| RRC ID |
44433
|
| 著者 |
Ando M, Kawazu M, Ueno T, Fukumura K, Yamato A, Soda M, Yamashita Y, Choi YL, Yamasoba T, Mano H.
|
| タイトル |
Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of ~50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-κB (NF-κB) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-κB signaling. Such NF-κB activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-κB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.
|
| 巻・号 |
104(8)
|
| ページ |
1002-8
|
| 公開日 |
2013-8-1
|
| DOI |
10.1111/cas.12191
|
| PMID |
23659359
|
| PMC |
PMC7657200
|
| MeSH |
Apoptosis / genetics
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinoma, Squamous Cell / enzymology
Carcinoma, Squamous Cell / genetics*
Carcinoma, Squamous Cell / metabolism
Carcinoma, Squamous Cell / pathology
Caspase 8 / genetics*
Caspase 8 / metabolism
Cell Line, Tumor
HEK293 Cells
Head and Neck Neoplasms / enzymology
Head and Neck Neoplasms / genetics*
Head and Neck Neoplasms / metabolism
Head and Neck Neoplasms / pathology
Humans
Mutation, Missense*
NF-kappa B / metabolism*
Signal Transduction
Squamous Cell Carcinoma of Head and Neck
|
| IF |
4.966
|
| 引用数 |
22
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202)
T3M-1 Cl-10(RCB1017) |
