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

Oncogene volume 35, pages 919–928 (2016)Cite this article

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Abstract

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, and that 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-EGFRL858R; 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-κB 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-rasG12D; 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.

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Acknowledgements

We thank Dr Vishva Dixit (Genentech Corporation) for providing Malt1-deficient mice and Dr Francesco J DeMayo (Baylor College of Medicine) for providing CCSP-Cre mice and Dr Jeffrey Whitsett (Cincinnati Children’s Hospital Medical Center) for providing CCSP-tTA mice. This work is partially supported by grants, RP120316 from Cancer Prevention Research Institute of Texas (CPRIT) to XL, GM079451 and GM065899 from National Institutes of Health (NIH) to XL and R01 CA164346 (NCI/NIH), Developmental Research Awards in Leukemia SPORE CA100632 to MJY, and Center for Inflammation and Cancer, Center for Genetics and Genomics, IRG, Sister Institution Network fund of UT MD Anderson Cancer Center, and Cancer Prevention Research Institute of Texas to MJY.

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Authors and Affiliations

  1. Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,

    D Pan, C Jiang, Z Ma, M Blonska & X Lin

  2. Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA

    D Pan, M J You & X Lin

  3. Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    M J You

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Correspondence to X Lin.

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Pan, D., Jiang, C., Ma, Z. et al. MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression. Oncogene 35, 919–928 (2016). https://doi.org/10.1038/onc.2015.146

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