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Evaluating antitumor activity of antiglypican-3 therapy in experimentally induced skin cancer in mice

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Abstract

Glypican-3 (GPC3) is considered as a cell surface heparan sulfate proteoglycan. It is overexpressed in skin cancer and promotes tumor progression and pathogenicity. Therefore, we aimed to find out the therapeutic effects of immuno-suppressing GPC3 in skin cancer experimentally induced in mice as well as to underline molecular mechanisms especially inflammatory and apoptotic pathways. Skin cancer was experimentally induced in mice by repeated rubbing of mice skin with 7,12-dimethylbenz (a) anthracene. Mice were injected with anti-GPC3. Skin samples were isolated to investigate the gene and protein expression of GPC3, Wnt-1, NFκB, TNF-α, IGF-1, p38 MAPK and caspase-3 using PCR, Western blot and ELISA. Moreover, skin sections were stained with hematoxylin and eosin. Treating skin cancer mice with anti-GPC3 significantly blocked GPC3, which is accompanied by amelioration of skin cancer-induced increase in the numbers of tumors and scratching behavior. Moreover, anti-GPC3 attenuated skin cancer-induced increase in the expression of Wnt-1, NFκB, TNF-α, IGF-1, p38 MAPK and caspase-3. In parallel, anti-GPC3 reduced degeneration of melanocyte cells and reduced phagocytic cells epidermal hyperplasia and dysplasia in skin sections stained with hematoxylin and eosin stain. In conclusion, anti-GPC3 produced anti-tumor effects against skin cancer, which can be explained by reduction in both inflammatory and apoptotic pathways. Targeting GPC3 is a promising therapeutic approach for skin cancer.

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References

  1. Alyoussef A (2018) Blocking TGF-beta type 1 receptor partially reversed skin tissue damage in experimentally induced atopic dermatitis in mice. Cytokine 106:45–53. https://doi.org/10.1016/j.cyto.2018.02.025

    Article  CAS  PubMed  Google Scholar 

  2. Alyoussef A (2020) The therapeutic effects of blocking IGF-R1 on mice model of skin cancer. J Dermatol Treat 1:9. https://doi.org/10.1080/09546634.2019.1708243

    Article  CAS  Google Scholar 

  3. Alyoussef A, Al-Gayyar MMH (2018) Cytotoxic and partial hepatoprotective activity of sodium ascorbate against hepatocellular carcinoma through inhibition of sulfatase-2 in vivo and in vitro. Biomed Pharma Biomed pharma 103:362–372. https://doi.org/10.1016/j.biopha.2018.04.060

    Article  CAS  Google Scholar 

  4. Alyoussef A, Taha M (2019) Antitumor activity of sulforaphane in mice model of skin cancer via blocking sulfatase-2. Exp Dermatol 28:28–34. https://doi.org/10.1111/exd.13802

    Article  CAS  PubMed  Google Scholar 

  5. Alyoussef A, Taha M (2019) Blocking Wnt as a therapeutic target in mice model of skin cancer. Arch Dermatol Res 311:595–605. https://doi.org/10.1007/s00403-019-01939-4

    Article  CAS  PubMed  Google Scholar 

  6. Amor NG, de Oliveira CE, Gasparoto TH, Vilas Boas VG, Perri G, Kaneno R, Lara VS, Garlet GP, da Silva JS, Martins GA, Hogaboam C, Cavassani KA, Campanelli AP (2018) ST2/IL-33 signaling promotes malignant development of experimental squamous cell carcinoma by decreasing NK cells cytotoxicity and modulating the intratumoral cell infiltrate. Oncotarget 9:30894–30904. https://doi.org/10.18632/oncotarget.25768

    Article  PubMed  PubMed Central  Google Scholar 

  7. Apalla Z, Nashan D, Weller RB, Castellsague X (2017) Skin cancer: epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches. Dermatol Ther 7:5–19. https://doi.org/10.1007/s13555-016-0165-y

    Article  Google Scholar 

  8. Bell S, Degitz K, Quirling M, Jilg N, Page S, Brand K (2003) Involvement of NF-kappaB signalling in skin physiology and disease. Cell Signal 15:1–7

    Article  CAS  Google Scholar 

  9. Berrocal A, Cabanas L, Espinosa E, Fernandez-de-Misa R, Martin-Algarra S, Martinez-Cedres JC, Rios-Buceta L, Rodriguez-Peralto JL (2014) Melanoma: diagnosis, staging, and treatment. Consens Group Recomm Adv Ther 31:945–960. https://doi.org/10.1007/s12325-014-0148-2

    Article  CAS  Google Scholar 

  10. Fei X, Zhang J, Zhao Y, Sun M, Zhao H, Li S (2018) miR-96 promotes invasion and metastasis by targeting GPC3 in non-small cell lung cancer cells. Oncology letters 15:9081–9086. https://doi.org/10.3892/ol.2018.8507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ghosh K, Capell BC (2016) The senescence-associated secretory phenotype: critical effector in skin cancer and aging. J Invest Dermatol 136:2133–2139. https://doi.org/10.1016/j.jid.2016.06.621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Halifu Y, Liang JQ, Zeng XW, Ding Y, Zhang XY, Jin TB, Yakeya B, Abudu D, Zhou YM, Liu XM, Hu FX, Chai L, Kang XJ (2016) Wnt1 and SFRP1 as potential prognostic factors and therapeutic targets in cutaneous squamous cell carcinoma. Genet Molecular Res GMR 15:1. https://doi.org/10.4238/gmr.15028187

    Article  CAS  Google Scholar 

  13. He SZ, Wang Q (2020) MicroRNA-548c-5p inhibits the proliferation of breast cancer cells through regulating Wnt/beta-catenin signaling pathway. Eur Rev Med Pharmacol Sci 24:3795–3804. https://doi.org/10.26355/eurrev_202004_20845

    Article  PubMed  Google Scholar 

  14. Hippo Y, Watanabe K, Watanabe A, Midorikawa Y, Yamamoto S, Ihara S, Tokita S, Iwanari H, Ito Y, Nakano K, Nezu J, Tsunoda H, Yoshino T, Ohizumi I, Tsuchiya M, Ohnishi S, Makuuchi M, Hamakubo T, Kodama T, Aburatani H (2004) Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma. Can Res 64:2418–2423. https://doi.org/10.1158/0008-5472.can-03-2191

    Article  CAS  Google Scholar 

  15. Kim JE, Kim JH, Lee Y, Yang H, Heo YS, Bode AM, Lee KW, Dong Z (2016) Bakuchiol suppresses proliferation of skin cancer cells by directly targeting Hck, Blk, and p38 MAP kinase. Oncotarget 7:14616–14627. https://doi.org/10.18632/oncotarget.7524

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lai V, Cranwell W, Sinclair R (2018) Epidemiology of skin cancer in the mature patient. Clin Dermatol 36:167–176. https://doi.org/10.1016/j.clindermatol.2017.10.008

    Article  PubMed  Google Scholar 

  17. Lewis DA, Travers JB, Somani AK, Spandau DF (2010) The IGF-1/IGF-1R signaling axis in the skin: a new role for the dermis in aging-associated skin cancer. Oncogene 29:1475–1485. https://doi.org/10.1038/onc.2009.440

    Article  CAS  PubMed  Google Scholar 

  18. Li J, Fang R, Wang J, Deng L (2018) NOP14 inhibits melanoma proliferation and metastasis by regulating Wnt/beta-catenin signaling pathway Brazilian. J Med Biol Res 52:e7952. https://doi.org/10.1590/1414-431X20187952

    Article  Google Scholar 

  19. Liu K, Yu D, Cho YY, Bode AM, Ma W, Yao K, Li S, Li J, Bowden GT, Dong Z, Dong Z (2013) Sunlight UV-induced skin cancer relies upon activation of the p38alpha signaling pathway. Can Res 73:2181–2188. https://doi.org/10.1158/0008-5472.CAN-12-3408

    Article  CAS  Google Scholar 

  20. Luke JJ, Flaherty KT, Ribas A, Long GV (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14:463–482. https://doi.org/10.1038/nrclinonc.2017.43

    Article  CAS  PubMed  Google Scholar 

  21. Moek KL, Fehrmann RSN, van der Vegt B, de Vries EGE, de Groot DJA (2018) Glypican 3 overexpression across a broad spectrum of tumor types discovered with functional genomic mRNA profiling of a large cancer database. Am J Pathol 188:1973–1981. https://doi.org/10.1016/j.ajpath.2018.05.014

    Article  CAS  PubMed  Google Scholar 

  22. Rahbari M, Pecqueux M, Aust D, Stephan H, Tiebel O, Chatzigeorgiou A, Tonn T, Baenke F, Rao V, Ziegler N, Greif H, Lin K, Weitz J, Rahbari NN, Kahlert C (2019) Expression of Glypican 3 is an independent prognostic biomarker in primary gastro-esophageal adenocarcinoma and corresponding serum exosomes. J Clini Med 8:1. https://doi.org/10.3390/jcm8050696

    Article  CAS  Google Scholar 

  23. Redondo P, Ribeiro M, Lopes M, Borges M, Goncalves FR (2019) Holistic view of patients with melanoma of the skin: how can health systems create value and achieve better clinical outcomes? Ecancermedicalscience 13:959. https://doi.org/10.3332/ecancer.2019.959

    Article  PubMed  PubMed Central  Google Scholar 

  24. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB, Coldiron BM (2010) Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146:283–287. https://doi.org/10.1001/archdermatol.2010.19

    Article  PubMed  Google Scholar 

  25. Rudman SM, Philpott MP, Thomas GA, Kealey T (1997) The role of IGF-I in human skin and its appendages: morphogen as well as mitogen? J Invest Dermatol 109:770–777. https://doi.org/10.1111/1523-1747.ep12340934

    Article  CAS  PubMed  Google Scholar 

  26. Sanchez-Zauco N, Torres J, Gomez A, Camorlinga-Ponce M, Munoz-Perez L, Herrera-Goepfert R, Medrano-Guzman R, Giono-Cerezo S, Maldonado-Bernal C (2017) Circulating blood levels of IL-6, IFN-gamma, and IL-10 as potential diagnostic biomarkers in gastric cancer: a controlled study. BMC cancer 17:384. https://doi.org/10.1186/s12885-017-3310-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Singh A, Singh A, Bauer SJ, Wheeler DL, Havighurst TC, Kim K, Verma AK (2016) Genetic deletion of TNFalpha inhibits ultraviolet radiation-induced development of cutaneous squamous cell carcinomas in PKCepsilon transgenic mice via inhibition of cell survival signals. Carcinogenesis 37:72–80. https://doi.org/10.1093/carcin/bgv162

    Article  CAS  PubMed  Google Scholar 

  28. Sun CK, Chua MS, He J, So SK (2011) Suppression of glypican 3 inhibits growth of hepatocellular carcinoma cells through up-regulation of TGF-beta2. Neoplasia 13:735–747. https://doi.org/10.1593/neo.11664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sun W, Rice MS, Park MK, Chun OK, Melough MM, Nan H, Willett WC, Li WQ, Qureshi AA, Cho E (2020) Intake of furocoumarins and risk of skin cancer in 2 prospective US cohort studies. J Nutri. https://doi.org/10.1093/jn/nxaa062

    Article  Google Scholar 

  30. Wang Y, Singhal U, Qiao Y, Kasputis T, Chung JS, Zhao H, Chammaa F, Belardo JA, Roth TM, Zhang H, Zaslavsky AB, Palapattu GS, Pienta KJ, Chinnaiyan AM, Taichman RS, Cackowski FC, Morgan TM (2020) Wnt signaling drives prostate cancer bone metastatic tropism and invasion. Trans Oncol 13:100747. https://doi.org/10.1016/j.tranon.2020.100747

    Article  Google Scholar 

  31. Wu C, Jin X, Tsueng G, Afrasiabi C, Su AI (2016) BioGPS: building your own mash-up of gene annotations and expression profiles. Nucleic Acids Res 44:D313–316. https://doi.org/10.1093/nar/gkv1104

    Article  CAS  PubMed  Google Scholar 

  32. Wu Y, Zhang P, Yang H, Ge Y, Xin Y (2017) Effects of demethoxycurcumin on the viability and apoptosis of skin cancer cells. Mole Med Rep 16:539–546. https://doi.org/10.3892/mmr.2017.6666

    Article  CAS  Google Scholar 

  33. Yu X, Li Y, Chen SW, Shi Y, Xu F (2015) Differential expression of glypican-3 (GPC3) in lung squamous cell carcinoma and lung adenocarcinoma and its clinical significance. Genet Mole Res GMR 14:10185–10192. https://doi.org/10.4238/2015.August.28.2

    Article  CAS  Google Scholar 

  34. Zaghloul RA, El-Shishtawy MM, El Galil KH, Ebrahim MA, Metwaly AA, Al-Gayyar MM (2015) Evaluation of antiglypican-3 therapy as a promising target for amelioration of hepatic tissue damage in hepatocellular carcinoma. Eur J Pharmacol 746:353–362. https://doi.org/10.1016/j.ejphar.2014.11.008

    Article  CAS  PubMed  Google Scholar 

  35. Zhang X, Bommareddy A, Chen W, Khalifa S, Kaushik RS, Fahmy H, Dwivedi C (2009) Sarcophine-diol, a chemopreventive agent of skin cancer, inhibits cell growth and induces apoptosis through extrinsic pathway in human epidermoid carcinoma A431 cells. Trans oncol 2:21–30. https://doi.org/10.1593/tlo.08190

    Article  Google Scholar 

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  1. Dept. of Internal Medicine (Dermatology), Faculty of Medicine, University of Tabuk, Tabuk, 71471, Saudi Arabia

    Abdullah Alyoussef

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Alyoussef, A. Evaluating antitumor activity of antiglypican-3 therapy in experimentally induced skin cancer in mice. Arch Dermatol Res 313, 263–273 (2021). https://doi.org/10.1007/s00403-020-02102-0

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  • DOI: https://doi.org/10.1007/s00403-020-02102-0

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