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.
Highlights
Signaling and POMC expression in the arcuate nucleus of the hypothalamus in response to insulin, suggesting that T-cell protein tyrosine phosphatase (TC-PTP) attenuates insulin signaling in POMC neurons[10]
Of the three PTPs involved in UVB-mediated STAT3 dephosphorylation, TC-PTP has a major role in regulating STAT3 signaling and significantly suppresses keratinocyte survival and proliferation following UVB irradiation[25]
We examined whether treatment with TPA, a potent tumor promoter, can result in rapid dephosphorylation of STAT3 because STAT3 plays a critical role in chemically-induced skin carcinogenesis[26,27,28,29]
Summary
Signaling and POMC expression in the arcuate nucleus of the hypothalamus in response to insulin, suggesting that TC-PTP attenuates insulin signaling in POMC neurons[10]. UVB-mediated activation of TC-PTP resulted in a significant decrease in cell proliferation corresponding with a decrease of STAT3 phosphorylation in mouse keratinocytes[25], suggesting that TC-PTP-mediated signaling may serve as part of a protective mechanism against skin carcinogenesis. In vivo studies using epidermal-specific TC-PTP knockout mice revealed that loss of TC-PTP significantly reduced 7,12-dimethylbenz[a]anthracene (DMBA)-induced apoptosis and increased TPA-induced cell proliferation mainly through the regulation of STAT3 and AKT phosphorylation, which resulted in enhanced skin cancer formation during DMBA/TPA skin carcinogenesis. These results suggest that TC-PTP plays a protective role against chemically-induced skin carcinogenesis
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