The long-term goal of this research is to determine the molecular/cellular basis for the gene- environment interactions in the pathogenesis of skin cancer. The major environmental risk factor for non-melanoma skin cancer is ultraviolet (UV) radiation in sunlight including UVB and UVA. Although UVA has different physical and biological targets from UVB, the UVA contribution to skin cancer susceptibility and its molecular basis is unclear. Preliminary data within this proposal demonstrate that a critical suppressor for human and mouse skin cancer is PTEN (phosphatase and tensin homologue deleted on chromosome 10). In epidermal keratinocytes, PTEN transcription is significantly down-regulated by UVA, whereas targeted deletion of PTEN in the epidermis accelerates skin carcinogenesis. Although the precise mechanisms responsible for the enhanced susceptibility to skin tumorigenesis are unknown, preliminary data within this proposal show that PTEN loss may impair repair and checkpoints in response to DNA damage. The central hypothesis of the proposed experiments is that UVA-induced down-regulation of PTEN transcription inhibits DNA repair and DNA damage checkpoints and thus increases skin cancer susceptibility. The overall aim of this proposal is to determine the molecular mechanisms and consequences of UVA-induced PTEN down-regulation.
The specific aims are to (1) test the hypothesis that PTEN down-regulation inhibits DNA repair and DNA damage checkpoints in response to low-level UV irradiation;(2) elucidate upstream regulators critical for UVA-induced down-regulation of PTEN transcription;and (3) analyze the consequences of PTEN down- regulation in skin cancer susceptibility in vivo. These experiments will provide new insights into the molecular and cellular basis for the UVA contribution to skin carcinogenesis. This knowledge can be used to develop better strategies to prevent and treat skin cancer.

Public Health Relevance

Project Narrative although much progress has been made in the last decades, the number of skin cancer cases continues to increase. In humans and in mice, a tumor suppressor protein, PTEN, contributes to skin cancer risk and is down-regulated by the ultraviolet A (UVA) radiation. Understanding how PTEN is regulated when we are exposed to UVA and its consequences in skin cancer will improve our ability to reduce the disease burden of this most common cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016936-02
Application #
8125007
Study Section
Special Emphasis Panel (ZES1-TN-J (R))
Program Officer
Humble, Michael C
Project Start
2010-08-09
Project End
2015-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$517,763
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Zhao, Baozhong; Shah, Palak; Qiang, Lei et al. (2017) Distinct Role of Sesn2 in Response to UVB-Induced DNA Damage and UVA-Induced Oxidative Stress in Melanocytes. Photochem Photobiol 93:375-381
Yang, Seungwon; Qiang, Lei; Sample, Ashley et al. (2017) NF-?B Signaling Activation Induced by Chloroquine Requires Autophagosome, p62 Protein, and c-Jun N-terminal Kinase (JNK) Signaling and Promotes Tumor Cell Resistance. J Biol Chem 292:3379-3388
Sample, Ashley; Zhao, Baozhong; Qiang, Lei et al. (2017) Adaptor protein p62 promotes skin tumor growth and metastasis and is induced by UVA radiation. J Biol Chem 292:14786-14795
Sample, Ashley; He, Yu-Ying (2017) Autophagy in UV Damage Response. Photochem Photobiol 93:943-955
Qiang, Lei; Sample, Ashley; Liu, Han et al. (2017) Epidermal SIRT1 regulates inflammation, cell migration, and wound healing. Sci Rep 7:14110
Sample, Ashley; Zhao, Baozhong; Wu, Chunli et al. (2017) The Autophagy Receptor Adaptor p62 is Up-regulated by UVA Radiation in Melanocytes and in Melanoma Cells. Photochem Photobiol :
Shah, Palak; Trinh, Elaine; Qiang, Lei et al. (2017) Arsenic Induces p62 Expression to Form a Positive Feedback Loop with Nrf2 in Human Epidermal Keratinocytes: Implications for Preventing Arsenic-Induced Skin Cancer. Molecules 22:
Qiang, Lei; Zhao, Baozhong; Shah, Palak et al. (2016) Autophagy positively regulates DNA damage recognition by nucleotide excision repair. Autophagy 12:357-68
Zhao, Baozhong; Qiang, Lei; Joseph, Joy et al. (2016) Mitochondrial dysfunction activates the AMPK signaling and autophagy to promote cell survival. Genes Dis 3:82-87
Qiang, L; Shah, P; Barcellos-Hoff, M H et al. (2016) TGF-? signaling links E-cadherin loss to suppression of nucleotide excision repair. Oncogene 35:3293-302

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