Mig-6 deficiency cooperates with oncogenic Kras to promote mouse lung tumorigenesis

Lung Cancer. 2017 Oct;112:47-56. doi: 10.1016/j.lungcan.2017.08.001. Epub 2017 Aug 5.

Abstract

Objectives: Lung cancer is the leading cause of cancer related deaths worldwide and mutation activating KRAS is one of the most frequent mutations found in lung adenocarcinoma. Identifying regulators of KRAS may aid in the development of therapies to treat this disease. The mitogen-induced gene 6, MIG-6, is a small adaptor protein modulating signaling in cells to regulate the growth and differentiation in multiple tissues. Here, we investigated the role of Mig-6 in regulating adenocarcinoma progression in the lungs of genetically engineered mice with activation of Kras.

Materials and methods: Using the CCSPCre mouse to specifically activate expression of the oncogenic KrasG12D in Club cells, we investigated the expression of Mig-6 in CCSPCreKrasG12D-induced lung tumors. To determine the role of Mig-6 in KrasG12D-induced lung tumorigenesis, Mig-6 was conditionally ablated in the Club cells by breeding Mig6f/f mice to CCSPCreKrasG12D mice, yielding CCSPCreMig-6d/dKrasG12D mice (Mig-6d/dKrasG12D).

Results: We found that Mig-6 expression is decreased in CCSPCreKrasG12D-induced lung tumors. Ablation of Mig-6 in the KrasG12D background led to enhanced tumorigenesis and reduced life expectancy. During tumor progression, there was increased airway hyperplasia, a heightened inflammatory response, reduced apoptosis in KrasG12D mouse lungs, and an increase of total and phosphorylated ERBB4 protein levels. Mechanistically, Mig-6 deficiency attenuates the cell apoptosis of lung tumor expressing KRASG12D partially through activating the ErbB4 pathway.

Conclusions: In summary, Mig-6 deficiency promotes the development of KrasG12D-induced lung adenoma through reducing the cell apoptosis in KrasG12D mouse lungs partially by activating the ErbB4 pathway.

Keywords: Apoptosis; ErbB signaling; ErbB4; Kras; Lung cancer/tumor; Mig-6 (ERRFI1).

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Apoptosis
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Disease Models, Animal
  • Gene Expression Regulation
  • Genes, ras*
  • Hyperplasia
  • Immunohistochemistry
  • Inflammation
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Kaplan-Meier Estimate
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Receptor, ErbB-4 / genetics
  • Signal Transduction
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • ERRFI1 protein, human
  • Errfi1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Tumor Suppressor Proteins
  • ERBB4 protein, human
  • Receptor, ErbB-4