Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development.
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.
Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA.
Hyunseung
H
Lee
Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA.
Mihwa
M
Kim
Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA.
Minwoo
M
Baek
Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA.
Liza D
LD
Morales
Division of Bioconvergence Analysis, Korea Basic Science Institute, Daejeon 305-333, Republic of Korea.
Ik-Soon
IS
Jang
Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Thomas J
TJ
Slaga
Division of Pharmacology &Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78723, USA.
John
J
DiGiovanni
Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78541, USA.
Dae Joon
DJ
Kim
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D006965:Hyperplasia; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010766:Phosphorylation; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D013755:Tetradecanoylphorbol Acetate