Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development.
Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development.
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DOI：
10.1038/srep45077
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发表时间：
2017-03-21
影响因子：
4.6
通讯作者：
Kim DJ
中科院分区：
文献类型：
--
作者：
Lee H;Kim M;Baek M;Morales LD;Jang IS;Slaga TJ;DiGiovanni J;Kim DJ
酪氨酸磷酸化是促进皮肤癌发生的重要机制。它受蛋白酪氨酸激酶（PTKs）和蛋白酪氨酸磷酸酶（PTPs）的抗活性调控。在这里，我们报道了由Ptpn2编码的t细胞蛋白酪氨酸磷酸酶（TC-PTP）通过STAT3和AKT信号的负调控在化学诱导的皮肤癌发生中的关键作用。通过表皮特异性TC-PTP敲除（k14cree . ptpn2fl /fl）小鼠，我们发现TC-PTP的缺失导致体内表皮和体外角质形成细胞对肿瘤启动剂7,12-二甲基苯[a]蒽（DMBA）诱导的凋亡脱敏。TC-PTP缺乏还导致暴露于肿瘤启动子12- o -十四烷酰基磷酸-13-乙酸酯（TPA）后表皮厚度显著增加和过度增生。Western blot分析显示，与对照组相比，TPA处理后tc - ptp缺陷小鼠表皮中磷酸化STAT3和磷酸化AKT的表达均显著增加。抑制STAT3或AKT可逆转TC-PTP缺乏对细胞凋亡和增殖的影响。最后，TC-PTP基因敲除小鼠在两期皮肤癌变过程中，肿瘤发生潜伏期缩短，肿瘤数量显著增加。我们的研究结果表明，TC-PTP可能通过调节STAT3和AKT信号传导而成为预防皮肤癌的新靶点。
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.