Senem KARABULUT, Aslı ÖRMECİ ÇİFTÇİBAŞI, Murat SERİLMEZ, Derya DURANYILDIZ, Filiz AKYÜZ, Vildan YASASEVER, Sabahattin KAYMAKOĞLU

Serum Glypican-3, Vascular Endothelial Growth Factor, and Interleukin-6 Levels in Hepatocellular Carcinoma

OBJECTIVEThe current study was an investigation of the serum levels of vascular endothelial growth factor (VEGF),interleukin 6 (IL-6), and glypican 3 (GPC-3), as potential diagnostic and prognostic indicators in cirrhoticpatients and patients with hepatocellular carcinoma (HCC) or who are predisposed to developHCC.METHODSA total of 54 HCC patients and 30 patients with cirrhosis were enrolled in this study. The pretreatmentserum level of GPC-3, VEGF, and IL-6 was determined using an enzyme-linked immunosorbent assay.A control group of 21 healthy age- and sex-matched individuals was also included.RESULTSThe serum VEGF level was statistically significantly higher in the HCC patients compared with the controlgroup (p=0.001). The serum IL-6 level was also higher in the HCC patients (p=0.002) and the cirrhoticpatients (p=0.006) compared with the control group, with a statistically significant difference. Therewas also a statistically significant difference between patients with HCC and the patients with cirrhosis(p=0.001). Furthermore, the serum GPC-3 level was significantly higher in the HCC patients (p=0.009)and the cirrhotic patients (p=0.001) compared with the healthy control group.CONCLUSIONTo our knowledge, this is the first study to determine the serum values of these parameters in patientswith HCC and cirrhosis. They may be useful markers to help clinicians reach a diagnosis of HCC.

PDF

___

Hamed MA, Ali SA. Non-viral factors contributing to hepatocellular carcinoma. World J Hepatol 2013;5(6):311–22.
Gomaa AI, Khan SA, Leen EL, Waked I, Taylor-Robinson SD. Diagnosis of hepatocellular carcinoma. World J Gastroenterol 2009;15(11):1301–14.
Song HH, Shi W, Xiang YY, Filmus J. The loss of glypican-3 induces alterations in Wnt signaling. J Biol Chem 2005;280(3):2116–25.
Stigliano I, Puricelli L, Filmus J, Sogayar MC, Bal de Kier Joffé E, Peters MG. Glypican-3 regulates migration, adhesion and actin cytoskeleton organization in mammary tumor cells through Wnt signaling modulation. Breast Cancer Res Treat 2009;114(2):251–62.
Torisu Y, Watanabe A, Nonaka A, Midorikawa Y, Makuuchi M, Shimamura T, et al. Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by beta-catenin/TCF. Cancer Sci 2008;99(6):1139–46.
Filmus J. The contribution of in vivo manipulation of gene expression to the understanding of the function of glypicans. Glycoconj J 2002;19(4-5):319–23.
Shirakawa H, Suzuki H, Shimomura M, Kojima M, Gotohda N, Takahashi S, et al. Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci 2009;100(8):1403–7.
Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003;125(1):89–97.
Nakatsura T, Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, et al. Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun 2003;306(1):16–25.
Zhou L, Liu J, Luo F. Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol 2006;12(8):1175–81.
Kanda M, Nomoto S, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, et al. Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J Surg Oncol 2008;98(3):190–6.
Li XM, Tang ZY, Qin LX, Zhou J, Sun HC. Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 1999;18(4):511–7.
Scheller J, Ohnesorge N, Rose-John S. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand J Immunol 2006;63(5):321–9.
Cheng KS, Tang HL, Chou FT, Chou JW, Hsu CH, Yu CJ, et al. Cytokine evaluation in liver cirrhosis and hepatocellular carcinoma. Hepatogastroenterology 2009;56(93):1105–10.
Hsia CY, Huo TI, Chiang SY, Lu MF, Sun CL, Wu JC, et al. Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma. Eur J Surg Oncol 2007;33(2):208–12.
Grizzi F, Franceschini B, Hamrick C, Frezza EE, Cobos E, Chiriva-Internati M. Usefulness of cancer-testis antigens as biomarkers for the diagnosis and treatment of hepatocellular carcinoma. J Transl Med 2007;5:3.
Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E, et al. Glypican-3: a novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology 2003;125(1):89–97.
Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, et al. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Cancer Res 2004;64(7):2418–23.
Wang XY, Degos F, Dubois S, Tessiore S, Allegretta M, Guttmann RD, et al. Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas. Hum Pathol 2006;37(11):1435–41
Yamauchi N, Watanabe A, Hishinuma M, Ohashi K, Midorikawa Y, Morishita Y, et al. The glypican 3 oncofetal protein is a promising diagnostic marker for hepatocellular carcinoma. Mod Pathol 2005;18(12):1591–8.
Amaoka N, Osada S, Kanematsu M, Imai H, Tomita H, Tokuyama Y, et al. Clinicopathological features of hepatocellular carcinoma evaluated by vascular endothelial growth factor expression. J Gastroenterol Hepatol 2007;22(12):2202–7.
Poon RT, Lau CP, Cheung ST, Yu WC, Fan ST. Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Res 2003;63(12):3121–6.
Sharma BK, Srinivasan R, Kapil S, Singla B, Saini N, Chawla YK, et al. Serum levels of angiogenic and anti-angiogenic factors: their prognostic relevance in locally advanced hepatocellular carcinoma. Mol Cell Biochem 2013;383(1-2):103–12.
Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 1998;227(3):398–404.
Zhu M, Paddock GV. Expression of the hepatocyte growth factor-like protein gene in human hepatocellular carcinoma and interleukin-6-induced increased expression in hepatoma cells. Biochim Biophys Acta 1999;1449(1):63–72.
Malaguarnera M, Di Fazio I, Laurino A, Romeo MA, Giugno I, Trovato BA. Role of interleukin 6 in hepatocellular carcinoma. Bull Cancer 1996;83(5):379–84.
Giannitrapani L, Cervello M, Soresi M, Notarbartolo M, La Rosa M, Virruso L, et al. Circulating IL-6 and sIL-6R in patients with hepatocellular carcinoma. Ann N Y Acad Sci 2002;963:46–52.
Parasole R, Izzo F, Perrone F, Pignata S, Galati MG, Leonardi E, et al. Prognostic value of serum biological markers in patients with hepatocellular carcinoma. Clin Cancer Res 2001;7(11):3504–9