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GPC3, part of the glypican family, is a large protein found on cell surfaces, weighing in at 66,000 kDa [1]. It plays a crucial role in regulating cell growth and death during development by interacting with other surface proteins and influencing the activity of growth factors [2].
Composed of a core protein weighing 70 kDa and two highly charged heparan sulfate side chains, GPC3 acts like a magnet, pulling in important signaling molecules from the surrounding tumor environment and helping cells recognize and respond to them [3]. In human liver cancer (hepatocellular carcinoma or HCC), GPC3 is particularly abundant, making it a promising diagnostic marker [4]. Its impact on cell behavior and tumor formation varies depending on the tissue involved [5].
In HCC, GPC3 fuels tumor growth by revving up the canonical Wnt pathway and tweaking other signaling routes like YAP and hedgehog [6][7]. It's a familiar face in liver and skin cancers, being notably high in melanoma [8]. Plus, during normal growth, it pitches in by controlling cell numbers through regulating cell birth and death [9].
Yet, despite its prominence, we're still scratching our heads over GPC3's exact role in cancer [10][11][12][13]. More digging is needed to uncover how and why GPC3 goes into overdrive in cancers like liver, skin, and thyroid [14][15]. Its link to changes in cell behavior, like the switch from stationary to mobile in liver cancer, is also ripe for exploration [16]. And it's not just liver and skin - GPC3 also seems to give a boost to cervical cancer cells [17].
References:
[1] X. Yu, Y. Li, S. Chen, Y. Shi, & F. Xu, "Differential expression of glypican-3 (gpc3) in lung squamous cell carcinoma and lung adenocarcinoma and its clinical significance", Genetics and Molecular Research, vol. 14, no. 3, p. 10185-10192, 2015. https://doi.org/10.4238/2015.august.28.2
[2] M. Mateos, K. Beyer, E. López‐Laso, J. Siles, J. Pérez-Navero, M. Peñaet al., "Simpson–golabi–behmel syndrome type 1 and hepatoblastoma in a patient with a novel exon 2–4 duplication of the gpc3 gene", American Journal of Medical Genetics Part A, vol. 161, no. 5, p. 1091-1095, 2013. https://doi.org/10.1002/ajmg.a.35738
[3] L. Sun, F. Gao, Z. Gao, L. Ao, N. Li, S. Maet al., "Shed antigen-induced blocking effect on car-t cells targeting glypican-3 in hepatocellular carcinoma", Journal for Immunotherapy of Cancer, vol. 9, no. 4, p. e001875, 2021. https://doi.org/10.1136/jitc-2020-001875
[4] B. Liu, S. Paranjpe, W. Bowen, A. Bell, J. Luo, Y. Yuet al., "Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation", The Faseb Journal, vol. 24, no. S1, 2010. https://doi.org/10.1096/fasebj.24.1_supplement.39.1
[5] L. Li, R. Jin, X. Zhang, F. Lv, L. Liu, D. Liuet al., "Oncogenic activation of glypican-3 by c-myc in human hepatocellular carcinoma", Hepatology, vol. 56, no. 4, p. 1380-1390, 2012. https://doi.org/10.1002/hep.25891
[6] A. Kolluri and M. Ho, "The role of glypican-3 in regulating wnt, yap, and hedgehog in liver cancer", Frontiers in Oncology, vol. 9, 2019. https://doi.org/10.3389/fonc.2019.00708
[7] J. Filmus and M. Capurro, "Glypican‐3: a marker and a therapeutic target in hepatocellular carcinoma", Febs Journal, vol. 280, no. 10, p. 2471-2476, 2013. https://doi.org/10.1111/febs.12126
[8] T. Nakatsura, H. Kohno, T. Kubo, Y. Yamada, S. Senju, T. Katagiriet al., "Mouse homologue of a novel human oncofetal antigen, glypican-3, evokes t-cell–mediated tumor rejection without autoimmune reactions in mice", Clinical Cancer Research, vol. 10, no. 24, p. 8630-8640, 2004. https://doi.org/10.1158/1078-0432.ccr-04-1177
[9] D. Baumhoer, L. Tornillo, S. Stadlmann, M. Roncalli, E. Diamantis, & L. Terracciano, "Glypican 3 expression in human nonneoplastic, preneoplastic, and neoplastic tissues", American Journal of Clinical Pathology, vol. 129, no. 6, p. 899-906, 2008. https://doi.org/10.1309/hcqwpwd50xhd2dw6
[10] M. Feng and M. Ho, "Glypican‐3 antibodies: a new therapeutic target for liver cancer", Febs Letters, vol. 588, no. 2, p. 377-382, 2013. https://doi.org/10.1016/j.febslet.2013.10.002
[11] M. Feng, R. Wang, W. Chen, Y. Man, W. Figg, X. Wanget al., "Therapeutically targeting glypican-3 via a conformation-specific single-domain antibody in hepatocellular carcinoma", Proceedings of the National Academy of Sciences, vol. 110, no. 12, 2013. https://doi.org/10.1073/pnas.1217868110
[12] X. Zhu, J. Yuan, T. Zhu, Y. Li, & X. Cheng, "Long noncoding rna glypican 3 (gpc3) antisense transcript 1 promotes hepatocellular carcinoma progression via epigenetically activating gpc3", Febs Journal, vol. 283, no. 20, p. 3739-3754, 2016. https://doi.org/10.1111/febs.13839
[13] M. Miura, N. Fujinami, Y. Shimizu, S. Mizuno, K. Saito, T. Suzukiet al., "Usefulness of plasma full‑length glypican‑3 as a predictive marker of hepatocellular carcinoma recurrence after radial surgery", Oncology Letters, 2020. https://doi.org/10.3892/ol.2020.11371
[14] T. Nakatsura, T. Kageshita, S. Ito, K. Wakamatsu, M. Monji, Y. Ikutaet al., "Identification of glypican-3 as a novel tumor marker for melanoma", Clinical Cancer Research, vol. 10, no. 19, p. 6612-6621, 2004. https://doi.org/10.1158/1078-0432.ccr-04-0348
[15] K. Yamanaka, Y. Ito, N. Okuyama, K. Noda, H. Matsumoto, H. Yoshidaet al., "Immunohistochemical study of glypican 3 in thyroid cancer", Oncology, vol. 73, no. 5-6, p. 389-394, 2007. https://doi.org/10.1159/000136159
[16] X. Qi, D. Wu, H. Cui, N. Ma, J. Su, Y. Wanget al., "Silencing of the glypican-3 gene affects the biological behavior of human hepatocellular carcinoma cells", Molecular Medicine Reports, vol. 10, no. 6, p. 3177-3184, 2014. https://doi.org/10.3892/mmr.2014.2600
[17] R. Hu and Z. Zhu, "Elk1‐activated gpc3‐as1/gpc3 axis promotes the proliferation and migration of cervical cancer cells", The Journal of Gene Medicine, vol. 21, no. 8, 2019. https://doi.org/10.1002/jgm.3099
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