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MALT1 is required for EGFR-induced NF-?B activation and contributes to EGFR-driven lung cancer progression.


ABSTRACT: The transcription factor nuclear factor kappa B (NF-?B) has been implicated in having a crucial role in the tumorigenesis of many types of human cancers. Although epidermal growth factor receptor (EGFR) can directly activate NF-?B, the mechanism by which EGFR induces NF-?B activation and the role of NF-?B in EGFR-associated tumor progression is still not fully defined. Herein, we found that mucosa-associated lymphoid tissue 1 (MALT1) is involved in EGFR-induced NF-?B activation in cancer cells, and that MALT1 deficiency impaired EGFR-induced NF-?B activation. MALT1 mainly functions as a scaffold protein by recruiting E3 ligase TRAF6 to IKK complex to activate NF-?B in response to EGF stimulation. Functionally, MALT1 inhibition shows significant defects in EGFR-associated tumor malignancy, including cell migration, metastasis and anchorage-independent growth. To further access a physiological role of MALT1-dependent NF-?B activation in EGFR-driven tumor progression, we generated triple-transgenic mouse model (tetO-EGFR(L858R); CCSP-rtTA; Malt1(-/-)), in which mutant EGFR-driven lung cancer was developed in the absence of MALT1 expression. MALT1-deficient mice show significantly less lung tumor burden when compared with its heterozygous controls, suggesting that MALT1 is required for the progression of EGFR-induced lung cancer. Mechanistically, MALT1 deficiency abolished both NF-?B and STAT3 activation in vivo, which is a result of a defect of interleukin-6 production. In comparison, MALT1 deficiency does not affect tumor progression in a mouse model (LSL-K-ras(G12D); CCSP-Cre; Malt1(-/-)) in which lung cancer is induced by expressing a K-ras mutant. Thus, our study has provided the cellular and genetic evidence that suggests MALT1-dependent NF-?B activation is important in EGFR-associated solid-tumor progression.

SUBMITTER: Pan D 

PROVIDER: S-EPMC4651666 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression.

Pan D D   Jiang C C   Ma Z Z   Blonska M M   You M J MJ   Lin X X  

Oncogene 20150518 7


The transcription factor nuclear factor kappa B (NF-κB) has been implicated in having a crucial role in the tumorigenesis of many types of human cancers. Although epidermal growth factor receptor (EGFR) can directly activate NF-κB, the mechanism by which EGFR induces NF-κB activation and the role of NF-κB in EGFR-associated tumor progression is still not fully defined. Herein, we found that mucosa-associated lymphoid tissue 1 (MALT1) is involved in EGFR-induced NF-κB activation in cancer cells,  ...[more]

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