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JNK1/2 represses Lkb1-deficiency-induced lung squamous cell carcinoma progression

Jian Liu1, Tianyuan Wang2, Chad J Creighton3,4,5

  • 1Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA.

Nature Communications
|May 16, 2019
PubMed

Insights

JNK1/2 signaling suppresses lung squamous cell carcinoma (LSCC) development by repressing ΔNp63. Activating JNK1/2 may offer a therapeutic strategy for LSCC and related squamous cell carcinomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • Mechanisms driving lung squamous cell carcinoma (LSCC) remain incompletely understood.
  • The role of JNK1/2 (c-Jun N-terminal kinase 1/2) in LSCC pathogenesis requires further elucidation.
  • Lkb1 (Liver kinase B1) is a critical tumor suppressor, and its deficiency is implicated in LSCC.

Purpose of the Study:

  • To investigate the role of JNK1/2 signaling in Lkb1-deficiency-driven LSCC.
  • To determine the relationship between JNK1/2 activity, Lkb1 status, and LSCC progression.
  • To explore the therapeutic potential of modulating JNK1/2 activity in LSCC.

Main Methods:

  • In vivo mouse models with Lkb1 ablation.
  • Pharmacological manipulation of JNK1/2 activity.
  • Analysis of signaling pathways including ΔNp63, MKK7, AMPKα, and mTOR.
  • Correlation analysis of JNK1/2 activity with patient survival in human LSCC and other squamous cell carcinomas.

Main Results:

  • Lkb1 ablation in vivo induces LSCC by reducing MKK7 and JNK1/2 activities, independent of AMPKα and mTOR.
  • JNK1/2 activity, positively regulated by MKK7, suppresses LSCC initiation and progression by repressing ΔNp63 signaling.
  • Pharmacological activation of JNK1/2 ameliorates Lkb1-dependent LSCC formation.
  • Compound mutations of Jnk1/2 and Lkb1 accelerate LSCC progression.
  • JNK1/2 is inactivated in a significant subset of human LSCC, and higher JNK1/2 activity correlates with improved survival in lung, cervical, and head and neck squamous cell carcinoma patients.

Conclusions:

  • JNK1/2 acts as a tumor suppressor in LSCC, functioning downstream of Lkb1.
  • JNK1/2 inactivation is a common event in human LSCC.
  • Enhancing JNK1/2 activity represents a promising therapeutic strategy for LSCC and related squamous cell carcinomas.

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