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

被引:51
作者
Pan, D. [1 ,2 ]
Jiang, C. [1 ]
Ma, Z. [1 ]
Blonska, M. [1 ]
You, M. J. [2 ,3 ]
Lin, X. [1 ,2 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Ctr Inflammat & Canc, Dept Mol & Cellular Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA
[2] Univ Texas Houston, Grad Sch Biomed Sci, Canc Biol Program, Houston, TX USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA
基金
美国国家卫生研究院;
关键词
T-CELL-ACTIVATION; LYMPHOID-TISSUE; SIGNALING PATHWAYS; ABC-DLBCL; IN-VIVO; K-RAS; ADENOCARCINOMAS; PHOSPHORYLATION; LYMPHOCYTES; PARACASPASE;
D O I
10.1038/onc.2015.146
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The transcription factor nuclear factor kappa B (NF-kappa 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-kappa B, the mechanism by which EGFR induces NF-kappa B activation and the role of NF-kappa 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-kappa B activation in cancer cells, and that MALT1 deficiency impaired EGFR-induced NF-kappa B activation. MALT1 mainly functions as a scaffold protein by recruiting E3 ligase TRAF6 to IKK complex to activate NF-kappa B in response to EGF stimulation. Functionally, MALT1 inhibition shows significant defects in EGFR-associated tumor malignancy, including cell migration, metastasis and anchorageindependent growth. To further access a physiological role of MALT1-dependent NF-kappa 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-kappa 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-kappa B activation is important in EGFR-associated solid-tumor progression.
引用
收藏
页码:919 / 928
页数:10
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