TSitologiya i Genetika 2019, vol. 53, no. 5, 94-96
Cytology and Genetics 2019, vol. 53, no. 5, 430–440, doi: https://www.doi.org/10.3103/S0095452719050037

The expression of glypican­3 in colorectal cancer

Sonia Azizpour, Razieh Ezati, Massoud Saidijam, Amirnader Emami Razavi, Farid Azizi Jalilian, Ali Mahdavinezhad, Hamid Eslami, Alireza Soltanian, Hadiseh Mohammadpour, Fatemeh Kamali, Razieh Amini

  1. Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
  2. Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
  3. Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
  4. Microbiology Department, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
  5. Modeling of Noncommunicable Disease Research Center, Department Of Biostatistics, School Of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran
  6. Cancer Research Center, Cancer Institute of Iran, Tehran university of Medical Sciences, Tehran, Iran

Glypican-3 (GPC3), a heparan sulfate proteoglycan is an emerging tumor marker; its overexpression has been stated in several types of cancer such as hepatocellular carcinoma (HCC), melanoma and etc. In this study, the expression of the GPC3 mRNA was investigated in 61 human colorectal cancer (CRC) tissues and 61 normal adjacent tissues, using the real-time PCR assay. Using immunohistochemistry (IHC), the expression of the GPC3 protein was examined in the cases that showed a marked elevation in the expression of the GPC3 mRNA in the tumor tissues, compared to the normal tissues. A significant increase in the expression of the GPC3 gene was revealed in 49.2% of the cases of CRC tumors, compared to the normal adjacent tissues. The expression of the GPC3 mRNA was found to significantly correlate with the pathological differentiation and the age of the patients. Interestingly, a significant reduction in the expression of the GPC3 mRNA was found in the tumor tissues of the 16 patients, who underwent the neoadjuvant chemotherapy, compared to the normal adjacent tissues. Unexpectedly, the GPC3 protein was not detected by IHC in 30 tissues, exhibiting the upregulation in the expression of the GPC3 mRNA. Our results indicated that GPC3 could be expressed in the CRC tissues at the mRNA level, while its expression could not be found at the protein level.

Keywords: Glypican-3; Colorectal cancer; Neoadjuvant chemotherapy; Immunohistochemistry

TSitologiya i Genetika
2019, vol. 53, no. 5, 94-96

Current Issue
Cytology and Genetics
2019, vol. 53, no. 5, 430–440,
doi: 10.3103/S0095452719050037

Full text and supplemented materials


1. Gervaz, P., Bouzourene, H., Cerottini, J.P., Chaubert, P., Benhattar, J., Secic, M., Wexner, S., Givel, J.C., and Belin, B., and Dukes, B., Colorectal cancer: distinct genetic categories and clinical outcome based on proximal or distal tumor location, Dis. Colon Rectum., 2001, vol. 44, no. 3, pp. 364–372.

2. Terzic, J., Grivennikov, S., Karin, E., and Karin, M., Inflammation and colon cancer, Gastroenterology, 2010, vol. 138, no. 6, pp. 2101–2114. e5. https://doi.org/10.1053/j.gastro.2010.01.058

3. Abdifard, E., Amini, S., Bab, S., Masroor, N., Khachian, A., and Heidari, M., Incidence trends of colorectal cancer in Iran during 2000–2009: a population-based study, Med. J. Islam. Repub. Iran, 2016, vol. 30, p. 382.

4. Center, M.M., Jemal, A., and Ward, E., International trends in colorectal cancer incidence rates, Cancer Epid. Prevent. Biomark., 2009, vol. 18, no. 6, pp. 1688–1694.

5. Siegel, R.L., Miller, K.D., Fedewa, S.A., Ahnen, D.J., Meester, R.G.S., Barzi, A., and Jemal, A., Colorectal cancer statistics. 2017, CA Cancer J. Clin., 2017, vol. 67, no. 3, pp. 177–93. https://doi.org/10.3322/caac.21395

6. De Cat, B. and David, G., Developmental roles of the glypicans, Semin. Cell Dev. Biol., 2001, vol. 12, no. 2, pp. 117–125. https://doi.org/10.1006/scdb.2000.0240

7. Wang, X.Y., Degos, F., Dubois, S., Tessiore, S., Allegretta, M., Guttmann, R.D., Jothy, S., Belghiti, J., Bedossa, P., and Paradis, V., Glypican-3 expression in hepatocellular tumors: diagnostic value for preneoplastic lesions and hepatocellular carcinomas, Hum. Pathol., 2006, vol. 37, no. 11, pp. 1435–1441. https://doi.org/10.1016/j.humpath.2006.05.016

8. Traister, A., Shi, W., and Filmus, J., Mammalian Notum induces the release of glypicans and other GPI-anchored proteins from the cell surface, Biochem. J., 2008, vol. 410, no. 3, pp. 503–511.

9. Ho, M. and Kim, H., Glypican-3: a new target for cancer immunotherapy, Eur. J. Cancer, 2011, vol. 47, no. 3, p. 333–338. https://doi.org/10.1016/j.ejca.2010.10.024

10. Pilia, G., Hughes-Benzi,e, R.M., MacKenzie, A., Baybayan, P., Chen, E.Y., Huber, R., Neri, G., Cao, A., Forabosco, A., and Schlessinger, D., Mutations in GPC3, a glypican gene, cause the Simpson–Golabi–Behmel overgrowth syndrome, Nat. Genet., 1996, vol. 12, no. 3, pp. 241–247. https://doi.org/10.1038/ng0396-241

11. Yun-Yan, X., Ladeda, V., and Filmus, J., Glypican-3 expression is silenced in human breast cancer, Oncogene, 2001, vol. 20, no. 50, pp. 7408–7412. https://doi.org/10.1038/sj.onc.1204925

12. Capurro, M.I., Xu, P., Shi, W., Li, F., Jia, A., and Filmus, J., Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding, Dev. Cell, 2008, vol. 14, no. 5, pp. 700–711. https://doi.org/10.1016/j.devcel.2008.03.006

13. Capurro, M.I., Xiang, Y.Y., Lobe, C., and Filmus, J., Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling, Cancer Res., 2005, vol. 65, no. 14, pp. 6245–6254. https://doi.org/10.1158/0008-5472.CAN-04-4244

14. Feng, M. and Ho, M., Glypican-3 antibodies: a new therapeutic target for liver cancer, FEBS Lett., 2014, vol. 588, no. 2, pp. 377–82. https://doi.org/10.1016/j.febslet.2013.10.002

15. Song, H.H., Shi, W., Xiang, Y.Y., and Filmus, J., The loss of glypican-3 induces alterations in Wnt signaling, J. Biol. Chem., 2005, vol. 280, no. 3, pp. 2116–2125. https://doi.org/10.1074/jbc.M410090200

16. Dwivedi, P., Lam, N., and Powell, B.C., Boning up on glypicans—opportunities for new insights into bone biology, Cell Biochem. Func., 2013, vol. 31, no. 2, pp. 91–114. https://doi.org/10.1002/cbf.2939

17. Capurro, M., Martin, T., Shi, W., and Filmus, J., Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling, J. Cell Sci., 2014, vol. 127, no. 7, pp. 1565–1575. https://doi.org/10.1242/jcs.140871

18. Sun, C.K., Chua, M.S., He, J., and So, S.K., Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-2, Neoplasia, 2011, vol. 13, no. 8, pp. 735–747. https://doi.org/10.1593/neo.11664

19. Yamanaka, K., Ito, Y., Okuyama, N., Noda, K., Matsumoto, H., Yoshida, H., Miyauchi, A., Capurro, M., Filmus, J., and Miyoshi, E., Immunohistochemical study of glypican 3 in thyroid cancer, Oncology, 2007, vol. 73, nos. 5/6, pp. 389–94. https://doi.org/10.1159/000136159

20. Shirakawa, H., Kuronuma, T., Nishimura, Y., Hasebe, T., Nakano, M., Gotohda, N., Takahashi, S., Nakagohri, T., Konishi, M., Kobayashi, N., Kinoshita, T., and Nakatsura, T., Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer, Int. J. Oncol., 2009, vol. 34, no. 3, pp. 649–656. https://doi.org/10.3892/ijo_00000190

21. 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., 2004, vol. 10, no. 19, p. 6612–6621. https://doi.org/10.1158/1078-0432.CCR-04-0348

22. Maeda, D., Ota, S., Takazawa, Y., Aburatani, H., Nakagawa, S., Yano, T., Taketani, Y., Kodama, T., and Fukayama, M., Glypican-3 expression in clear cell adenocarcinoma of the ovary, Mod. Pathol., 2009, vol. 22, no. 6, pp. 824–832. https://doi.org/10.1038/modpathol.2009.40

23. FFu, S.J., Qi, C.Y., Xiao, W.K., Li, S.Q., Peng, B.G., and Liang, L.J., Glypican-3 is a potential prognostic biomarker for hepatocellular carcinoma after curative resection, Surgery, 2013, vol. 154, no. 3, pp. 536–544. https://doi.org/10.1016/j.surg.2013.02.014

24. van Diest, P.J., van Dam, P., Henzen-Logmans, S.C., Berns, E., van der Burg, M.E., Green, J., and Vergote, I., A scoring system for immunohistochemical staining: consensus report of the task force for basic research of the EORTC-GCCG. European Organization for Research and Treatment of Cancer-Gynaecological Cancer Cooperative Group, J. Clin. Pathol., 1997, vol. 50, no. 10, pp. 801–804. https://doi.org/10.1136/jcp.50.10.801

25. Umezu, T., Shibata, K., Kajiyama, H., Yamamoto, E., Nawa, A., and Kikkawa, F., Glypican-3 expression predicts poor clinical outcome of patients with early-stage clear cell carcinoma of the ovary, J. Clin. Pathol., 2010, vol. 63, no. 11, pp. 962–966. https://doi.org/10.1136/jcp.2010.080234

26. Kendrick, N., A Gene’s mRNA Level Does Not Usually Predict Its Protein Level, Madison: Kendricklabscom, 2014.

27. Schwanhausser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., and Selbach, M., Global quantification of mammalian gene expression control, Nature, 2011, vol. 473, pp. 337–342.

28. Vogel, C., Abreu, Rde.S., Ko, D., Le, S.Y., Shapiro, B.A., Burns, S.C., Sandhu, D., Boutz, D.R., Marcotte, E.M., and Penalva, L.O., Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line, Mol. Syst. Biol., 2010, vol. 6, no. 1, p. 400. https://doi.org/10.1038/msb.2010.59

29. Asangani, I.A., Rasheed, S.A., Nikolova, D.A., Leupold, J.H., Colburn, N.H., Post, S., and Allgayer, H., microRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer, Oncogene, 2008, vol. 27, no. 15, pp. 2128–2136. https://doi.org/10.1038/sj.onc.1210856

30. Slaby, O., Svoboda, M., Michalek, J., and Vyzula, R., microRNAs in colorectal cancer: translation of molecular biology into clinical application, Mol. Cancer, 2009, vol. 8, no. 1, p. 102. https://doi.org/10.1186/1476-4598-8-102

31. Miao, H.L., Lei, C.J., Qiu, Z.D., Liu, Z.K., Li, R., Bao, S.T., and Li, M.Y., microRNA-520c-3p inhibits hepatocellular carcinoma cell proliferation and invasion through induction of cell apoptosis by targeting glypican-3, Hepatol. Res., 2014, vol. 44, no. 3, pp. 338–348. https://doi.org/10.1111/hepr.12121

32. Hay, E.D., Cell Biology of Extracellular Matrix, Springer Science and Business Media, 2013.

33. Joypaul, B.V., Newman, E.L., Hopwood, D., Grant, A., Qureshi, S., Lane, D.P., and Cuschieri, A., Expression of p53 protein in normal, dysplastic, and malignant gastric mucosa: an immunohistochemical study, J. Pathol., 1993, vol. 170, no. 3, pp. 279–283. https://doi.org/10.1002/path.1711700310

34. Yoneda, A., Lendorf, M.E., Couchman, J.R., and Multhaupt, H.A., Breast and ovarian cancers: a survey and possible roles for the cell surface heparan sulfate proteoglycans, J. Histochem. Cytochem., 2012, vol. 60, no. 1, pp. 9–21. https://doi.org/10.1369/0022155411428469

35. Araki, K. and Nagata, K., Protein folding and quality control in the ER, Cold Spring Harb. Perspect. Biol., 2011, vol. 3, no. 11, p. a007526. https://doi.org/10.1101/cshperspect.a007526

36. Montalbano, M., Georgiadis, J., Masterson, A.L., McGuire, J.T., Prajapati, J., Shirafkan, A., Rastellini, C., and Cicalese, L., Biology and function of glypican-3 as a candidate for early cancerous transformation of hepatocytes in hepatocellular carcinoma, Oncology Rep., 2017, vol. 37, no. 3, pp. 1291–1300. https://doi.org/10.3892/or.2017.5387

37. Haggar, F.A. and Boushey, R.P., Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors, Clin. Colon Rect. Surg., 2009, vol. 22, no. 4, pp. 191–197. https://doi.org/10.1055/s-0029-1242458