Usefulness of plasma full‑length glypican‑3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery

Miura,Masahiro; Fujinami,Norihiro; Shimizu,Yasuhiro; Mizuno,Shoichi; Saito,Keigo; Suzuki,Toshihiro; Konishi,Masaru; Takahashi,Shinichiro; Gotohda,Naoto; Suto,Kouzou; Yoshida,Tomokazu; Nakatsura,Tetsuya

doi:10.3892/ol.2020.11371

Usefulness of plasma full‑length glypican‑3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery

Authors:
- Masahiro Miura
- Norihiro Fujinami
- Yasuhiro Shimizu
- Shoichi Mizuno
- Keigo Saito
- Toshihiro Suzuki
- Masaru Konishi
- Shinichiro Takahashi
- Naoto Gotohda
- Kouzou Suto
- Tomokazu Yoshida
- Tetsuya Nakatsura
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Affiliations: Central Research Laboratories, Sysmex Corporation, Kobe, Hyōgo 651‑2271, Japan, Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba 277‑8577, Japan, Division of Hepatobiliary Pancreatic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba 277‑8577, Japan
Published online on: February 5, 2020 https://doi.org/10.3892/ol.2020.11371
Pages: 2657-2666
Copyright: © Miura et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Predicting the risk of hepatocellular carcinoma (HCC) recurrence before treatment is necessary for developing subsequent treatment policies. Several tumor markers found in blood, such as alpha‑fetoprotein (AFP) and protein induced by vitamin K absence or antagonist‑II (PIVKA‑II), are presently used to determine the occurrence and recurrence of HCC and to predict patient prognosis. However, these markers are insufficient for these purposes as certain patients have HCC recurrence despite exhibiting negative AFP and PIVKA‑II. The present study identified glypican‑3 (GPC3), an embryonal carcinoma antigen that is expressed specifically in HCC and is secreted into blood. Although the N‑terminal domain of GPC3 in sera may be a potential prognostic factor for HCC, its biological role remains unclear. By contrast, full‑length GPC3 (FL‑GPC3) is reported to serve important roles in cell differentiation, proliferation and signaling events that cause HCC. Given the biological roles of FL‑GPC3 in HCC progression, the present study evaluated its potential as a predictive marker of HCC recurrence. In the present study, a novel measurement system was constructed to specifically measure plasma FL‑GPC3. Subsequently, its ability to predict recurrence after radical surgery in 39 HCC patients was evaluated. The results revealed that preoperative FL‑GPC3 levels in patients with recurrence were significantly higher than those in patients without recurrence, suggesting that FL‑GPC3 could be a better predictive maker of risk of recurrence than AFP or PIVKA‑II. Furthermore, it was determined that the combination of FL‑GPC3, AFP and PIVKA‑II could predict recurrence within one year of radical surgery with high sensitivity and specificity. Based on these results, the validation of FL‑GPC3 as a predictive marker of HCC recurrence in a larger population is warranted.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Sawada Y, Yoshikawa T, Ofuji K, Yoshihura M, Tsuchiya N, Takahashi M, Nobuoka D, Gotohda N, Takahashi S, Kato Y, et al: Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 5:e11294832016. View Article : Google Scholar : PubMed/NCBI
3	Toyoda H, Kumada T, Osaki Y, Oka H, Urano F, Kudo M and Matsunaga T: Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers. Clin Gastroenterol Hepatol. 4:1528–1536. 2006. View Article : Google Scholar : PubMed/NCBI
4	Carr BI, Kanke F, Wise M and Satomura S: Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 52:776–782. 2007. View Article : Google Scholar : PubMed/NCBI
5	Bayati N, Silverman AL and Gordon SC: Serum alpha-fetoprotein levels and liver histology in patients with chronic hepatitis C. Am J Gastroenterol. 93:2452–2456. 1998. View Article : Google Scholar : PubMed/NCBI
6	Shirakawa H, Kuronuma T, Nishimura Y, Hasebe T, Nakano M, Gotohda N, Takahashi S, Nakagohri T, Konishi M, Kobayashi N, et al: Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. Int J Oncol. 34:649–656. 2009.PubMed/NCBI
7	Shirakawa H, Suzuki H, Shimomura M, Kojima M, Gotohda N, Takahashi S, Nakagohri T, Konishi M, Kobayashi N, Kinoshita T and Nakatsura T: Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma. Cancer Sci. 100:1403–1407. 2009. View Article : Google Scholar : PubMed/NCBI
8	Wang HL, Anatelli F, Zhai QJ, Adley B, Chuang ST and Yang XJ: Glypican-3 as a useful diagnostic marker that distinguishes hepatocellular carcinoma from benign hepatocellular mass lesions. Arch Pathol Lab Med. 132:1723–1728. 2008.PubMed/NCBI
9	Nakatsura T, Kageshita T, Ito S, Wakamatsu K, Monji M, Ikuta Y, Senju S, Ono T and Nishimura Y: Identification of glypican-3 as a novel tumor marker for melanoma. Clin Cancer Res. 10:6612–6621. 2004. View Article : Google Scholar : PubMed/NCBI
10	Toretsky JA, Zitomersky NL, Eskenazi AE, Voigt RW, Strauch ED, Sun CC, Huber R, Meltzer SJ and Schlessinger D: Glypican-3 expression in Wilms tumor and hepatoblastoma. J Pediatr Hematol Oncol. 23:496–499. 2001. View Article : Google Scholar : PubMed/NCBI
11	Saikali Z and Sinnett D: Expression of glypican 3 (GPC3) in embryonal tumors. Int J Cancer. 89:418–422. 2000. View Article : Google Scholar : PubMed/NCBI
12	Capurro M, Wanless IR, Sherman M, Deboer G, Shi W, Miyoshi E and Filmus J: Glypican-3: A novel serum and histochemical marker for hepatocellular carcinoma. Gastroenterology. 125:89–97. 2003. View Article : Google Scholar : PubMed/NCBI
13	De Cat B, Muyldermans SY, Coomans C, Degeest G, Vanderschueren B, Creemers J, Biemar F, Peers B and David G: Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J Cell Biol. 163:625–635. 2003. View Article : Google Scholar : PubMed/NCBI
14	Ho M and Kim H: Glypican-3: A new target for cancer immunotherapy. Eur J Cancer. 47:333–338. 2011. View Article : Google Scholar : PubMed/NCBI
15	Haruyama Y, Yorita K, Yamaguchi T, Kitajima S, Amano J, Ohtomo T, Ohno A, Kondo K and Kataoka H: High preoperative levels of serum glypican-3 containing N-terminal subunit are associated with poor prognosis in patients with hepatocellular carcinoma after partial hepatectomy. Int J Cancer. 137:1643–1651. 2015. View Article : Google Scholar : PubMed/NCBI
16	Nakatsura T, Yoshitake Y, Senju S, Monji M, Komori H, Motomura Y, Osaka S, Beppu T, Ishiko T, Kamohara H, et al: Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. Biochem Biophys Res Commun. 306:16–25. 2003. View Article : Google Scholar : PubMed/NCBI
17	Filmus J, Capurro M and Rast J: Glypicans. Genome Biol. 9:2242008. View Article : Google Scholar : PubMed/NCBI
18	Capurro M and Filmus J: Glypican-3 as a serum marker for hepatocellular carcinoma. Cancer Res. 65:372–373. 2005.PubMed/NCBI
19	Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, Tokita S, Iwanari H, Ito Y, Nakano K, et al: Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Cancer Res. 64:418–423. 2004. View Article : Google Scholar
20	Chen M, Li G, Yan J, Lu X, Cui J, Ni Z, Cheng W, Qian G, Zhang J and Tu H: Reevaluation of glypican-3 as a serological marker for hepatocellular carcinoma. Clin Chim Acta. 423:105–111. 2013. View Article : Google Scholar : PubMed/NCBI
21	Beale G, Chattopadhyay D, Gray J, Stewart S, Hudson M, Day C, Trerotoli P, Giannelli G, Manas D and Reeves H: AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease. BMC Cancer. 8:2002008. View Article : Google Scholar : PubMed/NCBI
22	Ozkan H, Erdal H, Kocak E, Tutkak H, Karaeren Z, Yakut M and Koklu S: Diagnostic and prognostic role of serum glypican 3 in patients with hepatocellular carcinoma. J Clin Lab Anal. 25:350–353. 2011. View Article : Google Scholar : PubMed/NCBI
23	Capurro M, Shi W, Izumikawa T, Kitagawa H and Filmus J: Processing by convertases is required for glypican-3-induced inhibition of Hedgehog signaling. J Biol Chem. 290:7576–7585. 2015. View Article : Google Scholar : PubMed/NCBI
24	Poon RT, Ng IO, Fan ST, Lai EC, Lo CM, Liu CL and Wong J: Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: A study of a prospective cohort. J Clin Oncol. 19:3037–3044. 2001. View Article : Google Scholar : PubMed/NCBI
25	Gao W, Tang Z, Zhang YF, Feng M, Qian M, Dimitrov DS and Ho M: Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis. Nat Commun. 6:65362015. View Article : Google Scholar : PubMed/NCBI
26	El-Saadany S, El-Demerdash T, Helmy A, Mayah WW, Hussein BE, Hassanien M, Elmashad N, Fouad MA and Basha EA: Diagnostic value of Glypican-3 for hepatocellular carcinomas. Asian Pac J Cancer Prev. 19:811–817. 2018.PubMed/NCBI
27	Chen IP, Ariizumi S, Nakano M and Yamomoto M: Positive glypican-3 expression in early hepatocellular carcinoma predicts recurrence after hepatectomy. J Gastroenterol. 49:117–125. 2014. View Article : Google Scholar : PubMed/NCBI
28	Ofuji K, Saito K, Suzuki S, Shimomura M, Shirakawa H, Nobuoka D, Sawada Y, Yoshimura M, Tshuchiya N, Takahashi M, et al: Perioperative plasma glypican-3 level may enable prediction of the risk of recurrence after surgery in patients with stage I hepatocellular carcinoma. Oncotarget. 8:37835–37844. 2017. View Article : Google Scholar : PubMed/NCBI
29	Kaseb AO, Hassan M, Lacin S, Abdel-Wahab R, Amin HM, Shalaby A, Wolff RA, Yao J, Rashid A, Vennapusa B, et al: Evaluating clinical and prognostic implications of Glypican-3 in hepatocellular carcinoma. Oncotarget. 7:69916–69926. 2016. View Article : Google Scholar : PubMed/NCBI
30	Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S, Sugawara Y, Minagawa M, Takayama T, Kawasaki S and Makuuchi M: Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 38:200–207. 2003. View Article : Google Scholar : PubMed/NCBI
31	Zhang D, Liu Z, Yin X, Qi X, Lu B, Liu Y and Hou J: Prognostic value of PIVKA-II in hepatocellular carcinoma patients receiving curative ablation: A systematic review and meta-analysis. Int J Biol Markers. 33:266–274. 2018. View Article : Google Scholar : PubMed/NCBI
32	Abbasi A, Bhutto AR, Butt N and Munir SM: Corelation of serum alpha fetoprotein and tumor size in hepatocellular carcinoma. J Pak Med Assoc. 62:33–36. 2012.PubMed/NCBI
33	Poté N, Cauchy F, Albuquerque M, Voitot H, Belghiti J, Castera L, Puy H, Bedossa P and Paradis V: Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion. J Hepatol. 62:848–854. 2015. View Article : Google Scholar : PubMed/NCBI
34	Imamura H, Matsuyama Y, Miyagawa Y, Ishida K, Shimada R, Miyagawa S, Makuuchi M and Kawasaki S: Prognostic significance of anatomical resection and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma. Br J Surg. 86:1032–1038. 1999. View Article : Google Scholar : PubMed/NCBI
35	Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M, Fujihara S, Kato T, Fujimoto J, Oriyama T, Furukawa K and Kawamura E: Prognostic factors after hepatectomy for hepatocellular carcinomas. A univariate and multivariate analysis. Cancer. 65:1104–1110. 1990. View Article : Google Scholar : PubMed/NCBI