title: MALT1 is required for EGFR-induced NF-κB activation and contributes to EGFR-driven lung cancer progression.
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-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-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-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.
authors.affiliation: Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Pan
authors.affiliation: Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Blonska
authors.affiliation: Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.|Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Molecular and Cellular Oncology, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: X
authors.identifier: http://orcid.org/0000-0003-0956-3654
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016328:NF-kappa B; D009363:Neoplasm Proteins; D066246:ErbB Receptors; D020169:Caspases; C400109:MALT1 protein, human; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein