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Cancer-associated missense mutations of caspase-8 activate nuclear factor-?B signaling.

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-?B (NF-?B) 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-?B signaling. Such NF-?B 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-?B signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.

SUBMITTER: Ando M

PROVIDER: S-EPMC7657200 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling.

Ando Mizuo M Kawazu Masahito M Ueno Toshihide T Fukumura Kazutaka K Yamato Azusa A Soda Manabu M Yamashita Yoshihiro Y Choi Young L YL Yamasoba Tatsuya T Mano Hiroyuki H

Cancer science 20130607 8

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 w ...[more]

PMID: 23659359

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Dataset Information

Cancer-associated missense mutations of caspase-8 activate nuclear factor-?B signaling.

Publications

Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling.

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