* Humans JNK Mitogen-Activated Protein Kinases / metabolism* Liver Neoplasms / drug therapy* Liver Neoplasms / metabolism* Male Mice Mice, Nude Middle Aged Neoplasm Transplantation Niacinamide / analogs & derivatives Peptides / metabolism* Phenylurea Compounds Prognosis Pyridines / therapeutic use* Sorafenib Transcriptional Activation Treatment Outcome |
| IF | 5.791 |
| 引用数 | 58 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | Hep G2 HuH-7 |