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Article

EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins

  • Authors:
    • Hong Fang
    • Yina Wang
    • Lina Xu
    • Sha Zhou
    • Juan Bai
    • Yinhua Wu
    • Jianjun Qiao
    • Xiaoling Jiang
    • Dingxian Zhu
    • Yingguo Ding
  • View Affiliations / Copyright

    Affiliations: Department of Dermatology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
  • Pages: 1522-1530
    |
    Published online on: December 31, 2018
       https://doi.org/10.3892/ijmm.2018.4046
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Abstract

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been frequently used in targeted therapy for lung cancer. However, the widespread use of gefitinib in targeted therapy for patients with lung cancer is hampered by its common skin toxicities. The present study aimed to investigate the mechanisms underlying the skin toxicities of gefitinib. Normal human epidermal keratinocytes (NHEKs) treated with gefitinib were used for a series of in vitro assays, including MTT, reverse transcription‑quantitative polymerase chain reaction, western blot analysis, immunohistochemistry and transepithelial electrical resistance and paracellular permeability detection. In the present study, it was determined that the skin toxicities of gefitinib may be due to claudin (CLDN)1 and CLDN4 downregulation and CLDN2 upregulation in NHEKs. Additionally, Src and signal transducer and activator of transcription 3 pathways were involved in gefitinib‑induced barrier function disruption in NHEKs. In conclusion, the present study may provide novel insights for improving skin toxicity of gefitinib in patients with lung cancer.
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1 

Ehmann LM, Ruzicka T and Wollenberg A: Cutaneous side-effects of EGFR inhibitors and their management. Skin Therapy Lett. 16:1–3. 2011.PubMed/NCBI

2 

Baas JM, Krens LL, Guchelaar HJ, Ouwerkerk J, de Jong FA, Lavrijsen AP and Gelderblom H: Recommendations on management of EGFR inhibitor-induced skin toxicity: A systematic review. Cancer Treat Rev. 38:505–514. 2012. View Article : Google Scholar

3 

Pomerantz RG, Mirvish ED and Geskin LJ: Cutaneous reactions to epidermal growth factor receptor inhibitors. J Drugs Dermatol. 9:1229–1234. 2010.PubMed/NCBI

4 

Reck M and Gutzmer R: Management of the cutaneous side effects of therapeutic epidermal growth factor receptor inhibition. Onkologie. 33:470–479. 2010. View Article : Google Scholar : PubMed/NCBI

5 

Overgaard CE, Daugherty BL, Mitchell LA and Koval M: Claudins: Control of barrier function and regulation in response to oxidant stress. Antioxid Redox Signal. 15:1179–1193. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Morita K, Miyachi Y and Furuse M: Tight junctions in epidermis: From barrier to keratinization. Eur J Dermatol. 21:12–17. 2011.PubMed/NCBI

7 

Kirschner N, Bohner C, Rachow S and Brandner JM: Tight junctions: Is there a role in dermatology? Arch Dermatol Res. 302:483–493. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Furuse M, Hata M, Furuse K, Yoshida Y, Haratake A, Sugitani Y, Noda T, Kubo A and Tsukita S: Claudin-based tight junctions are crucial for the mammalian epidermal barrier: A lesson from claudin-1-deficient mice. J Cell Biol. 156:1099–1111. 2002. View Article : Google Scholar : PubMed/NCBI

9 

Hadj-Rabia S, Baala L, Vabres P, Hamel-Teillac D, Jacquemin E, Fabre M, Lyonnet S, De Prost Y, Munnich A, Hadchouel M, et al: Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease. Gastroenterology. 127:1386–1390. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Turksen K and Troy TC: Barriers built on claudins. J Cell Sci. 117:2435–2447. 2004. View Article : Google Scholar : PubMed/NCBI

11 

Tran QT, Kennedy LH, Leon Carrion S, Bodreddigari S, Goodwin SB, Sutter CH and Sutter TR: EGFR regulation of epidermal barrier function. Physiol Genomics. 44:455–469. 2012. View Article : Google Scholar : PubMed/NCBI

12 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar

13 

Zhang J, Ni C, Yang Z, Piontek A, Chen H, Wang S, Fan Y, Qin Z and Piontek J: Specific binding of Clostridium perfringens enterotoxin fragment to Claudin-b and modulation of zebrafish epidermal barrier. Exp Dermatol. 24:605–610. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Adam AP: Regulation of endothelial adherens junctions by tyrosine phosphorylation. Mediators Inflamm. 2015:2728582015. View Article : Google Scholar : PubMed/NCBI

15 

Alsaffar H, Martino N, Garrett JP and Adam AP: Interleukin-6 promotes a sustained loss of endothelial barrier function via Janus kinase-mediated STAT3 phosphorylation and de novo protein synthesis. Am J Physiol Cell Physiol. 314:C589–C602. 2018. View Article : Google Scholar : PubMed/NCBI

16 

Sharma V, Singh SK, Anderson D, Tobin DJ and Dhawan A: Zinc oxide nanoparticle induced genotoxicity in primary human epidermal keratinocytes. J Nanosci Nanotechnol. 11:3782–3788. 2011. View Article : Google Scholar : PubMed/NCBI

17 

Mikami D, Sakai S, Sasaki S and Igarashi Y: Effects of asterias amurensis-derived sphingoid bases on the de novo ceramide synthesis in cultured normal human epidermal keratinocytes. J Oleo Sci. 65:671–680. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Szöllősi AG, Gueniche A, Jammayrac O, Szabó-Papp J, Blanchard C, Vasas N, Andrási M, Juhász I, Breton L and Bíró T: Bifidobacterium longum extract exerts pro-differentiating effects on human epidermal keratinocytes, in vitro. Exp Dermatol. 26:92–94. 2017. View Article : Google Scholar

19 

Dang NN, Pang SG, Song HY, An LG and Ma XL: Filaggrin silencing by shRNA directly impairs the skin barrier function of normal human epidermal keratinocytes and then induces an immune response. Braz J Med Biol Res. 48:39–45. 2015. View Article : Google Scholar :

20 

Woo SW, Rhim DB, Kim C and Hwang JK: Effect of standardized boesenbergia pandurata extract and its active compound panduratin A on skin hydration and barrier function in human epidermal keratinocytes. Prev Nutr Food Sci. 20:15–21. 2015. View Article : Google Scholar : PubMed/NCBI

21 

Mullin JM, Laughlin KV, Ginanni N, Marano CW, Clarke HM and Peralta Soler A: Increased tight junction permeability can result from protein kinase C activation/translocation and act as a tumor promotional event in epithelial cancers. Ann N Y Acad Sci. 915:231–236. 2000. View Article : Google Scholar

22 

Flores-Benitez D, Rincon-Heredia R, Razgado LF, Larre I, Cereijido M and Contreras RG: Control of tight junctional sealing: Roles of epidermal growth factor and prostaglandin E2. Am J Physiol Cell Physiol. 297:C611–C620. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Flores-Benítez D, Ruiz-Cabrera A, Flores-Maldonado C, Shoshani L, Cereijido M and Contreras RG: Control of tight junctional sealing: Role of epidermal growth factor. Am J Physiol Renal Physiol. 292:F828–F836. 2007. View Article : Google Scholar

24 

Kojima T, Yamamoto T, Lan M, Murata M, Takano K, Go M, Ichimiya S, Chiba H and Sawada N: Inhibition of MAP kinase activity moderates changes in expression and function of Cx32 but not claudin-1 during DNA synthesis in primary cultures of rat hepatocytes. Med Electron Microsc. 37:101–113. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Furuse M, Fujita K, Hiiragi T, Fujimoto K and Tsukita S: Claudin-1 and -2: Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 141:1539–1550. 1998. View Article : Google Scholar : PubMed/NCBI

26 

Amasheh S, Meiri N, Gitter AH, Schöneberg T, Mankertz J, Schulzke JD and Fromm M: Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci. 115:4969–4976. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, Günzel D and Fromm M: Claudin-2, a component of the tight junction, forms a paracellular water channel. J Cell Sci. 123:1913–1921. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, Furuse K, Sasaki H, Fujimura A, Imai M, et al: Claudin-2-deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci USA. 107:8011–8016. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Furuse M, Furuse K, Sasaki H and Tsukita S: Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Biol. 153:263–272. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Colegio OR, Van Itallie CM, McCrea HJ, Rahner C and Anderson JM: Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol. 283:C142–C147. 2002. View Article : Google Scholar : PubMed/NCBI

31 

Colegio OR, Van Itallie C, Rahner C and Anderson JM: Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. Am J Physiol Cell Physiol. 284:C1346–C1354. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Hou J, Gomes AS, Paul DL and Goodenough DA: Study of claudin function by RNA interference. J Biol Chem. 281:36117–36123. 2006. View Article : Google Scholar : PubMed/NCBI

33 

Ikari A, Takiguchi A, Atomi K and Sugatani J: Epidermal growth factor increases clathrin-dependent endocytosis and degradation of claudin-2 protein in MDCK II cells. J Cell Physiol. 226:2448–2456. 2011. View Article : Google Scholar : PubMed/NCBI

34 

Singh AB and Harris RC: Epidermal growth factor receptor activation differentially regulates claudin expression and enhances transepithelial resistance in Madin-Darby canine kidney cells. J Biol Chem. 279:3543–3552. 2004. View Article : Google Scholar

35 

Findley MK and Koval M: Regulation and roles for claudin-family tight junction proteins. IUBMB Life. 61:431–437. 2009. View Article : Google Scholar : PubMed/NCBI

36 

García-Hernández V, Flores-Maldonado C, Rincon-Heredia R, Verdejo-Torres O, Bonilla-Delgado J, Meneses-Morales I, Gariglio P and Contreras RG: EGF regulates claudin-2 and -4 expression through Src and STAT3 in MDCK cells. J Cell Physiol. 230:105–115. 2015. View Article : Google Scholar

37 

Singh AB, Sharma A and Dhawan P: Claudin-1 expression confers resistance to anoikis in colon cancer cells in a Src-dependent manner. Carcinogenesis. 33:2538–2547. 2012. View Article : Google Scholar : PubMed/NCBI

38 

Ogawa Y, Kiba T, Nakano K, Fujiwara K, Taniguchi H, Hosokawa A, Nakashima T, Kimoto S, Kajiume S, Okada Y, et al: Prospective study of biotin treatment in patients with erythema due to gefitinib or erlotinib. Gan To Kagaku Ryoho. 41:517–522. 2014.In Japanese. PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Fang H, Wang Y, Xu L, Zhou S, Bai J, Wu Y, Qiao J, Jiang X, Zhu D, Ding Y, Ding Y, et al: EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins. Int J Mol Med 43: 1522-1530, 2019.
APA
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y. ... Ding, Y. (2019). EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins. International Journal of Molecular Medicine, 43, 1522-1530. https://doi.org/10.3892/ijmm.2018.4046
MLA
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y., Qiao, J., Jiang, X., Zhu, D., Ding, Y."EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins". International Journal of Molecular Medicine 43.3 (2019): 1522-1530.
Chicago
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y., Qiao, J., Jiang, X., Zhu, D., Ding, Y."EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins". International Journal of Molecular Medicine 43, no. 3 (2019): 1522-1530. https://doi.org/10.3892/ijmm.2018.4046
Copy and paste a formatted citation
x
Spandidos Publications style
Fang H, Wang Y, Xu L, Zhou S, Bai J, Wu Y, Qiao J, Jiang X, Zhu D, Ding Y, Ding Y, et al: EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins. Int J Mol Med 43: 1522-1530, 2019.
APA
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y. ... Ding, Y. (2019). EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins. International Journal of Molecular Medicine, 43, 1522-1530. https://doi.org/10.3892/ijmm.2018.4046
MLA
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y., Qiao, J., Jiang, X., Zhu, D., Ding, Y."EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins". International Journal of Molecular Medicine 43.3 (2019): 1522-1530.
Chicago
Fang, H., Wang, Y., Xu, L., Zhou, S., Bai, J., Wu, Y., Qiao, J., Jiang, X., Zhu, D., Ding, Y."EGFR inhibitor gefitinib regulates barrier function in human epidermal keratinocytes via the modulation of the expression of claudins". International Journal of Molecular Medicine 43, no. 3 (2019): 1522-1530. https://doi.org/10.3892/ijmm.2018.4046
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