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Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation

Abstract

T-cell protein tyrosine phosphatase (TC-PTP), encoded by Ptpn2, has been shown to function as a tumor suppressor during skin carcinogenesis. In the current study, we generated a novel epidermal-specific TC-PTP-overexpressing (K5HA.Ptpn2) mouse model to show that TC-PTP contributes to the attenuation of chemically induced skin carcinogenesis through the synergistic regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling. We found overexpression of TC-PTP increased epidermal sensitivity to DMBA-induced apoptosis and it decreased TPA-mediated hyperproliferation, coinciding with reduced epidermal thickness. Inhibition of STAT1, STAT3, STAT5, or AKT reversed the effects of TC-PTP overexpression on epidermal survival and proliferation. Mice overexpressing TC-PTP in the epidermis developed significantly reduced numbers of tumors during skin carcinogenesis and presented a prolonged latency of tumor initiation. Examination of human papillomas and squamous cell carcinomas (SCCs) revealed that TC-PTP expression was significantly reduced and TC-PTP expression was inversely correlated with the increased grade of SCCs. Our findings demonstrate that TC-PTP is a potential therapeutic target for the prevention of human skin cancer given that it is a major negative regulator of oncogenic signaling.

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Fig. 1: Generation of epidermal-specific K5HA.Ptpn2 transgenic mouse.
Fig. 2: Effect of TC-PTP overexpression on DMBA-induced apoptosis in epidermis.
Fig. 3: TC-PTP overexpression sensitizes DMBA-induced apoptosis through regulation of STAT and AKT signaling pathways.
Fig. 4: Inhibition of STAT1, STAT3, STAT5, or AKT on DMBA-induced apoptosis in keratinocytes.
Fig. 5: Effect of TC-PTP overexpression on epidermal hyperproliferation induced by TPA.
Fig. 6: Overexpression of TC-PTP in epidermis reduces TPA-induced cell proliferation and survival through the regulation of STAT1, STAT3, STAT5, and PI3K/AKT signaling.
Fig. 7: Inhibition of STAT1, STAT3, STAT5, PI3K, or AKT during TPA-induced keratinocyte survival and proliferation.
Fig. 8: TC-PTP overexpression reduces tumor formation in the epidermis during two-stage skin carcinogenesis.
Fig. 9: TC-PTP expression in human skin tumors.

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Acknowledgements

We thank H. Lee for technical assistance. This work was supported by NIH/NIEHS ES022250 (to D.J. Kim) and NIH/NIAID AI119131 (to S. Mummidi).

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DJK conceived the project, designed the study, and interpreted the results. WJK, SM, CJ, AT, ISJ, and TJS also contributed to interpretation of the results. CJL, LDM, MK, SAO, and JH performed experiments. DJK wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Dae Joon Kim.

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Kim, M., Morales, L.D., Lee, C.J. et al. Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation. Oncogene 39, 4241–4256 (2020). https://doi.org/10.1038/s41388-020-1282-8

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