Hepatocellular carcinoma (HCC) is a common malignant solid tumor characterized by rich vascularization. Pregnancy-specific glycoprotein 9 (PSG9) is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy. We previously identified PSG9 as an HCC-related protein. However, the expression of PSG9 and its regulation during HCC carcinogenesis remain poorly explored. In the present study, we first found that the levels of PSG9 protein were significantly increased in the plasma of HCC patients. PSG9 overexpression also increased the proliferation ability of an HCC cell line. High expression of PSG9 was associated with angiogenesis by accelerating VEGFA expression. In addition, Cox’s proportional hazards model analysis revealed that the plasma level of PSG9 was an independent prognostic factor for overall survival. We propose that PSG9 is a novel indicator of prognosis in patients with HCC and could serve as a novel therapeutic target for HCC. Furthermore, our results indicate that PSG9 protein may facilitate the development of HCC by fostering angiogenesis via promoting VEGFA production in cancer cells.
National High Technology Research and Development Program of China(2012AA020206)
National Basic Research Program of China(2014CBA02004)
National Natural Science Foundation of China(81172035)
This work was supported by the National Natural Science Foundation of China (81172035), National High Technology Research and Development Program of China (2012AA020206), and National Basic Research Program of China (2014CBA02004).
The author(s) declare that they have no conflict of interest.
[1] Cao Y., E G., Wang E., Pal K., Dutta S.K., Bar-Sagi D., Mukhopadhyay D.. VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res, 2012, 72: 3912-3918 CrossRef PubMed Google Scholar
[2] Del Rio M., Molina F., Bascoul-Mollevi C., Copois V., Bibeau F., Chalbos P., Bareil C., Kramar A., Salvetat N., Fraslon C., Conseiller E., Granci V., Leblanc B., Pau B., Martineau P., Ychou M.. Gene expression signature in advanced colorectal cancer patients select drugs and response for the use of leucovorin, fluorouracil, and irinotecan. J Clin Oncol, 2007, 25: 773-780 CrossRef PubMed Google Scholar
[3] El-Assal O.N., Yamanoi A., Soda Y., Yamaguchi M., Igarashi M., Yamamoto A., Nabika T., Nagasue N.. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology, 1998, 27: 1554-1562 CrossRef PubMed Google Scholar
[4] Ellis L.M., Hicklin D.J.. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer, 2008, 8: 579-591 CrossRef PubMed Google Scholar
[5] Florio T., Morini M., Villa V., Arena S., Corsaro A., Thellung S., Culler M.D., Pfeffer U., Noonan D.M., Schettini G., Albini A.. Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology, 2003, 144: 1574-1584 CrossRef PubMed Google Scholar
[6] Folkman J.. Angiogenesis-dependent diseases. Semin Oncol, 2001, 28: 536-542 CrossRef Google Scholar
[7] Ha C.T., Wu J.A., Irmak S., Lisboa F.A., Dizon A.M., Warren J.W., Ergun S., Dveksler G.S.. Human pregnancy specific beta-1-glycoprotein 1 (PSG1) has a potential role in placental vascular morphogenesis. Biol Reprod, 2010, 83: 27-35 CrossRef Google Scholar
[8] Jemal A., Bray F., Center M.M., Ferlay J., Ward E., Forman D.. Global cancer statistics. CA Cancer J Clin, 2011, 61: 69-90 CrossRef PubMed Google Scholar
[9] Li M., Xiao T., Zhang Y., Feng L., Lin D., Liu Y., Mao Y., Guo S., Han N., Di X., Zhang K., Cheng S., Gao Y.. Prognostic significance of matrix metalloproteinase-1 levels in peripheral plasma and tumour tissues of lung cancer patients. Lung Cancer, 2010, 69: 341-347 CrossRef PubMed Google Scholar
[10] Lisboa F.A., Warren J., Sulkowski G., Aparicio M., David G., Zudaire E., Dveksler G.S.. Pregnancy-specific glycoprotein 1 induces endothelial tubulogenesis through interaction with cell surface proteoglycans. J Biol Chem, 2011, 286: 7577-7586 CrossRef PubMed Google Scholar
[11] Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.F., de Oliveira A.C., Santoro A., Raoul J.L., Forner A., Schwartz M., Porta C., Zeuzem S., Bolondi L., Greten T.F., Galle P.R., Seitz J.F., Borbath I., H?ussinger D., Giannaris T., Shan M., Moscovici M., Voliotis D., Bruix J., Bruix J.. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 2008, 359: 378-390 CrossRef PubMed Google Scholar
[12] Mazzocca A., Fransvea E., Lavezzari G., Antonaci S., Giannelli G.. Inhibition of transforming growth factor β receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology, 2009, 50: 1140-1151 CrossRef PubMed Google Scholar
[13] Mei Z., Jiao H.K., Wang W., Li J., Chen G.Q., Xu Y.. Polycomb chromobox 4 enhances migration and pulmonary metastasis of hepatocellular carcinoma cell line MHCC97L. Sci China Life Sci, 2014, 57: 610-617 CrossRef PubMed Google Scholar
[14] Pang R., Poon R.T.P.. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett, 2006, 242: 151-167 CrossRef PubMed Google Scholar
[15] Salahshor S., Goncalves J., Chetty R., Gallinger S., Woodgett J.R.. Differential gene expression profile reveals deregulation of pregnancy specific β1 glycoprotein 9 early during colorectal carcinogenesis. BMC Cancer, 2005, 5: 66 CrossRef PubMed Google Scholar
[16] Sapra P., Kraft P., Pastorino F., Ribatti D., Dumble M., Mehlig M., Wang M., Ponzoni M., Greenberger L.M., Horak I.D.. Potent and sustained inhibition of HIF-1α and downstream genes by a polyethyleneglycol-SN38 conjugate, EZN-2208, results in anti-angiogenic effects. Angiogenesis, 2011, 14: 245-253 CrossRef PubMed Google Scholar
[17] Sasaki Y., Yamamura H., Kawakami Y., Yamada T., Hiratsuka M., Kameyama M., Ohigashi H., Ishikawa O., Imaoka S., Ishiguro S., Takahashi K.. Expression of smooth muscle calponin in tumor vessels of human hepatocellular carcinoma and its possible association with prognosis. Cancer, 2002, 94: 1777-1786 CrossRef PubMed Google Scholar
[18] Shi G.M., Ke A.W., Zhou J., Wang X.Y., Xu Y., Ding Z.B., Devbhandari R.P., Huang X.Y., Qiu S.J., Shi Y.H., Dai Z., Yang X.R., Yang G.H., Fan J.. CD151 modulates expression of matrix metalloproteinase 9 and promotes neoangiogenesis and progression of hepatocellular carcinoma. Hepatology, 2010, 52: 183-196 CrossRef PubMed Google Scholar
[19] Snyder S.K., Wessells J.L., Waterhouse R.M., Dveksler G.S., Wessner D.H., Wahl L.M., Zimmermann W.. Pregnancy-specific glycoproteins function as immunomodulators by inducing secretion of IL-10, IL-6 and TGF-beta1 by human monocytes. Am J Reprod Immunol, 2001, 45: 205-216 CrossRef Google Scholar
[20] Sun W., Sohal D., Haller D.G., Mykulowycz K., Rosen M., Soulen M.C., Caparro M., Teitelbaum U.R., Giantonio B., O'Dwyer P.J., Shaked A., Reddy R., Olthoff K.. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer, 2011, 117: 3187-3192 CrossRef PubMed Google Scholar
[21] Tseng P.L., Tai M.H., Huang C.C., Wang C.C., Lin J.W., Hung C.H., Chen C.H., Wang J.H., Lu S.N., Lee C.M., Changchien C.S., Hu T.H.. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients. J Surg Oncol, 2008, 98: 349-357 CrossRef PubMed Google Scholar
[22] Vinciguerra M., Carrozzino F., Peyrou M., Carlone S., Montesano R., Benelli R., Foti M.. Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol, 2009, 50: 1132-1141 CrossRef PubMed Google Scholar
[23] Xiao T., Ying W., Li L., Hu Z., Ma Y., Jiao L., Ma J., Cai Y., Lin D., Guo S., Han N., Di X., Li M., Zhang D., Su K., Yuan J., Zheng H., Gao M., He J., Shi S., Li W., Xu N., Zhang H., Liu Y., Zhang K., Gao Y., Qian X., Cheng S.. An approach to studying lung cancer-related proteins in human blood. Mol Cell Proteomics, 2005, 4: 1480-1486 CrossRef PubMed Google Scholar
[24] Yang X.R., Xu Y., Yu B., Zhou J., Qiu S.J., Shi G.M., Zhang B.H., Wu W.Z., Shi Y.H., Wu B., Yang G.H., Ji Y., Fan J.. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut, 2010, 59: 953-962 CrossRef PubMed Google Scholar
[25] Zhang X., Xiao T., Cheng S., Tong T., Gao Y.. Cigarette smoke suppresses the ubiquitin-dependent degradation of OLC1. Biochem Biophys Res Commun, 2011, 407: 753-757 CrossRef PubMed Google Scholar
[26] Zhao X., Li J., Zhuo J., Cai L.. Reexpression of ARHI inhibits tumor growth and angiogenesis and impairs the mTOR/VEGF pathway in hepatocellular carcinoma. Biochem Biophys Res Commun, 2010, 403: 417-421 CrossRef PubMed Google Scholar
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