Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma
Shu Zhang
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorHui Wang
Departments of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
Search for more papers by this authorPengfei Mao
Department of Gastroenterology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, China
Search for more papers by this authorQi Sun
Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorHaochen Su
Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, China
Search for more papers by this authorYixuan Zhang
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorShanshan Shen
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorGuifang Xu
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorLei Wang
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorCorresponding Author
Xiaoping Zou
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qiang Zhan
Departments of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Ying Lv
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorShu Zhang
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorHui Wang
Departments of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
Search for more papers by this authorPengfei Mao
Department of Gastroenterology, Suzhou Hospital of Integrated Traditional Chinese and Western Medicine, Suzhou, China
Search for more papers by this authorQi Sun
Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorHaochen Su
Department of Gastroenterology, Nanjing Medical University Affiliated Drum Tower Clinical Medical College, Nanjing, China
Search for more papers by this authorYixuan Zhang
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorShanshan Shen
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorGuifang Xu
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorLei Wang
Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Search for more papers by this authorCorresponding Author
Xiaoping Zou
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Qiang Zhan
Departments of Gastroenterology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Ying Lv
Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
Correspondence Xiaoping Zou and Ying Lv, Department of Gastroenterology, Affiliated Taikang Xianlin Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
Email: [email protected] and [email protected]
Qiang Zhan, Departments of Gastroenterology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
Email: [email protected]
Search for more papers by this authorShu Zhang, Hui Wang, Pengfei Mao, Xiaoping Zou, Qiang Zhan, and Ying Lv contributed equally to this study.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive tumor with a dismal prognosis. Recent studies have demonstrated PTPN2 (protein tyrosine phosphatase nonreceptor type 2) as a potential target for cancer therapy. However, the functions of PTPN2 in PDAC progression remain poorly understood. In this study, we found PTPN2 expression was downregulated in PDAC tissues, and decreased PTPN2 expression was associated with unfavorable prognosis. Functional studies indicated that PTPN2 knockdown promoted the migration and invasion abilities of PDAC cells in vitro, and the liver metastasis in vivo through epithelial–mesenchymal transition process. Mechanistically, MMP-1 was identified as a downstream target of PTPN2 via RNA-seq data and was responsible for the enhanced metastasis of PDAC cells upon PTPN2 knockdown. Moreover, according to chromatin immunoprecipitation and electrophoretic mobility shift assay, PTPN2 depletion transcriptionally activated MMP-1 via regulating the interaction of p-STAT3 with its distal promoter. This study, for the first time, demonstrated that PTPN2 inhibited PDAC metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in PDAC progression.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| mc23554-sup-0001-supplementary_figure1.tif29.8 MB | Supporting information. |
| mc23554-sup-0002-supplementary_figure_2.tif31.1 MB | Supporting information. |
| mc23554-sup-0003-supmat.docx17.5 KB | Supporting information. |
| mc23554-sup-0004-Supplementary_Table_1.docx19.3 KB | Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021; 71: 7-33.
- 2Rawla P, Sunkara T, Gaduputi V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J Oncol. 2019; 10: 10-27.
- 3Stromnes IM, DelGiorno KE, Greenberg PD, Hingorani SR. Stromal reengineering to treat pancreas cancer. Carcinogenesis. 2014; 35: 1451-1460.
- 4Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014; 46: 372-383.
- 5Hunter T. Tyrosine phosphorylation: thirty years and counting. Curr Opin Cell Biol. 2009; 21: 140-146.
- 6Pearlman SM, Serber Z, Ferrell JE. A mechanism for the evolution of phosphorylation sites. Cell. 2011; 147: 934-946.
- 7Li X, Wilmanns M, Thornton J, Köhn M. Elucidating human phosphatase-substrate networks. Sci Signaling. 2013; 6:rs10.
- 8Scharl M, Mwinyi J, Fischbeck A, et al. Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy. Inflamm Bowel Dis. 2012; 18: 900-912.
- 9Scharl M, McCole DF, Weber A, et al. Protein tyrosine phosphatase N2 regulates TNFα-induced signalling and cytokine secretion in human intestinal epithelial cells. Gut. 2011; 60: 189-197.
- 10Scharl M, Paul G, Weber A, et al. Protection of epithelial barrier function by the Crohn's disease associated gene protein tyrosine phosphatase n2. Gastroenterology. 2009; 137: 2030-2040.
- 11Wiede F, Shields BJ, Chew SH, et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011; 121: 4758-4774.
- 12Fukushima A, Loh K, Galic S, et al. T-cell protein tyrosine phosphatase attenuates STAT3 and insulin signaling in the liver to regulate gluconeogenesis. Diabetes. 2010; 59: 1906-1914.
- 13Gurzov EN, Tran M, Fernandez-Rojo MA, et al. Hepatic oxidative stress promotes insulin-STAT-5 signaling and obesity by inactivating protein tyrosine phosphatase N2. Cell Metab. 2014; 20: 85-102.
- 14Krishnan M, McCole DF. T cell protein tyrosine phosphatase prevents STAT1 induction of claudin-2 expression in intestinal epithelial cells. Ann NY Acad Sci. 2017; 1405: 116-130.
- 15Simoncic PD, Lee-Loy A, Barber DL, Tremblay ML, McGlade CJ. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr Biol. 2002; 12: 446-453.
- 16ten Hoeve J, De Jesus ibarra-Sanchez M, Fu Y, et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol. 2002; 22: 5662-5668.
- 17Kleppe M, Lahortiga I, El Chaar T, et al. Deletion of the protein tyrosine phosphatase gene PTPN2 in T-cell acute lymphoblastic leukemia. Nat Genet. 2010; 42: 530-535.
- 18Shields BJ, Wiede F, Gurzov EN, et al. TCPTP regulates SFK and STAT3 signaling and is lost in triple-negative breast cancers. Mol Cell Biol. 2013; 33: 557-570.
- 19Klingler-Hoffmann M, Fodero-Tavoletti MT, Mishima K, et al. The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor. J Biol Chem. 2001; 276: 46313-46318.
- 20Wang Y, Ning H, Ren F, et al. GdX/UBL4A specifically stabilizes the TC45/STAT3 association and promotes dephosphorylation of STAT3 to repress tumorigenesis. Mol Cell. 2014; 53: 752-765.
- 21Baek M, Kim M, Lim JS, 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.
- 22Lee H, Kim M, Baek M, 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.
- 23Chen J, Zhao X, Yuan Y, Jing JJ. The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers. Cancer Cell Int. 2020; 20:238.
- 24LaFleur MW, Nguyen TH, Coxe MA, et al. PTPN2 regulates the generation of exhausted CD8(+) T cell subpopulations and restrains tumor immunity. Nat Immunol. 2019; 20: 1335-1347.
- 25Wiede F, Lu KH, Du X, et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 2020; 39:e103637.
- 26Huang Z, Liu M, Li D, et al. PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells. J Biol Chem. 2020; 295: 18343-18354.
- 27Sonnenblick A, Shriki A, Galun E, et al. Tissue microarray-based study of patients with lymph node-positive breast cancer shows tyrosine phosphorylation of signal transducer and activator of transcription 3 (tyrosine705-STAT3) is a marker of good prognosis. Clin Transl Oncol. 2012; 14: 232-236.
- 28Zhang S, Yang Y, Huang S, et al. SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling. J Cell Physiol. 2019; 234: 15395-15406.
- 29Harati R, Hafezi S, Mabondzo A, Tlili A. Silencing miR-202-3p increases MMP-1 and promotes a brain invasive phenotype in metastatic breast cancer cells. PLoS One. 2020; 15:e0239292.
- 30Yu CL, Yu YL, Yang SF, et al. Praeruptorin A reduces metastasis of human hepatocellular carcinoma cells by targeting ERK/MMP1 signaling pathway. Environ Toxicol. 2021; 36: 540-549.
- 31Chen JL, Lai CY, Ying TH, et al. Modulating the ERK1/2-MMP1 axis through corosolic acid inhibits metastasis of human oral squamous cell carcinoma cells. Int J Mol Sci. 2021; 22(16):8641.
- 32Lim CP, Cao X. Structure, function, and regulation of STAT proteins. Mol BioSyst. 2006; 2: 536-550.
- 33Oh MK, Park HJ, Kim NH, Park SJ, Park IY, Kim IS. Hypoxia-inducible factor-1α enhances haptoglobin gene expression by improving binding of STAT3 to the promoter. J Biol Chem. 2011; 286: 8857-8865.
- 34Chen Z, Han ZC. STAT3: a critical transcription activator in angiogenesis. Med Res Rev. 2008; 28: 185-200.
- 35Garg M, Shanmugam MK, Bhardwaj V, et al. The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy. Med Res Rev. 2020; 41: 1291-1336.
- 36Huang C, Cao J, Huang KJ, et al. Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci. 2006; 97: 1417-1423.
- 37Qiu Z, Huang C, Sun J, et al. RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells. Cancer Sci. 2007; 98: 1099-1106.
- 38Xie T, Huang FJ, Aldape KD, et al. Activation of stat3 in human melanoma promotes brain metastasis. Cancer Res. 2006; 66: 3188-3196.
- 39Hsieh FC, Cheng G, Lin J. Evaluation of potential Stat3-regulated genes in human breast cancer. Biochem Biophys Res Commun. 2005; 335: 292-299.
- 40Itoh M, Murata T, Suzuki T, et al. Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene. 2006; 25: 1195-1204.
