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Nat Commun. 2019 May 14;10(1):2148. doi: 10.1038/s41467-019-09843-1.

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

Author information

1
Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA.
2
Integrative Bioinformatics, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA.
3
The Dan L. Duncan Cancer Center, Baylor College of Medicine (BCM), Houston, 77030, TX, USA.
4
Department of Medicine, Baylor College of Medicine (BCM), Houston, 77030, TX, USA.
5
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.
6
Integrated Laboratory Systems, Research Triangle Park, 27709, NC, USA.
7
Department of Molecular and Cellular Biology, BCM, Houston, 77030, TX, USA.
8
Department of Pathology & Immunology, BCM, Houston, 77030, TX, USA.
9
Howard Hughes Medical Institute (HHMI), University of Massachusetts Medical School, Worcester, 01655, MA, USA.
10
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01655, MA, USA.
11
Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. francesco.demayo@nih.gov.

Abstract

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.

PMID:
31089135
PMCID:
PMC6517592
DOI:
10.1038/s41467-019-09843-1
[Indexed for MEDLINE]
Free PMC Article

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