Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality and carries a dismal prognosis. The present study aimed to identify the tumour-suppressive role and clinical implications of PTPN13 in HCC progression. We tested the effects of PTPN13 expression in proliferation, invasion, epithelial–mesenchymal transition and associated pathways in HCC cell lines in vitro. Furthermore, its clinical relevance was evaluated in a tissue microarray analysis of samples from 282 HCC patients. Various HCC cell lines expressed relatively low PTPN13 protein levels in vitro. PTPN13 overexpression significantly inhibited the progression of HCC cells, possibly by inhibiting epithelial–mesenchymal transition through inactivation of the EGFR/ERK signalling pathway. Tissue microarray analysis revealed that high PTPN13 expression was correlated with a favourable prognosis in postoperative HCC patients. This study demonstrated the tumour suppressor, PTPN13, as an alternative therapeutic target for HCC.
Hepatocellular carcinoma Protein tyrosine phosphatases Non-receptor type 13 (PTPN13) Epithelial–mesenchymal transition Metastasis Prognosis
This is a preview of subscription content, log in to check access.
This work was supported by the National Natural Science Foundation of China (Grant No. 81502502 and 81472672) and the Yangfan Project for Young Scientists of Shanghai (Grant No. 15YF1402200).
Compliance with ethical standards
This study was conducted in accordance with the ethical principles of research and was approved by the Zhongshan Hospital Ethics Committee. Informed consent was obtained from each patient following institutional review board protocols.
Conflicts of interest
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA: Cancer J Clin. 2015;65(2):87–108.Google Scholar
Julien SG, Dube N, Hardy S, Tremblay ML. Inside the human cancer tyrosine phosphatome. Nat Rev Cancer. 2011;11:35–49.CrossRefPubMedGoogle Scholar
Gao Q, Zhao YJ, Wang XY, et al. Activating mutations in PTPN3 promote cholangiocarcinoma cell proliferation and migration and are associated with tumor recurrence in patients. Gastroenterology. 2014;146:1397–407.CrossRefPubMedGoogle Scholar
Chan G, Kalaitzidis D, Neel BG. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 2008;27:179–92.CrossRefPubMedGoogle Scholar
Yeh SH, Wu DC, Tsai CY, et al. Genetic characterization of Fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res. 2006;12:1097–108.CrossRefPubMedGoogle Scholar
Wang Z, Shen D, Parsons DW, et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Sci N Y. 2004;304:1164–6.CrossRefGoogle Scholar
Zhu JH, Chen R, Yi W, et al. Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling. Oncogene. 2008;27:2525–31.CrossRefPubMedGoogle Scholar
Sotelo NS, Schepens JT, Valiente M, et al. PTEN-PDZ domain interactions: binding of PTEN to PDZ domains of PTPN13. Methods. 2015;77–78:147–56.CrossRefPubMedGoogle Scholar
Freiss G, Chalbos D. PTPN13/PTPL1: an important regulator of tumor aggressiveness. Anti Cancer Agents Med Chem. 2011;11:78–88.CrossRefGoogle Scholar
Sun HC, Zhang W, Qin LX, et al. Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007;47:684–90.CrossRefPubMedGoogle Scholar
Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 2009;15:971–9.CrossRefGoogle Scholar
Zhou SL, Dai Z, Zhou ZJ, et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatol Baltimo, Md. 2012;56:2242–54.CrossRefGoogle Scholar
Wang J, Ren J, Wu B, et al. Activation of Rab8 guanine nucleotide exchange factor Rabin8 by ERK1/2 in response to EGF signaling. Proc Natl Acad Sci U S A. 2015;112:148–53.CrossRefPubMedGoogle Scholar
Ying J, Li H, Cui Y, et al. Epigenetic disruption of two proapoptotic genes MAPK10/JNK3 and PTPN13/FAP-1 in multiple lymphomas and carcinomas through hypermethylation of a common bidirectional promoter. Leukemia. 2006;20:1173–5.CrossRefPubMedGoogle Scholar
Lucci MA, Orlandi R, Triulzi T, et al. Expression profile of tyrosine phosphatases in HER2 breast cancer cells and tumors. Cell Oncol. 2010;32:361–72.PubMedPubMedCentralGoogle Scholar
Wieckowski E, Atarashi Y, Stanson J, et al. FAP-1-mediated activation of NF-kappaB induces resistance of head and neck cancer to Fas-induced apoptosis. J Cell Biochem. 2007;100:16–28.CrossRefPubMedGoogle Scholar
Castilla C, Flores ML, Conde JM, et al. Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells. Clin Exp Metastasis. 2012;29:349–58.CrossRefPubMedGoogle Scholar
Scrima M, De Marco C, De Vita F, et al. The nonreceptor-type tyrosine phosphatase PTPN13 is a tumor suppressor gene in non-small cell lung cancer. Am J Pathol. 2012;180:1202–14.CrossRefPubMedGoogle Scholar
Glondu-Lassis M, Dromard M, Lacroix-Triki M, et al. PTPL1/PTPN13 regulates breast cancer cell aggressiveness through direct inactivation of Src kinase. Cancer Res. 2010;70:5116–26.CrossRefPubMedPubMedCentralGoogle Scholar
Revillion F, Puech C, Rabenoelina F, et al. Expression of the putative tumor suppressor gene PTPN13/PTPL1 is an independent prognostic marker for overall survival in breast cancer. Int J Cancer. 2009;124:638–43.CrossRefPubMedPubMedCentralGoogle Scholar
Dromard M, Bompard G, Glondu-Lassis M, et al. The putative tumor suppressor gene PTPN13/PTPL1 induces apoptosis through insulin receptor substrate-1 dephosphorylation. Cancer Res. 2007;67:6806–13.CrossRefPubMedGoogle Scholar
Gloire G, Charlier E, Piette J. Regulation of CD95/APO-1/Fas-induced apoptosis by protein phosphatases. Biochem Pharmacol. 2008;76:1451–8.CrossRefPubMedGoogle Scholar
Winterhoff BJ, Arlt A, Duttmann A, et al. Characterisation of FAP-1 expression and CD95 mediated apoptosis in the A818-6 pancreatic adenocarcinoma differentiation system. Differentiation. 2012;83:148–57.CrossRefPubMedGoogle Scholar
Cuppen E, Nagata S, Wieringa B, Hendriks W. No evidence for involvement of mouse protein-tyrosine phosphatase-BAS-like Fas-associated phosphatase-1 in Fas-mediated apoptosis. J Biol Chem. 1997;272:30215–20.CrossRefPubMedGoogle Scholar