Role of Krüppel-like factor 4 and heat shock protein 27 in cancer of the larynx

Karam,Jihad; Fadous‑Khalifé,Marie  Claude; Tannous,Rita; Fakhreddine,Sally; Massoud,Marcel; Hadchity,Joseph; Aftimos,Georges; Hadchity,Elie

doi:10.3892/mco.2017.1412

Role of Krüppel-like factor 4 and heat shock protein 27 in cancer of the larynx

Authors:
- Jihad Karam
- Marie Claude Fadous‑Khalifé
- Rita Tannous
- Sally Fakhreddine
- Marcel Massoud
- Joseph Hadchity
- Georges Aftimos
- Elie Hadchity
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Affiliations: Anti‑Tumor Therapeutic Targeting Laboratory, Faculty of Sciences, Lebanese University, Hadat 1003, Lebanon, Notre Dame de Secours University Hospital, Jbeil 1401, Lebanon, National Institute of Pathology, Baabda 1003, Lebanon
Published online on: September 19, 2017 https://doi.org/10.3892/mco.2017.1412
Pages: 808-814

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Abstract

Late detection and lack of standard treatment strategies in larynx cancer patients result in high levels of mortality and poor prognosis. Prognostic stratification of larynx cancer patients based on molecular prognostic tumor biomarkers may lead to more efficient clinical management. Krüppel-like factor 4 (KLF4) and Heat Shock Protein 27 (HSP27) have an important role in tumorigenesis and are considered promising candidate biomarkers for various types of cancer. However, their role in larynx carcinoma remains to be elucidated. The present study aimed to determine KLF4 and HSP27 expression profiles in laryngeal tumors. The protein and mRNA expression levels of KLF4 and HSP27 were evaluated by immunohistochemical and reverse transcription‑polymerase chain reaction analyses in 44 larynx carcinoma samples and 21 normal tissue samples, and then correlated with clinical characteristics. A differential expression of KLF4 and HSP27 was observed between normal and tumor tissues. The protein and mRNA expression levels of KLF4 were significantly decreased in larynx squamous cell carcinoma (LSCC) compared with normal tissue, whereas HSP27 was significantly overexpressed in tumor tissues compared with normal tissues, at the protein and mRNA levels. KLF4 expression decreased gradually with tumor progression whereas HSP27 expression increased. A significant difference was observed between stages I and IV. KLF4 and HSP27 exhibit opposite functions and roles in the carcinogenic process of LSCC. Their role in laryngeal cancer initiation and progression emphasizes their use as potential future targets for prognosis and treatment. KLF4 and HSP27 expression levels may act as potential biomarkers in patients with cancer of the larynx.

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1	Santos TS, Estêvão R, Antunes L, Certal V, Silva JC and Monteiro E: Clinical and histopathological prognostic factors in locoregional advanced laryngeal cancer. J Laryngol Otol. 130:948–953. 2016. View Article : Google Scholar : PubMed/NCBI
2	Marur S and Forastiere AA: Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment. Mayo Clin Proc. 91:386–396. 2016. View Article : Google Scholar : PubMed/NCBI
3	Ding B, Liu P, Liu W, Sun P and Wang CL: Emerging roles of Krüppel-like factor 4 in cancer and cancer stem cells. Asian Pac J Cancer Prev. 16:3629–3633. 2015. View Article : Google Scholar : PubMed/NCBI
4	Evans PM and Liu C: Roles of Krüpel-like factor 4 in normal homeostasis, cancer and stem cells. Acta Biochim Biophys Sin (Shanghai). 40:554–564. 2008. View Article : Google Scholar : PubMed/NCBI
5	Rowland BD and Peeper DS: KLF4, p21 and context-dependent opposing forces in cancer. Nat Rev Cancer. 6:11–23. 2006. View Article : Google Scholar : PubMed/NCBI
6	Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE and Yang VW: Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene. 23:395–402. 2004. View Article : Google Scholar : PubMed/NCBI
7	Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S and Xie K: Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression. Cancer Res. 65:2746–2754. 2005. View Article : Google Scholar : PubMed/NCBI
8	Wei D, Kanai M, Huang S and Xie K: Emerging role of KLF4 in human gastrointestinal cancer. Carcinogenesis. 27:23–31. 2006. View Article : Google Scholar : PubMed/NCBI
9	Hu W, Hofstetter WL, Li H, Zhou Y, He Y, Pataer A, Wang L, Xie K, Swisher SG and Fang B: Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma. Clin Cancer Res. 15:5688–5695. 2009. View Article : Google Scholar : PubMed/NCBI
10	Pandya AY, Talley LI, Frost AR, Fitzgerald TJ, Trivedi V, Chakravarthy M, Chhieng DC, Grizzle WE, Engler JA, Krontiras H, et al: Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer. Clin Cancer Res. 10:2709–2719. 2004. View Article : Google Scholar : PubMed/NCBI
11	Chen CJ, Lin SE, Lin YM, Lin SH, Chen DR and Chen CL: Association of expression of kruppel-like factor 4 and kruppel-like factor 5 with the clinical manifestations of breast cancer. Pathol Oncol Res. 18:161–168. 2012. View Article : Google Scholar : PubMed/NCBI
12	Rowland BD, Bernards R and Peeper DS: The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene. Nat Cell Biol. 7:1074–1082. 2005. View Article : Google Scholar : PubMed/NCBI
13	Tai SK, Yang MH, Chang SY, Chang YC, Li WY, Tsai TL, Wang YF, Chu PY and Hsieh SL: Persistent Krüppel-like factor 4 expression predicts progression and poor prognosis of head and neck squamous cell carcinoma. Cancer Sci. 102:895–902. 2011. View Article : Google Scholar : PubMed/NCBI
14	Fadous-Khalifé MC, Aloulou N, Jalbout M, Hadchity J, Aftimos G, Paris F and Hadchity E: Krüppel-like factor 4: A new potential biomarker of lung cancer. Mol Clin Oncol. 5:35–40. 2016. View Article : Google Scholar : PubMed/NCBI
15	Zoubeidi A and Gleave M: Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol. 44:1646–1656. 2012. View Article : Google Scholar : PubMed/NCBI
16	Lianos GD, Alexiou GA, Mangano A, Mangano A, Rausei S, Boni L, Dionigi G and Roukos DH: The role of heat shock proteins in cancer. Cancer Lett. 360:114–118. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kaigorodova EV and Bogatyuk MV: Heat shock proteins as prognostic markers of cancer. Curr Cancer Drug Targets. 14:713–726. 2014. View Article : Google Scholar : PubMed/NCBI
18	Sherman M and Multhoff G: Heat shock proteins in cancer. Ann N Y Acad Sci. 1113:192–201. 2007. View Article : Google Scholar : PubMed/NCBI
19	Ciocca DR, Arrigo AP and Calderwood SK: Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: An update. Arch Toxicol. 87:19–48. 2013. View Article : Google Scholar : PubMed/NCBI
20	Lo WY, Tsai MH, Tsai Y, Hua CH, Tsai FJ, Huang SY, Tsai CH and Lai CC: Identification of over-expressed proteins in oral squamous cell carcinoma (OSCC) patients by clinical proteomic analysis. Clin Chim Acta. 376:101–107. 2007. View Article : Google Scholar : PubMed/NCBI
21	Cordonnier T, Bishop JL, Shiota M, Nip KM, Thaper D, Vahid S, Heroux D, Gleave M and Zoubeidi A: Hsp27 regulates EGF/β-catenin mediated epithelial to mesenchymal transition in prostate cancer. Int J Cancer. 136:E496–E507. 2015. View Article : Google Scholar : PubMed/NCBI
22	Shiota M, Bishop JL, Nip KM, Zardan A, Takeuchi A, Cordonnier T, Beraldi E, Bazov J, Fazli L, Chi K, et al: Hsp27 regulates epithelial mesenchymal transition, metastasis and circulating tumor cells in prostate cancer. Cancer Res. 73:3109–3119. 2013. View Article : Google Scholar : PubMed/NCBI
23	Stope MB, Weiss M, Preuss M, Streitbörger A, Ritter CA, Zimmermann U, Walther R and Burchardt M: Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol Rep. 32:2380–2386. 2014. View Article : Google Scholar : PubMed/NCBI
24	Hansen RK, Parra I, Lemieux P, Oesterreich S, Hilsenbeck SG and Fuqua SA: Hsp27 overexpression inhibits doxorubicin-induced apoptosis in human breast cancer cells. Breast Cancer Res Treat. 56:187–196. 1999. View Article : Google Scholar : PubMed/NCBI
25	Hsu HS, Lin JH, Huang WC, Hsu TW, Su K, Chiou SH, Tsai YT and Hung SC: Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27. Cancer. 117:1516–1528. 2011. View Article : Google Scholar : PubMed/NCBI
26	Ciocca DR and Calderwood SK: Heat shock proteins in cancer: Diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 10:86–103. 2005. View Article : Google Scholar : PubMed/NCBI
27	Hadchity E, Aloy MT, Paulin C, Armandy E, Watkin E, Rousson R, Gleave M, Chapet O and Rodriguez-Lafrasse C: Heat shock protein 27 as a new therapeutic target for radiation sensitization of head and neck squamous cell carcinoma. Mol Ther. 17:1387–1394. 2009. View Article : Google Scholar : PubMed/NCBI
28	Aloy MT, Hadchity E, Bionda C, Diaz-Latoud C, Claude L, Rousson R, Arrigo AP and Rodriguez-Lafrasse C: Protective role of Hsp27 protein against gamma radiation-induced apoptosis and radiosensitization effects of Hsp27 gene silencing in different human tumor cells. Int J Radiat Oncol Biol Phys. 70:543–553. 2008. View Article : Google Scholar : PubMed/NCBI
29	Lelj-Garolla B, Kumano M, Beraldi E, Nappi L, Rocchi P, Ionescu DN, Fazli L, Zoubeidi A and Gleave ME: Hsp27 inhibition with OGX-427 sensitizes non-small cell lung cancer cells to erlotinib and chemotherapy. Mol Cancer Ther. 14:1107–1116. 2015. View Article : Google Scholar : PubMed/NCBI
30	Chi KN, Yu EY, Jacobs C, Bazov J, Kollmannsberger C, Higano CS, Mukherjee SD, Gleave ME, Stewart PS and Hotte SJ: A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol. 27:1116–1122. 2016. View Article : Google Scholar : PubMed/NCBI
31	Kaigorodova EV, Zavyalova MV, Bychkov VA, Perelmuter VM and Choynzonov EL: Functional state of the Hsp27 chaperone as a molecular marker of an unfavorable course of larynx cancer. Cancer Biomark. 17:145–153. 2016. View Article : Google Scholar : PubMed/NCBI
32	Xu X, Zhao M and Shi Y: Expression of heat shock proteins in laryngeal carcinoma. Zhonghua Er Bi Yan Hou Ke Za Zhi. 33:232–234. 1998.(In Chinese). PubMed/NCBI
33	Ghaleb AM and Yang VW: Krüppel-like factor 4 (KLF4): What we currently know. Gene. 611:27–37. 2017. View Article : Google Scholar : PubMed/NCBI
34	Wu J, Liu T, Rios Z, Mei Q, Lin X and Cao S: Heat Shock Proteins and Cancer. Trends Pharmacol Sci. 38:226–256. 2017. View Article : Google Scholar : PubMed/NCBI
35	Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F and Yoshida T: Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem Biophys Res Commun. 308:251–256. 2003. View Article : Google Scholar : PubMed/NCBI
36	Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN and Wu M: Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer. World J Gastroenterol. 8:966–970. 2002. View Article : Google Scholar : PubMed/NCBI
37	Zhang Z, Wang Z, Liu X, Shi M, Chen G, Zhang B, Li Z and Song L: Correlation of KLF4 and SPARC expression with the clinical characteristics of non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 15:720–724. 2012.(In Chinese). PubMed/NCBI
38	Yoshihama R, Yamaguchi K, Imajyo I, Mine M, Hiyake N, Akimoto N, Kobayashi Y, Chigita S, Kumamaru W, Kiyoshima T, et al: Expression levels of SOX2, KLF4 and brachyury transcription factors are associated with metastasis and poor prognosis in oral squamous cell carcinoma. Oncol Lett. 11:1435–1446. 2016.PubMed/NCBI
39	Acunzo J, Andrieu C, Baylot V, So A and Rocchi P: Hsp27 as a therapeutic target in cancers. Curr Drug Targets. 15:423–431. 2014. View Article : Google Scholar : PubMed/NCBI
40	Friedman MJ, Li S and Li XJ: Activation of gene transcription by heat shock protein 27 may contribute to its neuronal protection. J Biol Chem. 284:27944–27951. 2009. View Article : Google Scholar : PubMed/NCBI
41	Deaton RA, Gan Q and Owens GK: Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle. Am J Physiol Heart Circ Physiol. 296:H1027–H1037. 2009. View Article : Google Scholar : PubMed/NCBI
42	Zhang JP, Zhang H, Wang HB, Li YX, Liu GH, Xing S, Li MZ and Zeng MS: Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma. J Transl Med. 12:2222014. View Article : Google Scholar : PubMed/NCBI