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

Authors

Hyunseung Lee
Mihwa Kim, The University of Texas Rio Grande Valley
Minwoo Baek
Liza D. Morales, The University of Texas Rio Grande Valley
Ik-Soon Jang
Thomas J. Slaga, University of Texas Health Science Center at San Antonio
John DiGiovanni
Dae Joon Kim, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

3-21-2017

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.

Comments

Copyright © 2017, The Author(s)

Recommended Citation

Lee, H., Kim, M., Baek, M., Morales, L. D., Jang, I. S., Slaga, T. J., ... & Kim, D. J. (2017). Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development. Scientific reports, 7(1), 45077. https://doi.org/10.1038/srep45077

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Publication Title

Scientific reports

DOI

10.1038/srep45077

Academic Level

faculty

Mentor/PI Department

Immunology and Microbiology