The role of cytokeratins in ensuring the basic cellular functions and in diagnosis of disorders

Mykhaliuk V.V., Vhavryliak.V., Salyha Y.T.

Review 

SUMMARY. Cytokeratins are a large group of intermediate filament proteins that form the cytoskeleton of epithelial cells and their appendages (hair, nails). Biochemically, cytokeratins are divided into two main types: acidic and basic. Each cytokeratin pair necessarily contains both acidic and basic cytokeratins in equimolar amounts. This significantly distinguishes cytokeratins from other intermediate filament proteins and is essential for proper organization of the cytoskeleton. Cytokeratins also provide signaling in the cell and participate in cell-cell adhesion, and apoptosis. Today, the general principles of cytokeratin expression at different stages of epithelial cell development are known. The expression of cytokeratins is organ-specific, depending on the type of epithelial cells, the degree of differentiation, and tissue development. Therefore, the cytokeratins profile can be used to diagnose various pathological processes. Special attention in the review is paid to cytokeratins 8, 18, and 19 as possible biomarkers of carcinogenesis.

Key words: cytokeratins, intermediate filaments, keratinocytes, cytoskeleton, expression

Tsitologiya i Genetika 2022, vol. 56, no. 6, pp. 63-75

1. Institute of Animal Biology NAAS, 38 Stus street, Lviv 79034, Ukraine
2. Lviv Polytechnic National University, Institute of Chemistry and Chemical Technologies, 3/4 St Yura Square, Lviv 79013, Ukraine

E-mail: vasylyna.v.m gmail.com, vitahavryliak gmail.com, yursalyha yahoo.com

Mykhaliuk V.V., Vhavryliak.V., Salyha Y.T. The role of cytokeratins in ensuring the basic cellular functions and in diagnosis of disorders, Tsitol Genet., 2022, vol. 56, no. 6, pp. 63-75.

In "Cytology and Genetics":
V. V. Mykhaliuk, V. V. Havryliak & Y. T. Salyha The Role of Cytokeratins in Ensuring the Basic Cellular Functions and in Dignosis of Disorders, Cytol Genet., 2022, vol. 56, no. 6, pp. 530–540
DOI: 10.3103/S0095452722060093

References

Alam, H., Kundu, S.T., Dalal, S.N., and Vaidya, M.M., Loss of keratins 8 and 18 leads to alterations in α6β4-integrin-mediated signalling and decreased neoplastic progression in an oral-tumour-derived cell line, J. Cell Sci., 2011, vol. 124, no. 12, pp. 2096–2106. https://doi.org/10.1242/jcs.073585

Alsharif, S., Sharma, P., Bursch, K., Milliken, R., Lam, V., Fallatah, A., and Chung, B.M., Keratin 19 maintains E-cadherin localization at the cell surface and stabilizes cell-cell adhesion of MCF7 cells, Cell Adhes. Migr., 2021, vol. 15, no. 1, pp. 1−17. https://doi.org/10.1080/19336918.2020.1868694

Awasthi, P., Thahriani, A., and Bhattacharya, A., (2016) Keratins or cytokeratins − a review article, J. Adv. Med. Dent. Sci. Res., doi.org/https://doi.org/10.21276/jamdsr.2016.4.4.30

Baek, A.R., Seo, H.J., Lee, J.H., Park, S.W., Jang, A.S., Paik, S.H., and Kim, D.J., Prognostic value of baseline carcinoembryonic antigen and cytokeratin 19 fragment levels in advanced non-small cell lung cancer, Cancer Biomarkers, 2018, vol. 22, no. 1, pp. 55–62.

Bambang, I.F., Lu, D., Li, H., Chiu, L.L., Lau, Q.C., Koay, E., and Zhang, D., Cytokeratin 19 regulates endoplasmic reticulum stress and inhibits ERp29 expression via p38 MAPK/XBP-1 signaling in breast cancer cells, Exp. Cell Res., 2009, vol. 315, no. 11, pp. 1964−1974. https://doi.org/10.1016/j.yexcr.2009.02.017

Barak, V., Goike, H., Panaretakis, K.W., and Einarsson, R., Clinical utility of cytokeratins as tumor markers, Clin. Biochem., 2004, vol. 37, pp. 529−540. https://doi.org/10.1016/j.clinbiochem.2004.05.009

Bernerd, F., Magnaldo, T., Freedberg, I.M., and Blumenberg, M., Expression of the carcinoma-associated keratin K6 and the role of AP-1 proto-oncoproteins, Gene Exp., 1993, vol. 3, no. 2, pp. 187–199.

Bozza, W.P., Zhang, Y., and Zhang, B., Cytokeratin 8/18 protects breast cancer cell lines from TRAIL-induced apoptosis, Oncotarget, 2018, vol. 9, pp. 23264–23273. https://doi.org/10.18632/oncotarget.25297

Calvete, J., Larrinaga, G., Errarte, P., Martín, A.M., Dotor, A., Esquinas, C., and Angulo, J.C., The coexpression of fibroblast activation protein (FAP) and basal-type markers (CK 5/6 and CD44) predicts prognosis in high-grade invasive urothelial carcinoma of the bladder, Hum. Pathol., 2019, vol. 91, pp. 61−68. https://doi.org/10.1016/j.humpath.2019.07.002

Chan, J.K., Yuen, D., Too, M., Sun, Y., Willard, B., Man, D., and Tam, C., Keratin 6a reorganization for ubiquitin–proteasomal processing is a direct antimicrobial response, J. Cell Biol., 2018, vol. 217, no. 2, pp. 731−744. https://doi.org/10.1083/jcb.201704186

Chen, B., Xu, X., Lin, D.D., Chen, X., Xu, Y.T., Liu, X., and Dong, W.G., KRT18 modulates alternative splicing of genes involved in proliferation and apoptosis processes in both gastric cancer cells and clinical samples, Front. Genet., 2021, vol. 12, p. 635429. https://doi.org/10.3389/fgene.2021.635429

Choi, W., Czerniak, B., Ochoa, A., Su, X., Siefker-Radtke, A., Dinney, C., and McConkey, D.J., Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer, Nat. Rev. Urol., 2014, vol. 11, pp. 400−410. https://doi.org/10.1038/nrurol.2014.129

Choi, W., Porten, S., Kim, S., Willis, D., Plimack, E., Hoffman-Censits, J., and McConkey, D.J., Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy, Cancer Cell, 2014, vol. 25, no. 2, pp. 152−165. https://doi.org/10.1016/j.ccr.2014.01.009

Dmello, C., Srivastava, S.S., Tiwari, R., Chaudhari, P.R., Sawant, S., and Vaidya, M.M., Multifaceted role of keratins in epithelial cell differentiation and transformation, J. Biosci., 2019, vol. 44, no. 2, p. 33. https://doi.org/10.1007/s12038-019-9864-8

Guy, C.D., Suzuki, A., Burchette, J.L., Brunt, E.M., Abdelmalek, M.F., and Cardona, D., Costaining for keratins 8/18 plus ubiquitin improves detection of hepatocyte injury in nonalcoholic fatty liver disease, Hum. Pathol., 2012, vol. 43, no. 6, pp. 790−800. https://doi.org/10.1016/j.humpath.2011.07.007

Havryliak, V. and Mykhaliuk, V., The comparative analysis of the methods for keratin extraction from sheep wool and human hair, Animal Biol., 2020, vol. 22, pp. 9–12. https://doi.org/10.15407/animbiol22.04.009

Huang, Y., Yang, L., Lin, Y., Chang, X., Wu, H., and Chen, Y., Prognostic value of non-invasive serum Cytokeratin 18 detection in gastrointestinal cancer: a meta-analysis, J. Cancer, 2019, vol. 10, no. 20, pp. 4814–4823.

Iyer, S.V., Dange, P.P., Alam, H., Sawant, S.S., Ingle, A.D., Borges, A.M., Shirsat, N.V., Dalal, S.N., and Vaidya, M.M., Understanding the role of keratins 8 and 18 in neoplastic potential of breast cancer derived cell lines, PloS One, 2013, vol. 8, no. 1, p. e53532. https://doi.org/10.1371/journal.pone.0053532

Jacob, J.T., Coulombe, P.A., Kwan, R., and Omary, M.B., Types I and II keratin intermediate filaments, Cold Spring Harbor Perspect. Biol., 2018, vol. 10, no. 4, pp. 1–10. https://doi.org/10.1101/cshperspect.a018275

Jiang, C.K., Magnaldo, T., Ohtsuki, M., Freedberg, I.M., Bernerd, F., and Blumenberg, M., Epidermal growth factor and transforming growth factor alpha specifically induce the activation- and hyperproliferation-associated keratins 6 and 16, Proc. Natl. Acad. Sci. U. S. A., 1993, vol. 90, no. 14, pp. 6786–6790. https://doi.org/10.1073/pnas.90.14.6786

Ju, J.H., Yang, W., Lee, K.M., Oh, S., Nam, K., Shim, S., and Shin, I., Regulation of cell proliferation and migration by keratin19-induced nuclear import of early growth response-1 in breast cancer cells, Clin. Cancer Res., 2013, vol. 19, pp. 4335−4346. https://doi.org/10.1158/1078-0432.CCR-12-3295

Kanapathy, M., Hachach-Haram, N., Bystrzonowski, N., Connelly, J.T., O’Toole, E.A., Becker, D.L., and Richards, T., Epidermal grafting for wound healing: a review on the harvesting systems, the ultrastructure of the graft and the mechanism of wound healing, Int. Wound J., 2017, vol. 14, pp. 16−23. https://doi.org/10.1111/iwj.12686

Kanapathy, M., Hachach-Haram, N., Bystrzonowski, N., Becker, D.L., Mosahebi, A., and Richards, T., Epidermal graft encourages wound healing by down-regulation of gap junctional protein and activation of wound bed without graft integration as opposed to split-thickness skin graft, Int. Wound J., 2021, vol. 18, no. 3, pp. 332−341. https://doi.org/10.1111/iwj.13536

Komine, M., Rao, L.S., Freedberg, I.M., Simon, M., Milisavljevic, V., and Blumenberg, M., Interleukin-1 induces transcription of keratin K6 in human epidermal keratinocytes, J. Invest. Dermatol., 2001, vol. 116, no. 2, pp. 330–338. https://doi.org/10.1046/j.1523-1747.2001.01249.x

Kuburich, N.A., den Hollander, P., Pietz, J.T., and Mani, S.A., Vimentin and cytokeratin: good alone, bad together, Semin. Cancer Biol., 2021. https://doi.org/10.1016/j.semcancer.2021.12.006

Kucukoglu, O., Guldiken, N., Chen, Y., Usachov, V., El-Heliebi, A., Haybaeck, J., and Strnad, P., High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8, Hepatology, 2014, vol. 60, no. 1, pp. 169–178. https://doi.org/10.1002/hep.27068

Kumar, A. and Jagannathan, N., Cytokeratin: A review on current concepts, Int. J. Orofacial Biol., 2018, vol. 2, no. 1, pp. 6−11.

Kurokawa, I., Mizutani, H., Kusumoto, K., Nishijima, S., Tsujita-Kyutoku, M., Shikata, N., Tsubura, A., Cytokeratin, filaggrin, and p63 expression in reepithelialization during human cutaneous wound healing, Wound Repair Regener., 2006, vol. 14, pp. 38–45. https://doi.org/10.1111/j.1524-475X.2005.00086.x

Laly, A.C., Sliogeryte, K., Pundel, O.J., Ross, R., Keeling, M.C., Avisetti, D., Waseem, A., Gavara, N., and Connelly, J.T., The keratin network of intermediate filaments regulates keratinocyte rigidity sensing and nuclear mechanotransduction, Sci. Adv., 2021, vol. 7, no. 5, p. eabd6187.

Linder, S., Cytokeratin markers come of age, Tumor Biol., 2007, vol. 28, no. 4, pp. 189−195.

Lowery, E.R., Kuczmarski, H., and Herrmann, R.D., Intermediate filaments play a pivotal role in regulating cell architecture and function, J. Biol. Chem., 2015, vol. 290, no. 28, pp. 17145–17153. :doi https://doi.org/10.1074/jbc.R115.640359

McCarthy, M.K. and Weinberg, J.B., The immunoproteasome and viral infection: a complex regulator of inflammation, Front. Microbiol., 2015, vol. 6, p. 21. https://doi.org/10.3389/fmicb.2015.00021

Menz, A., Weitbrecht, T., Gorbokon, N., Büscheck, F., Luebke, A.M., Kluth, M., and Simon, R., Diagnostic and prognostic impact of cytokeratin 18 expression in human tumors: a tissue microarray study on 11,952 tumors, Mol. Med., 2021, vol. 27, no. 1, p. 16.

Moll, R., Franke, W.W., Schiller, D.L., Geiger, B., and Krepler, R., The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells, Cell, 1982, vol. 31, pp. 11−24. https://doi.org/10.1016/0092-8674(82)90400-7

Moll, R., Divo, M., and Langbein, L., The human keratins: biology and pathology, Histochem. Cell Biol., 2008, vol. 129, pp. 705−733. https://doi.org/10.1007/s00418-008-0435-6

Ohman, T., Lietzén, N., Valimaki, E., Melchjorsen, J., Matikainen, S., and Nyman, T.A., Cytosolic RNA recognition pathway activates 14-3-3 protein mediated signaling and caspase-dependent disruption of cytokeratin network in human keratinocytes, J. Proteome Res., 2010, vol. 9, no. 3, pp. 1549−1564. https://doi.org/10.1021/pr901040u

Paramio, J.M., Casanova, M.L., Segrelles, C., Mittnacht, S., Lane, E.B., and Jorcano, J.L., Modulation of cell proliferation by cytokeratins K10 and K16, Mol. Cell. Biol., 1999, vol. 19, no. 4, pp. 3086−3094. https://doi.org/10.1128/MCB.19.4.3086

Raja, S.K., Garcia, M.S., and Isseroff, R.R., Wound re-epithelialization: modulating keratinocyte migration in wound healing, Front. Biosci., 2007, vol. 12, no. 8, pp. 2849−2868.

Santos, M., Paramio, J.M., Bravo, A., Ramirez, A., and Jorcano, J.L., The expression of keratin k10 in the basal layer of the epidermis inhibits cell proliferation and prevents skin tumorigenesis, J. Biol. Chem., 2002, vol. 277, no. 21, pp. 19122−19130.

Sawant, M.S. and Leube, R.E., Consequences of keratin phosphorylation for cytoskeletal organization and epithelial functions, Int. Rev. Cell Mol. Biol., 2017, vol. 330, pp. 171−225. https://doi.org/10.1016/bs.ircmb.2016.09.005

Seiler, R., Ashab, H.D., Erho, N., van Rhijn, B.W., Winters, B., Douglas, J., and Black, P.C., Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy, Eur. Urol., 2017, vol. 72, no. 4, pp. 544−554.

Shafraz, O., Rübsam, M., Stahley, S.N., Caldara, A.L., Kowalczyk, A.P., Niessen, C.M., and Sivasankar, S., E-cadherin binds to desmoglein to facilitate desmosome assembly, J. Invest. Dermatol., 2018. https://doi.org/10.1016/j.jid.2018.03.881

Sharma, P., Alsharif, S., Bursch, K., Parvathaneni, S., Anastasakis, D.G., Chahine, J., and Chung, B.M., Keratin 19 regulates cell cycle pathway and sensitivity of breast cancer cells to CDK inhibitors, Sci. Rep., 2019, vol. 9, p. 14650. https://doi.org/10.1038/s41598-019-51195-9

Snider, N.T. and Omary, M.B., Post-translational modifications of intermediate filament proteins: mechanisms and functions, Nat. Rev. Mol. Cell Biol., 2014, vol. 15, pp. 163–177. https://doi.org/10.1038/nrm3753

Snider, N.T., Park, H., and Omary, M.B., A conserved rod domain phosphotyrosine that is targeted by the phosphatase PTP1B promotes keratin 8 protein insolubility and filament organization, J. Biol. Chem., 2013, vol. 288, no. 43, pp. 31329−31337. https://doi.org/10.1074/jbc.m113.502724

Strelkov, S.V., Herrmann, H., and Aebi, U., Molecular architecture of intermediate filaments, BioEssays, 2003, vol. 25, no. 3, pp. 243−251. https://doi.org/10.1002/bies.10246

Takayama, Y., Molecular regulation of skin wound healing, Lactoferrin and its Role in Wound Healing, Springer-Verlag, 2012, pp. 1–23. https://doi.org/10.1007/978-94-007-2467-9_1

Book

Tam, C., Mun, J.J., Evans, D.J., and Fleiszig, S.M., Cytokeratins mediate epithelial innate defense through their antimicrobial properties, J. Clin. Invest., 2012, vol. 122, pp. 3665–3677. https://doi.org/10.1172/JCI64416

Toivola, D.M., Ku, N.O., Resurreccion, E.Z., Nelson, D.R., Wright, T.L., and Omary, M.B., Keratin 8 and 18 hyperphosphorylation is a marker of progression of human liver disease, Hepatology, 2004, vol. 40, no. 2, pp. 459−466. https://doi.org/10.1002/hep.20277

Toivola, D.M., Boor, P., Alam, C., and Strnad, P., Keratins in health and disease, Curr. Opin. Cell Biol., 2015, vol. 32, pp. 73−81. https://doi.org/10.1016/j.ceb.2014.12.008

Ueno, T., Toi, M., and Linder, S., Detection of epithelial cell death in the body by cytokeratin 18 measurement, Biomed. Pharmacother., 2005, vol. 59, no. 2, pp. 359−362. https://doi.org/10.1016/S0753-3322(05)80078-2

Vaidya, M.M. and Kanojia, D., Keratins: Markers of cell differentiation or regulators of cell differentiation?, J. Biosci., 2007, vol. 32, pp. 629−634. https://doi.org/10.1007/s12038-007-0062-8

Wiche, G., Plectin-mediated intermediate filament functions: Why isoforms matter, Cells, 2021, vol. 10, no. 8, p. 2154. https://doi.org/10.3390/cells10082154

Wong, P. and Coulombe, P.A., Loss of keratin 6 (K6) proteins reveals a function for intermediate filaments during wound repair, J. Cell Biol., 2003, vol. 163, no. 2, pp. 327−337.

Yang, J., Gao, S., Xu, J., and Zhu, J., Prognostic value and clinicopathological significance of serum- and tissue-based cytokeratin 18 express level in breast cancer: a meta-analysis, Biosci. Rep., 2018, vol. 38, no. 2.

Yoon, S. and Leube, R.E., Keratin intermediate filaments: intermediaries of epithelial cell migration, Essays Biochem., 2019, vol. 63, no. 5, pp. 521−533. https://doi.org/10.1042/EBC20190017

Zatloukal, K., Stumptner, C., Fuchsbichler, A., Fickert, P., Lackner, C., Trauner, M., and Denk, H., The keratin cytoskeleton in liver diseases, J. Pathol., 2004, vol. 204, no. 4, pp. 367−376. https://doi.org/10.1002/path.1649

Zhang, L.J., Keratins in skin epidermal development and diseases, in Keratin, IntechOpen, 2018. https://doi.org/10.5772/intechopen.79050

Book

Zhang, B., Wang, J., Liu, W., Yin, Y., Qian, D., Zhang, H., and Wang, C., Cytokeratin 18 knockdown decreases cell migration and increases chemosensitivity in non-small cell lung cancer, J. Cancer Res. Clin. Oncol., 2016, vol. 142, pp. 2479−2487. https://doi.org/10.1007/s00432-016-2253-x

Zhang, X., Yin, M., and Zhang, L.J., Keratin 6, 16 and 17 − critical barrier alarmin molecules in skin wounds and psoriasis, Cells, 2019, vol. 8, p. 807. https://doi.org/10.3390/cells8080807