PMID- 31089135 OWN - NLM STAT- MEDLINE DCOM- 20190701 LR - 20211204 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 10 IP - 1 DP - 2019 May 14 TI - JNK(1/2) represses Lkb(1)-deficiency-induced lung squamous cell carcinoma progression. PG - 2148 LID - 10.1038/s41467-019-09843-1 [doi] LID - 2148 AB - 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. FAU - Liu, Jian AU - Liu J AUID- ORCID: 0000-0002-1447-0973 AD - Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. FAU - Wang, Tianyuan AU - Wang T AUID- ORCID: 0000-0002-3970-0771 AD - Integrative Bioinformatics, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. FAU - Creighton, Chad J AU - Creighton CJ AUID- ORCID: 0000-0002-6090-703X AD - The Dan L. Duncan Cancer Center, Baylor College of Medicine (BCM), Houston, 77030, TX, USA. AD - Department of Medicine, Baylor College of Medicine (BCM), Houston, 77030, TX, USA. AD - Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA. FAU - Wu, San-Pin AU - Wu SP AUID- ORCID: 0000-0001-9626-784X AD - Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. FAU - Ray, Madhumita AU - Ray M AUID- ORCID: 0000-0001-6029-108X AD - Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. FAU - Janardhan, Kyathanahalli S AU - Janardhan KS AUID- ORCID: 0000-0002-5774-9317 AD - Integrated Laboratory Systems, Research Triangle Park, 27709, NC, USA. FAU - Willson, Cynthia J AU - Willson CJ AUID- ORCID: 0000-0003-0942-3723 AD - Integrated Laboratory Systems, Research Triangle Park, 27709, NC, USA. FAU - Cho, Sung-Nam AU - Cho SN AUID- ORCID: 0000-0001-7366-1465 AD - Department of Molecular and Cellular Biology, BCM, Houston, 77030, TX, USA. FAU - Castro, Patricia D AU - Castro PD AUID- ORCID: 0000-0001-5286-8037 AD - Department of Pathology & Immunology, BCM, Houston, 77030, TX, USA. FAU - Ittmann, Michael M AU - Ittmann MM AUID- ORCID: 0000-0003-4802-0978 AD - Department of Pathology & Immunology, BCM, Houston, 77030, TX, USA. FAU - Li, Jian-Liang AU - Li JL AUID- ORCID: 0000-0002-6487-081X AD - Integrative Bioinformatics, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. FAU - Davis, Roger J AU - Davis RJ AUID- ORCID: 0000-0002-0130-1652 AD - Howard Hughes Medical Institute (HHMI), University of Massachusetts Medical School, Worcester, 01655, MA, USA. AD - Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01655, MA, USA. FAU - DeMayo, Francesco J AU - DeMayo FJ AUID- ORCID: 0000-0002-9480-7336 AD - Reproductive & Developmental Biology Laboratory, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park (RTP), 27709, NC, USA. francesco.demayo@nih.gov. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P30 CA125123/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190514 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (TP63 protein, human) RN - 0 (Transcription Factors) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.1.24 (Mitogen-Activated Protein Kinase 9) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (STK11 protein, human) RN - EC 2.7.11.1 (Stk11 protein, mouse) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 2.7.12.2 (MAP Kinase Kinase 7) RN - EC 2.7.12.2 (MAP2K7 protein, human) SB - IM MH - AMP-Activated Protein Kinase Kinases MH - AMP-Activated Protein Kinases MH - Aged MH - Aged, 80 and over MH - Animals MH - Carcinoma, Squamous Cell/genetics/mortality/*pathology MH - Disease Progression MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/genetics/mortality/*pathology MH - MAP Kinase Kinase 7/metabolism MH - Male MH - Mice MH - Mice, Knockout MH - Middle Aged MH - Mitogen-Activated Protein Kinase 8/genetics/*metabolism MH - Mitogen-Activated Protein Kinase 9/genetics/*metabolism MH - Protein Serine-Threonine Kinases/*deficiency/genetics MH - Survival Rate MH - Transcription Factors/metabolism MH - Tumor Suppressor Proteins/metabolism PMC - PMC6517592 COIS- The authors declare no competing interests. EDAT- 2019/05/16 06:00 MHDA- 2019/07/02 06:00 PMCR- 2019/05/14 CRDT- 2019/05/16 06:00 PHST- 2018/06/11 00:00 [received] PHST- 2019/03/22 00:00 [accepted] PHST- 2019/05/16 06:00 [entrez] PHST- 2019/05/16 06:00 [pubmed] PHST- 2019/07/02 06:00 [medline] PHST- 2019/05/14 00:00 [pmc-release] AID - 10.1038/s41467-019-09843-1 [pii] AID - 9843 [pii] AID - 10.1038/s41467-019-09843-1 [doi] PST - epublish SO - Nat Commun. 2019 May 14;10(1):2148. doi: 10.1038/s41467-019-09843-1.