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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate DMBA-TPA
Published on: December 19, 2019
REGγ is critical for skin carcinogenesis by modulating the Wnt/β-catenin pathway
Lei Li1,2, Yongyan Dang2, Jishen Zhang1
1Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
Abstract:
Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.
Insights
Mice lacking proteasome activator REGγ resist skin tumor development. REGγ activation by TPA triggers MAPK/p38 and Wnt/β-catenin pathways, promoting keratinocyte proliferation and papilloma formation.
Area of Science:
- Molecular Biology
- Dermatology
- Oncology
Background:
- The proteasome activator REGγ plays a role in cellular processes.
- Skin tumorigenesis involves complex signaling pathways.
- TPA is a known inducer of skin inflammation and tumor promotion.
Purpose of the Study:
- To investigate the role of REGγ in TPA-induced skin tumorigenesis.
- To elucidate the signaling pathways regulated by REGγ in skin cells.
Main Methods:
- Mice deficient for REGγ were used to assess TPA-induced skin effects.
- Analysis of signaling pathways including MAPK/p38 and Wnt/β-catenin.
- Gene expression analysis of downstream targets like CyclinD1 and c-Myc.
Main Results:
- REGγ-deficient mice showed resistance to TPA-induced keratinocyte proliferation, hyperplasia, and papilloma formation.
- TPA treatment increased REGγ levels, activating MAPK/p38 signaling.
- REGγ was found to activate Wnt/β-catenin signaling by degrading GSK-3β, leading to increased CyclinD1 and c-Myc levels.
Conclusions:
- REGγ is a key mediator in TPA-induced skin tumorigenesis.
- REGγ promotes skin tumor development by activating the MAPK/p38 and Wnt/β-catenin signaling pathways.
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