Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-03-21

AUTHORS

Hyunseung Lee, Mihwa Kim, Minwoo Baek, Liza D. Morales, Ik-Soon Jang, Thomas J. Slaga, John DiGiovanni, Dae Joon Kim

ABSTRACT

Tyrosine phosphorylation is a vital mechanism that contributes to skin carcinogenesis. It is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here, we report the critical role of T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, in chemically-induced skin carcinogenesis via the negative regulation of STAT3 and AKT signaling. Using epidermal specific TC-PTP knockout (K14Cre.Ptpn2fl/fl) mice, we demonstrate loss of TC-PTP led to a desensitization to tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis both in vivo epidermis and in vitro keratinocytes. TC-PTP deficiency also resulted in a significant increase in epidermal thickness and hyperproliferation following exposure to the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Western blot analysis showed that both phosphorylated STAT3 and phosphorylated AKT expressions were significantly increased in epidermis of TC-PTP-deficient mice compared to control mice following TPA treatment. Inhibition of STAT3 or AKT reversed the effects of TC-PTP deficiency on apoptosis and proliferation. Finally, TC-PTP knockout mice showed a shortened latency of tumorigenesis and significantly increased numbers of tumors during two-stage skin carcinogenesis. Our findings reveal that TC-PTP has potential as a novel target for the prevention of skin cancer through its role in the regulation of STAT3 and AKT signaling. More... »

PAGES

45077

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/srep45077

DOI

http://dx.doi.org/10.1038/srep45077

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1084132925

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28322331


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