Reference - Detail
| RRC ID | 44433 |
|---|---|
| Author | Ando M, Kawazu M, Ueno T, Fukumura K, Yamato A, Soda M, Yamashita Y, Choi YL, Yamasoba T, Mano H. |
| Title | Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling. |
| Journal | 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. |
| Volume | 104(8) |
| Pages | 1002-8 |
| Published | 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 |
| Times Cited | 22 |
| WOS Category | ONCOLOGY |
| Altmetric score |
オルトメトリクス指標項目
|
| Total number of mentions | 0 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 293T(RCB2202) T3M-1 Cl-10(RCB1017) |