期刊
THERANOSTICS
卷 12, 期 6, 页码 2613-2630出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.70744
关键词
PINCH-1; IGF-1 receptor; NEDD4; GRB10; Skin cancer
资金
- National Key R&D Program of China [2019FYA090060000]
- Natural Science Foundation of Guangdong Province [2021A1515111132, 2017B030301018]
- Special Support Program for Training High-Level Talents in Guangdong [2019TQ05Y518]
- Shenzhen Innovation Committee of Science and Technology [JCYJ20190809115017189, JCYJ20180302174228311, JCYJ20180307123807944, ZDSYS201405091427 21429]
- Lombardi and Shinozuka Experimental Pathology Research Endowment Fund, University of Pittsburgh
This study identifies the critical role of PINCH-1 in regulating IGF-1R expression and skin cell behavior, and reveals a PINCH-1-NEDD4-IGF-1R signaling axis that promotes skin tumorigenesis.
Background: Insulin-like growth factor 1 receptor (IGF-1R) expression and signaling play important roles in promotion of skin cancer progression. Identification of signaling pathways that regulate IGF-1R is crucial for understanding the pathogenesis and therapeutic treatment of skin cancer. Methods: Molecular, cellular and genetic approaches were used to investigate the function of PINCH-1 in regulation of IGF-1R expression and skin cell behavior. Furthermore, conditional PINCH-1 knockout mouse and carcinogen (7, 12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA))-induced skin cancer model were employed to determine the function of PINCH-1 in regulation of IGF-1R expression and skin carcinogenesis in vivo. Results: Knockdown of PINCH-1 from HaCaT keratinocytes or A431 squamous carcinoma cells diminished IGF-1R levels, suppressed cell proliferation and increased apoptosis. Re-expression of PINCH-1 in PINCH-1 knockdown cells restored IGF-1R expression, cell proliferation and survival. Furthermore, depletion of NEDD4 effectively reversed PINCH-1 deficiency-induced down-regulation of IGF-1R expression, cell proliferation and survival. Conditional knockout of PINCH-1 from keratin 5 (K5) positive keratinocytes in mice, like depletion of PINCH-1 from keratinocytes in culture, reduced the IGF-1R level. Using a mouse model of DMBA/TPA-induced skin cancer, we show that the levels of both PINCH-1 and IGF-1R were significantly increased in response to treatment with the carcinogens. Genetic ablation of PINCH-1 from the epidermis markedly reduced the IGF-1R expression and cell proliferation despite stimulation with DMBA/TPA, resulting in resistance to chemical carcinogen-induced skin cancer initiation and progression. Conclusions: Our results reveal a PINCH-1-NEDD4-IGF-1R signaling axis that is critical for promotion of skin tumorigenesis and suggest a new strategy for therapeutic control of skin cancer progression.
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