Overexpression of TC-PTP in murine epidermis attenuates skin tumor formation.
Animals
Carcinoma, Squamous Cell
/ enzymology
Cell Proliferation
Cell Survival
Epidermis
/ metabolism
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Mice
Mice, Transgenic
Neoplasm Proteins
/ genetics
Papilloma
/ enzymology
Protein Tyrosine Phosphatase, Non-Receptor Type 2
/ biosynthesis
Signal Transduction
Skin Neoplasms
/ enzymology
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
26
03
2019
accepted:
23
03
2020
revised:
18
03
2020
pubmed:
15
4
2020
medline:
25
11
2020
entrez:
15
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32286519
doi: 10.1038/s41388-020-1282-8
pii: 10.1038/s41388-020-1282-8
pmc: PMC7244373
mid: NIHMS1579167
doi:
Substances chimiques
Neoplasm Proteins
0
PTPN2 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 2
EC 3.1.3.48
Ptpn2 protein, mouse
EC 3.1.3.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4241-4256Subventions
Organisme : NIEHS NIH HHS
ID : R01 ES022250
Pays : United States
Références
Lim WA, Pawson T. Phosphotyrosine signaling: evolving a new cellular communication system. Cell. 2010;142:661–7.
doi: 10.1016/j.cell.2010.08.023
Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009;21:140–6.
doi: 10.1016/j.ceb.2009.01.028
Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer. 2012;12:387–400.
doi: 10.1038/nrc3277
Hendriks WJ, Elson A, Harroch S, Stoker AW. Protein tyrosine phosphatases: functional inferences from mouse models and human diseases. FEBS J. 2008;275:816–30.
doi: 10.1111/j.1742-4658.2008.06249.x
Hendriks WJ, Pulido R. Protein tyrosine phosphatase variants in human hereditary disorders and disease susceptibilities. Biochim Biophys Acta. 2013;1832:1673–96.
doi: 10.1016/j.bbadis.2013.05.022
Cuppen E, Wijers M, Schepens J, Fransen J, Wieringa B, Hendriks W. A FERM domain governs apical confinement of PTP-BL in epithelial cells. J Cell Sci. 1999;112:3299–308.
pubmed: 10504335
Cool DE, Tonks NK, Charbonneau H, Walsh KA, Fischer EH, Krebs EG. cDNA isolated from a human T-cell library encodes a member of the protein-tyrosine-phosphatase family. Proc Natl Acad Sci USA. 1989;86:5257–61.
doi: 10.1073/pnas.86.14.5257
Mosinger B Jr., Tillmann U, Westphal H, Tremblay ML. Cloning and characterization of a mouse cDNA encoding a cytoplasmic protein-tyrosine-phosphatase. Proc Natl Acad Sci USA. 1992;89:499–503.
doi: 10.1073/pnas.89.2.499
Bourdeau A, Dube N, Tremblay ML. Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol. 2005;17:203–9.
doi: 10.1016/j.ceb.2005.02.001
Tillmann U, Wagner J, Boerboom D, Westphal H, Tremblay ML. Nuclear localization and cell cycle regulation of a murine protein tyrosine phosphatase. Mol Cell Biol. 1994;14:3030–40.
doi: 10.1128/MCB.14.5.3030
Kamatkar S, Radha V, Nambirajan S, Reddy RS, Swarup G. Two splice variants of a tyrosine phosphatase differ in substrate specificity, DNA binding, and subcellular location. J Biol Chem. 1996;271:26755–61.
doi: 10.1074/jbc.271.43.26755
Kim M, Morales LD, Baek M, Slaga TJ, DiGiovanni J, Kim DJ. UVB-induced nuclear translocation of TC-PTP by AKT/14-3-3sigma axis inhibits keratinocyte survival and proliferation. Oncotarget. 2017;8:90674–92.
doi: 10.18632/oncotarget.21794
Dube N, Tremblay ML. Involvement of the small protein tyrosine phosphatases TC-PTP and PTP1B in signal transduction and diseases: from diabetes, obesity to cell cycle, and cancer. Biochim Biophys Acta. 2005;1754:108–17.
doi: 10.1016/j.bbapap.2005.07.030
Xu D, Qu CK. Protein tyrosine phosphatases in the JAK/STAT pathway. Front Biosci. 2008;13:4925–32.
doi: 10.2741/3051
Kim M, Morales LD, Jang IS, Cho YY, Kim DJ. Protein tyrosine phosphatases as potential regulators of STAT3 signaling. Int J Mol Sci. 2018;19:2708.
doi: 10.3390/ijms19092708
Shields BJ, Wiede F, Gurzov EN, Wee K, Hauser C, Zhu HJ, et al. TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Mol Cell Biol. 2013;33:557–70.
doi: 10.1128/MCB.01016-12
Kleppe M, Lahortiga I, El Chaar T, De Keersmaecker K, Mentens N, Graux C, et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet. 2010;42:530–5.
doi: 10.1038/ng.587
Lee CF, Ling ZQ, Zhao T, Fang SH, Chang WC, Lee SC, et al. Genomic-wide analysis of lymphatic metastasis-associated genes in human hepatocellular carcinoma. World J Gastroenterol. 2009;15:356–65.
doi: 10.3748/wjg.15.356
Karlsson E, Veenstra C, Emin S, Dutta C, Perez-Tenorio G, Nordenskjold B, et al. Loss of protein tyrosine phosphatase, non-receptor type 2 is associated with activation of AKT and tamoxifen resistance in breast cancer. Breast Cancer Res Treat. 2015;153:31–40.
doi: 10.1007/s10549-015-3516-y
Lee H, Kim M, Baek M, Morales LD, Jang IS, Slaga TJ, et al. Targeted disruption of TC-PTP in the proliferative compartment augments STAT3 and AKT signaling and skin tumor development. Sci Rep. 2017;7:45077.
doi: 10.1038/srep45077
Baek M, Kim M, Lim JS, Morales LD, Hernandez J, Mummidi S, et al. Epidermal-specific deletion of TC-PTP promotes UVB-induced epidermal cell survival through the regulation of Flk-1/JNK signaling. Cell Death Dis. 2018;9:730.
doi: 10.1038/s41419-018-0781-9
Manguso RT, Pope HW, Zimmer MD, Brown FD, Yates KB, Miller BC, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547:413–8.
doi: 10.1038/nature23270
Lee H, Morales LD, Slaga TJ, Kim DJ. Activation of T-cell protein-tyrosine phosphatase suppresses keratinocyte survival and proliferation following UVB irradiation. J Biol Chem. 2015;290:13–24.
doi: 10.1074/jbc.M114.611681
Hennings H, Glick AB, Lowry DT, Krsmanovic LS, Sly LM, Yuspa SH. FVB/N mice: an inbred strain sensitive to the chemical induction of squamous cell carcinomas in the skin. Carcinogenesis. 1993;14:2353–8.
doi: 10.1093/carcin/14.11.2353
Abel EL, Angel JM, Kiguchi K, DiGiovanni J. Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications. Nat Protoc. 2009;4:1350–62.
doi: 10.1038/nprot.2009.120
DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther. 1992;54:63–128.
doi: 10.1016/0163-7258(92)90051-Z
Kim DJ, Tremblay ML, Digiovanni J. Protein tyrosine phosphatases, TC-PTP, SHP1, and SHP2, cooperate in rapid dephosphorylation of Stat3 in keratinocytes following UVB irradiation. PLoS ONE. 2010;5:e10290.
doi: 10.1371/journal.pone.0010290
Bozeman R, Abel EL, Macias E, Cheng T, Beltran L, DiGiovanni J. A novel mechanism of skin tumor promotion involving interferon-gamma (IFNgamma)/signal transducer and activator of transcription-1 (Stat1) signaling. Mol Carcinog. 2015;54:642–53.
doi: 10.1002/mc.22132
Chan KS, Carbajal S, Kiguchi K, Clifford J, Sano S, DiGiovanni J. Epidermal growth factor receptor-mediated activation of Stat3 during multistage skin carcinogenesis. Cancer Res. 2004;64:2382–9.
doi: 10.1158/0008-5472.CAN-03-3197
Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science. 1997;278:1630–2.
doi: 10.1126/science.278.5343.1630
Zhang JJ, Zhao Y, Chait BT, Lathem WW, Ritzi M, Knippers R, et al. Ser727-dependent recruitment of MCM5 by Stat1alpha in IFN-gamma-induced transcriptional activation. EMBO J. 1998;17:6963–71.
doi: 10.1093/emboj/17.23.6963
Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–50.
doi: 10.1016/0092-8674(95)90311-9
Agrawal S, Agarwal ML, Chatterjee-Kishore M, Stark GR, Chisolm GM. Stat1-dependent, p53-independent expression of p21(waf1) modulates oxysterol-induced apoptosis. Mol Cell Biol. 2002;22:1981–92.
doi: 10.1128/MCB.22.7.1981-1992.2002
DeVries TA, Kalkofen RL, Matassa AA, Reyland ME. Protein kinase Cdelta regulates apoptosis via activation of STAT1. J Biol Chem. 2004;279:45603–12.
doi: 10.1074/jbc.M407448200
Zimmerman MA, Rahman NT, Yang D, Lahat G, Lazar AJ, Pollock RE, et al. Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance. Cancer Res. 2012;72:4724–32.
doi: 10.1158/0008-5472.CAN-12-1347
Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8:627–44.
doi: 10.1038/nrd2926
Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.
doi: 10.3109/07853890.2014.912836
Dlugosz AA, Glick AB, Tennenbaum T, Weinberg WC, Yuspa SH. Isolation and utilization of epidermal keratinocytes for oncogene research. Methods Enzymol. 1995;254:3–20.
doi: 10.1016/0076-6879(95)54003-2