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

D. Pan, C. Jiang, Z. Ma, Marzenna Blonska, M. J. You, X. Lin

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)919-928
Number of pages10
JournalOncogene
Volume35
Issue number7
DOIs
StatePublished - Feb 18 2016
Externally publishedYes

Fingerprint

NF-kappa B
Lymphoid Tissue
Epidermal Growth Factor Receptor
Lung Neoplasms
Mucous Membrane
Neoplasms
TNF Receptor-Associated Factor 6
Ubiquitin-Protein Ligases
Tumor Burden
Epidermal Growth Factor
Transgenic Mice
Cell Movement
Interleukin-6
Carcinogenesis
Transcription Factors
Neoplasm Metastasis

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression. / Pan, D.; Jiang, C.; Ma, Z.; Blonska, Marzenna; You, M. J.; Lin, X.

In: Oncogene, Vol. 35, No. 7, 18.02.2016, p. 919-928.

Research output: Contribution to journalArticle

Pan, D. ; Jiang, C. ; Ma, Z. ; Blonska, Marzenna ; You, M. J. ; Lin, X. / MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression. In: Oncogene. 2016 ; Vol. 35, No. 7. pp. 919-928.
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