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01-07-2016 | Original Article

Downregulated Expression of PTPN9 Contributes to Human Hepatocellular Carcinoma Growth and Progression

Authors: Baoying Hu, Xia Yan, Fang Liu, Changlai Zhu, Huiling Zhou, Yuyan Chen, Jinxia Liu, Xingxing Gu, Runzhou Ni, Tianyi Zhang

Published in: Pathology & Oncology Research | Issue 3/2016

Abstract

Human hepatocellular carcinoma (HCC) is one of the most common malignant cancers, whose molecular mechanisms is remains largely. PTPN9 has recently been reported to play a critical role in breast cancer development. However, the role of PTPN9 in human HCC remains elusive. The present study aimed at investigating the potential role of PTPN9 in HCC. Western blot and immunohistochemistry were used to examine the expression of PTPN9 protein in HCC and adjacent non-tumorous tissues in 45 patients. Furthermore, Cell Counting Kit-8, flow cytometry and RNA interference experiments were performed to analyze the role of PTPN9 in the regulation of HCC cell proliferation. We showed that the expression level of PTPN9 was significantly reduced in HCC, compared with adjacent non-tumorous tissues. PTPN9 expression was inversely associated with Tumor size (P = 0.014), serum AFP level (P = 0.004) and Ki-67 expression. Low expression of PTPN9 predicted poor survival in HCC patients. Moreover, PTPN9 interference assay that PTPN9 inhibited cell proliferation in HepG2 cells. Cell apoptosis assay revealed that, silencing of PTPN9 expression significantly reduced cell apoptosis, compared with control ShRNA treatment group. Our results suggested that PTPN9 expression was down-regulated in HCC tumor tissues, and reduced PTPN9 expression was associated with worsened overall survival in HCC patients. Depletion of PTPN9 inhibits the apoptosis and promotes the proliferation of HCC cells.

Wenzh El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118–1127CrossRef

El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576CrossRefPubMed

But D-Y-K, Lai C-L, Yuen M-F (2008) Natural history of hepatitis-related hepatocellular carcinoma. World J Gastroenterol 14:1652–1656CrossRefPubMedPubMedCentral

Poon RT, Ng IO, Fan ST, Lai EC, Lo CM, Liu CL et al (2001) Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort. J Clin Oncol 19:3037–3044PubMed

Frau M, Biasi F, Feo F et al (2010) Prognostic markers and putative therapeutic targets for hepatocellular carcinoma. Mol Asp Med 31:179–193CrossRef

Tonks NK (2006) Nat Rev Mol Cell Biol 7:833–846CrossRefPubMed

den Hertog J, Ostman A, Bohmer FD (2008) Protein tyrosine phosphatases:regulatory mechanisms. FEBS J 275:831–847CrossRef

Glondu-Lassis M, Dromard M, Lacroix-Triki M, Nirde P, Puech C, Knani D, Chalbos D, Freiss G (2010) PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res 70:5116–5126CrossRefPubMedPubMedCentral

Aoki N, Matsuda T (2002) A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol Endocrinol 16:58–69CrossRefPubMed

10.

Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H (2010) PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol

11.

Lu X, Malumbres R, Shields B, Jiang X, Sarosiek KA, Natkunam Y, Tiganis T, Lossos IS (2008) PTP1B is a negative regulator of interleukin 4-induced STAT6 signaling. Blood 112:4098–4108CrossRefPubMedPubMedCentral

12.

Tebbutt NC, Giraud AS, Inglese M, Jenkins B, Waring P, Clay FJ, Malki S, Alderman BM, Grail D, Hollande F, Heath JK, Ernst M (2002) Reciprocal regulation of gastrointestinal homeostasis by SHP2 and STAT-mediated trefoil gene activation in gp130 mutant mice. Nat Med 8:1089–1097CrossRefPubMed

13.

Baron M, Davignon JL (2008) Inhibition of IFN-gamma-induced STAT1 tyrosine phosphorylation by human CMV is mediated by SHP2. J Immunol 181:5530–5536CrossRefPubMed

14.

Tsai CC, Kai JI, Huang WC, Wang CY, Wang Y, Chen CL, Fang YT, Lin YS, Anderson R, Chen SH, Tsao CW, Lin CF (2009) Glycogen synthase kinase-3beta facilitates IFN-gamma-induced STAT1 activation by regulating Src homology-2 domain-containing phosphatase 2. J Immunol 183:856–864CrossRefPubMed

15.

ten Hoeve J, de Jesus I-SM, Fu Y, Zhu W, Tremblay M, David M, Shuai K (2002) Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol Cell Biol 22:5662–5668CrossRefPubMedPubMedCentral

16.

Meyer T, Hendry L, Begitt A, John S, Vinkemeier U (2004) A single residue modulates tyrosine dephosphorylation, oligomerization, and nuclear accumulation of stat transcription factors. J Biol Chem 279:18998–19007CrossRefPubMed

17.

Huynh H, Bottini N, Williams S, Cherepanov V, Musumeci L, Saito K, Bruckner S, Vachon E, Wang X, Kruger J, Chow CW, Pellecchia M, Monosov E, Greer PA, Trimble W, Downey GP, Mustelin T (2004) Nat Cell Biol 6:831–839CrossRefPubMed

18.

Xu MJ, Sui X, Zhao R, Dai C, Krantz SB, Zhao ZJ (2003) Blood 102:4354–4360CrossRefPubMed

19.

Wang Y, Vachon E, Zhang J, Cherepanov V, Kruger J, Li J, Saito K, Shannon P, Bottini N, Huynh H, Ni H, Yang H, McKerlie C, Quaggin S, Zhao ZJ, Marsden PA, Mustelin T, Siminovitch KA, Downey GP (2005) J Exp Med 202:1587–1597CrossRefPubMedPubMedCentral

20.

Furth PA, Nakles RE, Millman S, Diaz-Cruz ES, Cabrera MC (2011) Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer. Breast Cancer Res 13:220CrossRefPubMedPubMedCentral

21.

Yuan T, Wang Y, Zhao ZJ, Gu H (2010) Protein-tyrosine phosphatase PTPN9 negatively regulates ErbB2 and epidermal growth factor receptor signaling in breast cancer cells. J Biol Chem 285:14861–14870CrossRefPubMedPubMedCentral

22.

Su F, Ren F et al (2012) Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer. Breast Cancer Res. doi:10.1186/bcr3134

23.

Xu X, Yamamoto H, Sakon M et al (2003) Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin Cancer Res 9:1764–1772PubMed

24.

Yu C, Chen K, Zheng H et al (2009) Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 30:894–901CrossRefPubMed

25.

Xue Q, Lv L, Wan C, Chen B, Li M, Ni T et al (2013) Expression and clinical role of small glutamine-rich tetratricopeptide repeat (TPR)-containing protein alpha (SGTA) as a novel cell cycle protein in NSCLC. J Cancer Res Clin Oncol 139(9):1539–1549. doi:10.1007/s00432-013-1474-5 CrossRefPubMed

26.

Wan C, Hou S, Shen A et al (2015) MIF4G domain containing protein regulates cell cycle and hepatic carcinogenesis by antagonizing CDK2-dependent p27 stability. Oncogene 34(2):237–245. doi:10.1038/onc.2013.536 CrossRefPubMed

27.

Sun T, Aceto N, Meerbrey KL, Kessler JD, Zhou C, Migliaccio I, Nguyen DX, Pavlova NN, Botero M, Huang J, Bernardi RJ, Schmitt E, Hu G, Li MZ, Dephoure N, Gygi SP, Rao M, Creighton CJ, Hilsenbeck SG, Shaw CA, Muzny D, Gibbs RA, Wheeler DA, Osborne CK, Schiff R, Bentires-Alj M, Elledge SJ, Westbrook TF (2011) Activation of multiple proto-oncogenic tyrosinekinases in breast cancer via loss of the PTPN12 phosphatase. Cell 144:703–718CrossRefPubMed

28.

Julien SG, Dube N, Hardy S, Tremblay ML (2010) Inside the human cancer tyrosine phosphatome. Nat Rev Cancer 11:35–49CrossRef

29.

Hu TH, Huang CC, Lin PR et al (2003) Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer 97:1929–1940CrossRefPubMed

30.

Sánchez A, Nagy P, Thorgeirsson SS (2003) STAT-3 activity in chemically-induced hepatocellular carcinoma. Eur J Cancer 39:2093–2098CrossRefPubMed

31.

Fuke H, Shiraki K, Sugimoto K, Tanaka J, Beppu T, Yoneda K, Yamamoto N, Ito K, Masuya M, Takei Y (2007) Jak inhibitor induces S phase cell-cycle arrest and augments TRAIL-induced apoptosis in human hepatocellular carcinoma cells. Biochem Biophys Res Commun 363:738–744CrossRefPubMed

32.

Leslie K, Lang C, Devgan G, Azare J, Berishaj M, Gerald W, Kim YB, Paz K, Darnell JE, Albanese C, Sakamaki T, Pestell R, Bromberg J (2006) Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3. Cancer Res 66:2544–2552CrossRefPubMed

33.

Bowman T, Broome MA, Sinibaldi D, Wharton W, Pledger WJ, Sedivy JM, Irby R, Yeatman T, Courtneidge SA, Jove R (2001) Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc Natl Acad Sci U S A 98:7319–7324CrossRefPubMedPubMedCentral

34.

Yue P, Turkson J (2009) Targeting STAT3 in cancer: how successful are we? Expert Opin Investig Drugs 18:45–56CrossRefPubMedPubMedCentral

35.

Du WW, Fang L, Yang BB et al (2013) MicroRNA miR-24 enhances tumor invasion and metastasis by targeting PTPN9 and PTPRF to promote EGF signaling. J Cell Sci 126(6):1440–1453. doi:10.1242/jcs.118299 CrossRefPubMed

36.

Huang X, Gschweng E, Witte ON et al (2011) Regulated expression of microRNAs-126/126* inhibits erythropoiesis from human embryonic stem cells. Blood 117(7):2157–2165. doi:10.1182/blood-2010-08-302711 CrossRefPubMedPubMedCentral

Title: Downregulated Expression of PTPN9 Contributes to Human Hepatocellular Carcinoma Growth and Progression
Authors: Baoying Hu
Xia Yan
Fang Liu
Changlai Zhu
Huiling Zhou
Yuyan Chen
Jinxia Liu
Xingxing Gu
Runzhou Ni
Tianyi Zhang
Publication date: 01-07-2016
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 3/2016
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-015-0038-1

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