Abstract
The transcription factor NF-κB has been implicated in playing 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, and MALT1 deficiency impaired EGFR-induced NF-κB activation. MALT1 mainly functions as a scaffold protein by recruiting E3 ligase TRAF6 to IKK complex to activate NF-κB 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-κB 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 to its heterozygous controls, suggesting that MALT1 is required for the progression of EGFR-induced lung cancer. Mechanistically, MALT1 deficiency abolished both NF-κB and STAT3 activation
in vivo
, which is a result of a defect of IL-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-κB activation is important in EGFR-associated solid tumor progression.
