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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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, Jian; Wang, Tianyuan; Creighton, Chad J.; Wu, San-Pin; Ray, Madhumita; Janardhan, Kyathanahalli S.; Willson, Cynthia J.; Cho, Sung-Nam; Castro, Patricia D.; Ittmann, Michael M.; Li, Jian-Liang; Davis, Roger J.; and DeMayo, Francesco J., "JNK(1/2) represses Lkb(1)-deficiency-induced lung squamous cell carcinoma progression" (2019). Open Access Articles. 3858.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.