American Journal of Cancer Prevention
ISSN (Print): 2328-7314 ISSN (Online): 2328-7322 Website: Editor-in-chief: Nabil Abdel-Hamid
Open Access
Journal Browser
American Journal of Cancer Prevention. 2016, 4(4), 57-63
DOI: 10.12691/ajcp-4-4-3
Open AccessReview Article

The Role of Endocan in the Development of Hepatocellular Carcinoma

Xiao-hong Zhou1, Xing Lai2, De-an Mu2, Jian-ping Gong2 and Qing-gang Yin3,

1Department of Hepatobiliary Surgery, Bishan District People's Hospital, Chongqing, China

2Department of Hepatobiliary, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

3Department of Hepatobiliary and Thoracic Surgery, Tongliang District People's Hospital, Chongqing, China

Pub. Date: January 05, 2017

Cite this paper:
Xiao-hong Zhou, Xing Lai, De-an Mu, Jian-ping Gong and Qing-gang Yin. The Role of Endocan in the Development of Hepatocellular Carcinoma. American Journal of Cancer Prevention. 2016; 4(4):57-63. doi: 10.12691/ajcp-4-4-3


Endocan is a dermatan sulfate proteoglycan, constituted of a core protein with 165 amino acids and a single dermatan sulfate chain covalently linked to the serine 137. It is mainly expressed by the activated endothelial cell and regulated by various cytokines and growth factors. In hepatocellular carcinoma (HCC), the expression of endocan increases significantly, and it can induce tumorigenesis and promote the tumor progression. Endocan involves in the proliferation of HCC cell, angiogenesis, metastasis and immunity via a variety of complicated pathways, which cover the regulation of hepatic inflammation-fibrosis-cancer (IFC) axis through nuclear factor-kappa B (NF-кB), modulating cell cycle, interaction with vascular endothelial growth factors (VEGF), the collapse of cell-cell junction, inhibiting of lymphocyte function associated antigen-1 /intercellular adhesion molecule-1(LFA-1/ICAM-1) and changing of tumor microenvironment. Therefore, it is a potential marker and promising therapy target of HCC.

endocan Hepatocellular carcinoma NF-кB vascular endothelial growth factor lymphocyte function associated antigen-1

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit


[1]  Lassalle P, Molet S, Janin A, et al. ESM-1 is a novel human endothelial cell specific molecule expressed in lung and regulated by cytokines. J Biol Chem, 1996; 271(34): 20458-64.
[2]  Béchard D, Gentina T, Delehedde M, et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem, 2001; 276(51): 48341-9.
[3]  Delehedde M, Devenyns L, Maurage CA, et al. Endocan in cancers: a lesson from a circulating dermatan sulfate proteoglycan. Int J Cell Biol, 2013; 2013: 705027.
[4]  Mihajlovic DM, Lendak DF, Brkic SV, et al. Endocan is useful biomarker of survival and severity in sepsis. Microvasc Res, 2014; 93: 92-7.
[5]  Tsai JC, Zhang J, Minami T, et al. Cloning and characterization of the human lung endothelial-cell-specific molecule-1 promoter. J Vasc Res, 2002; 39(2): 148-59.
[6]  Cong R, Jiang X, Wilson CM, et al. Hhex is a direct repressor of endothelial cell-specific molecule 1 (ESM-1). Biochem Biophys Res Commun, 2006; 346(2): 535-45.
[7]  Sarrazin S, Adam E, Lyon M, et al. Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. Biochim Biophys Acta, 2006; 1765(1): 25-37.
[8]  Sarrazin S, Lyon M, Deakin JA, et al. Characterization and binding activity of the chondroitin/dermatan sulfate chain from Endocan, a soluble endothelial proteoglycan. Glycobiology, 2010; 20(11): 1380-8.
[9]  Aitkenhead M, Wang SJ, Nakatsu MN, et al. Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM. Microvasc Res, 2002; 63(2): 159-71.
[10]  Depontieu F, Grigoriu BD, Scherpereel A, et al. Loss of Endocan tumorigenic properties after alternative splicing of exon 2. BMC Cancer, 2008; 8: 14.
[11]  Bechard D, Meignin V, Scherpereel A, et al. Characterization of the secreted form of endothelial-cell-specific molecule 1 by specific monoclonal antibodies. J Vasc Res, 2000; 37(5): 417-25.
[12]  Wellner M, Herse F, Janke J, et al. Endothelial cell specific molecule-1--a newly identified protein in adipocytes. Horm Metab Res, 2003; 35(4): 217-21.
[13]  Zhang SM, Zuo L, Zhou Q, et al. Expression and distribution of endocan in human tissues. Biotech Histochem, 2012; 87(3): 172-8.
[14]  Grigoriu BD, Depontieu F, Scherpereel A, et al. Endocan expression and relationship with survival in human non-small cell lung cancer. Clin Cancer Res, 2006; 12(15): 4575-82.
[15]  Roudnicky F, Poyet C, Wild P, et al. Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis. Cancer Res, 2013; 73(3): 1097-106.
[16]  Maurage CA, Adam E, Mineo JF, et al. Endocan expression and localization in human glioblastomas. J Neuropathol Exp Neurol, 2009; 68(6): 633-41.
[17]  Leroy X, Aubert S, Zini L, et al. Vascular endocan (ESM-1) is markedly overexpressed in clear cell renal cell carcinoma. Histopathology, 2010; 56(2): 180-7.
[18]  Rennel E, Mellberg S, Dimberg A, et al. Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer. Exp Cell Res, 2007; 313(7): 1285-94.
[19]  Ji NY, Kim YH, Jang YJ, et al. Identification of endothelial cell-specific molecule-1 as a potential serum marker for colorectal cancer. Cancer Sci, 2010; 101(10): 2248-53.
[20]  Kang YH, Ji NY, Lee CI, et al. ESM-1 silencing decreased cell survival, migration, and invasion and modulated cell cycle progression in hepatocellular carcinoma. Amino Acids, 2011; 40(3): 1003-13.
[21]  Scherpereel A, Depontieu F, Grigoriu B, et al. Endocan, a new endothelial marker in human sepsis. Crit Care Med, 2006; 34(2): 532-7.
[22]  De Freitas Caires N, Legendre B, Parmentier E, et al. identification of a 14 kDa endocan fragment generated by cathepsin G, a novel circulating biomarker in patients with sepsis. J Pharm Biomed Anal, 2013; 78-79: 45-51.
[23]  Hatfield KJ, Lassalle P, Leiva RA, Serum levels of endothelium-derived endocan are increased in patients with untreated acute myeloid leukemia. Hematology, 2011; 16(6): 351-6
[24]  Gerritsen ME, Tomlinson JE, Zlot C,et al. Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol, 2003; 140(4): 595-610.
[25]  Abid MR, Yi X, Yano K, et al. Vascular endocan is preferentially expressed in tumor endothelium. Microvasc Res, 2006; 72(3): 136-45.
[26]  Zhao X, Ramsey KE, Stephan DA, et al. Gene aand protein expression changes in human trabecular meshwork cells treated with transforming growth factor-beta. Invest Ophthalmol Vis Sci, 2004; 45(11): 4023-34.
[27]  Lee W, Ku SK, Kim SW, et al. Endocan elicits severe vascular inflammatory responses in vitro and in vivo. J Cell Physiol, 2014; 229(5): 620-30.
[28]  Kim JH, Park MY, Kim CN, et al. Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1α in human colon carcinoma: impact of ESM-1 on prognosis and its correlation with clinicopathological features. Oncol Rep, 2012; 28(5): 1701-8.
[29]  Ozaki K, Toshikuni N, George J, et al. Serum endocan as a novel prognostic biomarker in patients with hepatocellular carcinoma. J Cancer, 2014; 5(3): 221-30.
[30]  Elsharkawy AM, Mann DA. Nuclear factor-kappa B and the hepatic inflammation-fibrosis-cancer axis. Hepatology, 2007; 46(2): 590-7.
[31]  Connolly MK, Bedrosian AS, Mallen-St Clair J, et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J Clin Invest, 2009; 119(11): 3213-25.
[32]  Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut, 2006; 55(3): 415-24.
[33]  Carrillo LM, Arciniegas E, Rojas H, et al. Immunolocalization of endocan during endothelial-mesenchymal transition process. Eur J Histochem, 2011; 55(2): e13.
[34]  Zeisberg EM, Tarnavski O, Zeisberg M, et al. Endothelial-to mesenchymal transition contributes to cardiac fibrosis. Nat Med, 2007; 13(8): 952-61.
[35]  Zeisberg EM, Potenta SE, Sugimoto H, et al. Fibroblasts in kindney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol, 2008; 19(12): 2282-7.
[36]  Hashimoto N, , Imaizumi K, et al. Endothelial mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol, 2010; 43(2): 161-72.
[37]  Zhang SH, Wen KM, Wu W, et al. Efficacy of HGF carried by ultrasound microbubble-cationic nano-liposomes complex for treating hepatic fibrosis in a bile duct ligation rat model, and its relationship with the diffusion-weighted MRI parameters. Clin Res Hepatol Gastroenterol, 2013; 37(6): 602-7.
[38]  Wang ZX, Wang ZG, Ran HT, et al. The treatment of liver fibrosis induced by hepatocyte growth factor-directed, ultrasound-targeted microbubble destruction in rats. Clin Imaging, 2009; 33(6): 454-61.
[39]  Li S, Wang L, Wang C, et al. Detection on dynamic changes of endothelial cell specific molecule acute rejection after renal transplantation. Urology, 2012; 80(3): 738.e1-8.
[40]  Balta I, Balta S, Koryurek OM, et al. Serum ednocan levels as a marker of disease activity in patients with Behcet disease. J Am Acad Dermatol, 2014; 70(2): 291-6.
[41]  Adekola H, Romero R, Chaemsaithong P, et al. Endocan, a putative endothelial cell marker, is elevated in preeclampsia, decreased in acute pyelonephritis, and unchanged in other obstetrical syndromes. J Matern Fetal Neonatal Med, 2014; 11: 1-35.
[42]  Balta S, Mikhailidis DP, Demirkol S, et al. Endocan-a novel inflammatory indicator in newly diagnosised patients with hypertension: a pilot study. Angiology, 2014; 65(9): 773-7.
[43]  Iwakiri Y. endothelial dysfunction in the regulation of cirrhosis and portal hypertension. Liver Int. 2012; 32(2): 199-213.
[44]  Lin HC, Huang YT, Yang YY, et al. Beneficial effects of dual vascular endothelial growth factor receptor/fibroblast growth factor receptor inhibitor brivanib alaninate in cirrhotic portal hypertension. J Gastroenterol Hepatol, 2014; 29(5): 1073-82.
[45]  Rocha SF, Schiller M, Jing D. Esm 1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability. Circ Res, 2014; 115(6): 581-90.
[46]  Tok D, Ekiz F, Basar O. Serum endocan levels in patients with chronic liver disease. Int J Clin Exp Med, 2014; 7(7): 1802-7.
[47]  Zoil M, Sutton A, Calderaro J, et al. ESM-1 expression in stromal cells is predictive of recurrence after radiofrequency ablation in early hepatocellular carcinoma. J Hepatol, 2013; 59(6): 1264-70.
[48]  Scherpereel A, Gentina T, Grigoriu B. Overexpression of endocan induces tumor formation. Cancer Res, 2003; 63(18): 6084-9.
[49]  Chen LY, Liu X, Wang SL, et al. over-expression of the endocan gene in endothelial cells from hepatocellular carcinoma is associated with angiogenesis and tumor invasion. J Int Med Res, 2010; 38(2): 498-510.
[50]  Huang GW, Tao YM, Ding X. Endocan expression correlated with poor survival in human hepatocellular carcinoma. Dig Dis Sci, 2009; 54(2): 389-94.
[51]  Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol, 2009; 135: 1359-67.
[52]  Minata M, Harada KH, Kudo M, et al. The prognostic value of vascular endothelial growth factor in hepatocellular carcinoma for predicting metastasis after curative resection. Oncology, 2013; 84: 75-81.
[53]  Tseng PL, Tai MH, Huang CC, et al. Overexpression of VEGF is associated with positive p53 immunostaining in hepatocellular carcinoma (HCC) and adverse outcome of HCC patients. J Surg Oncol, 2008; 98: 349-57
[54]  Schoenleber SJ, Kurtz DM, Talwalkar JA, et al. Prognostic role of vascular endothelial growth factor in hepatocellualr carcinoma: systematic review and meta-analysis. Br J Cancer, 2009; 100(9): 1385-92.
[55]  Zhan P, Qian Q, Yu LK. Prognostic significance of vascular endothelial growth factor expressiom in hepatocellular carcinoms tissue: a meta-analysis. Hepatobiliary Surg Nutr, 2013; 2(3): 148-55.
[56]  Takahashi S. Vascular endothelial growth factor(VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull, 2011; 34(12): 1785-8.
[57]  del Toro R, Prahst C, Mathiver T, et al. Identification and functional analysis of endothelial tip cell-enriched gene. Blood, 2010; 116(19): 4025-33.
[58]  De Smet F, Segura I, De Bock K, et al. Mechanisms of vessel branching: filopodia on endothelial tip cells lead the way. Arterioscler Thromb Vasc Biol, 2009; 29(5): 639-49.
[59]  Strasser GA, Kaminker JS, Tesssier-Lavigne M. Microarray analysis of retinal endothelial tip cells identifies CXCR4 as mediator of tip cell morphology and branching. Blood, 2010; 115(24): 5102-10.
[60]  García-Román J, Zentella-Dehesa A. Vascular permeability changes involved in tumor metastasis. Cancer Lett, 2013; 335(2): 259-69.
[61]  Mouta Carreira C, Nasser SM, di Tomaso E. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res, 2001; 61(22): 8079-84.
[62]  Shin JW, Huggenberger R, Detmar M. Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis. Blood, 2008; 112(6): 2318-26.
[63]  Anderson ME, Siahaan TJ. Targeting ICAM-1/LFA-1 interaction for controlling autoimmune diseases: designing peptide and small molecule inhibitors. Peptides, 2003; 24(3): 487-501.
[64]  Herter J, Zarbock A. Integrin Regulation during Leukocyte Recruitment. J Immunol, 2013; 190(9): 4451-7.
[65]  Takeichi T, Mocevicius P, Deduchovas O, et al. αL β2 integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer. Int J Cancer, 2012; 130(9): 2067-76.
[66]  Béchard D, Scherpereel A, Hammad H, et al. Human endothelial-cell specific molecule-1 binds directly to the integrin CD/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1. J Immunol, 2001; 167(6): 3099-106.
[67]  Leonardi GC, Candido S, Cervello M, et al. The tumor microenvironment in hepatocellular carcinoma (review). Int J Oncol, 2012; 40(6): 1733-47.
[68]  Lin F, Wang N, Zhang TC. The role of endothelial-mesenchymal transition in development and pathological process. IUBMB Life, 2012; 64(9): 717-23.
[69]  Zeisberg EM, Potenta S, Xie L, et al. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res, 2007; 67(21): 10123-8.
[70]  Nault JC, Goouyot E, Laguillier C, et al. Serum proteoglycans as prognostic biomarker of hepatocellular carcinoma in patients with alcoholic cirrhosis. Cancer Epidemiol Biomarkers Prev, 2013; 22(8): 1343-52.
[71]  Sumie S, Kuromatsu R, Okuda K, et al. Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors. Ann Surg Oncol, 2008; 15(5): 1375-82.
[72]  Ikai I, Arii S, Kojiro M, et al. Reevaluation of prognostic factors for survival after liver resection in patients with hepatocellular carcinoma in a Japanese nationwide survey. Cancer, 2004; 101(4): 796-802.
[73]  Poon RT, Fan ST, Lo CM, et al. Difference in tumor invasiveness in cirrhotic patients with hepatocellular carcinoma fulfilling the Milan criteria treated by resection and transplantation: impact on long-term survival. Ann Surg, 2007; 245(1): 51-8.
[74]  Yamamoto J, Kosuge T, Saiura A, et al. Effectiveness of hepatic resection for early-stage hepatocellular carcinoma in cirrhotic patients: subgroup analysis according to Milan criteria. Jpn J Clin Oncol, 2007; 37(4): 287-95.
[75]  Xiang ZL, Zeng ZC, Fan J, et al. The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome. Mol Biol Rep, 2012; 39(2): 2021-9.