Program in Molecular Medicine; Davis Lab
Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Developmental Biology | Enzymes and Coenzymes | Genetic Phenomena | Neoplasms
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 DeltaNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKalpha 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.
Non-small-cell lung cancer, Stress signalling, Cancer genomics, Prognostic markers, Cancer models
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Copyright © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Nat Commun. 2019 May 14;10(1):2148. doi: 10.1038/s41467-019-09843-1. Link to article on publisher's site
Liu J, Wang T, Creighton CJ, Wu S, Ray M, Janardhan KS, Willson CJ, Cho S, Castro PD, Ittmann MM, Li J, Davis RJ, DeMayo FJ. (2019). JNK(1/2) represses Lkb(1)-deficiency-induced lung squamous cell carcinoma progression. Open Access Publications by UMMS Authors. https://doi.org/10.1038/s41467-019-09843-1. Retrieved from https://escholarship.umassmed.edu/oapubs/3858
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.