Antimicrobial peptide LL-37 promotes the proliferation and invasion of skin squamous cell carcinoma by upregulating DNA-binding protein A

Wang,Wei; Jia,Jinjing; Li,Changji; Duan,Qiqi; Yang,Jiao; Wang,Xin; Li,Ruilian; Chen,Caifeng; Yan,Huling; Zheng,Yan

doi:10.3892/ol.2016.4865

Antimicrobial peptide LL-37 promotes the proliferation and invasion of skin squamous cell carcinoma by upregulating DNA-binding protein A

Authors:
- Wei Wang
- Jinjing Jia
- Changji Li
- Qiqi Duan
- Jiao Yang
- Xin Wang
- Ruilian Li
- Caifeng Chen
- Huling Yan
- Yan Zheng
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Affiliations: Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: July 15, 2016 https://doi.org/10.3892/ol.2016.4865
Pages: 1745-1752
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The antimicrobial peptide LL-37 not only contributes to the host defence against microbial invasion but also regulates immune activity, angiogenesis and cell proliferation. Studies have shown that LL-37 participates in the development of a variety of tumours, such as lung cancer, ovarian cancer, breast cancer and melanoma. However, the role of LL‑37 in the development of skin squamous cell carcinoma (SCC) is not clear. The present study used immunohistochemistry to confirm that the expression of human DNA‑binding protein A (dbpA) was increased in SCC tissues. After stimulating SCC A341 cells, LL-37 was shown promote the proliferation, migration and invasion of these malignant cells. LL-37 also promoted the upregulation of dbpA mRNA and protein expression. In addition, after using small interfering RNA to silence the normal dbpA expression in these malignant cells, the proliferation and invasion of the tumor cells were significantly reduced. When the NF-κB inhibitor PDTC was used to inhibit the process of LL-37‑stimulated cells, it was found that the original upregulated expression of dbpA was downregulated. Overall, the present demonstrated that by upregulating the expression of dbpA, LL-37 can promote the proliferation and invasion of tumour cells, and that this process depends on the NF-κB signalling pathway.

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1	Knackstedt TJ, Brennick JB, Perry AE, Li Z, Quatrano NA and Samie FH: Frequency of squamous cell carcinoma (SCC) invasion in transected SCC in situ referred for Mohs surgery: The Dartmouth-Hitchcock experience. Int J Dermatol. 54:830–833. 2015. View Article : Google Scholar : PubMed/NCBI
2	Rogers HW, Weinstock MA, Feldman SR and Coldiron BM: Incidence estimate of nonmelanoma skin cancer (keratinocyte carcinomas) in the US population, 2012. JAMA Dermatol. 151:1081–1086. 2015. View Article : Google Scholar : PubMed/NCBI
3	Sapijaszko M, Zloty D, Bourcier M, Poulin Y, Janiszewski P and Ashkenas J: Canadian Non-melanoma Skin Cancer Guidelines Committee: Non-melanoma skin cancer in Canada chapter 5: Management of squamous cell carcinoma. J Cutan Med Surg. 19:249–259. 2015. View Article : Google Scholar : PubMed/NCBI
4	Sakura H, Maekawa T, Imamoto F, Yasuda K and Ishii S: Two human genes isolated by a novel method encode DNA-binding proteins containing a common region of homology. Gene. 73:499–507. 1988. View Article : Google Scholar : PubMed/NCBI
5	Kudo S, Mattei MG and Fukuda M: Characterization of the gene for dbpA, a family member of the nucleic-acid-binding proteins containing a cold-shock domain. Eur J Biochem. 231:72–82. 1995. View Article : Google Scholar : PubMed/NCBI
6	Balda MS and Matter K: The tight junction protein ZO-1 and an interacting transcription factor regulate ErbB-2 expression. EMBO J. 19:2024–2033. 2000. View Article : Google Scholar : PubMed/NCBI
7	Wolffe AP: Structural and functional properties of the evolutionarily ancient Y-box family of nucleic acid binding proteins. Bioessays. 16:245–251. 1994. View Article : Google Scholar : PubMed/NCBI
8	Kohno K, Izumi H, Uchiumi T, Ashizuka M and Kuwano M: The pleiotropic functions of the Y-box-binding protein, YB-1. Bioessays. 25:691–698. 2003. View Article : Google Scholar : PubMed/NCBI
9	Uramoto H, Izumi H, Ise T, Tada M, Uchiumi T, Kuwano M, Yasumoto K, Funa K and Kohno K: p73 Interacts with c-Myc to regulate Y-box-binding protein-1 expression. J Biol Chem. 277:31694–31702. 2002. View Article : Google Scholar : PubMed/NCBI
10	Sourisseau T, Georgiadis A, Tsapara A, Ali RR, Pestell R, Matter K and Balda MS: Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA. Mol Cell Biol. 26:2387–2398. 2006. View Article : Google Scholar : PubMed/NCBI
11	Tobita H, Kajino K, Inami K, Kano S, Yasen M, Imamura O, Kinoshita Y and Hino O: Gene expression profile of DNA binding protein A transgenic mice. Int J Oncol. 29:673–679. 2006.PubMed/NCBI
12	Dürr UH, Sudheendra US and Ramamoorthy A: LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 1758:1408–1425. 2006. View Article : Google Scholar : PubMed/NCBI
13	Bucki R, Leszczynska K, Namiot A and Sokolowski W: Cathelicidin LL-37: A multitask antimicrobial peptide. Arch Immunol Ther Exp (Warsz). 58:15–25. 2010. View Article : Google Scholar : PubMed/NCBI
14	Wu WK, Wang G, Coffelt SB, Betancourt AM, Lee CW, Fan D, Wu K, Yu J, Sung JJ and Cho CH: Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. Int J Cancer. 127:1741–1747. 2010. View Article : Google Scholar : PubMed/NCBI
15	Coffelt SB and Scandurro AB: Tumors sound the alarmin(s). Cancer Res. 68:6482–6485. 2008. View Article : Google Scholar : PubMed/NCBI
16	Hensel JA, Chanda D, Kumar S, Sawant A, Grizzle WE, Siegal GP and Ponnazhagan S: LL-37 as a therapeutic target for late stage prostate cancer. Prostate. 71:659–670. 2011. View Article : Google Scholar : PubMed/NCBI
17	Gill K, Mohanti BK, Singh AK, Mishra B and Dey S: The over expression of cathelicidin peptide LL37 in head and neck squamous cell carcinoma: The peptide marker for the prognosis of cancer. Cancer Biomark. 10:125–134. 2011.2012. PubMed/NCBI
18	Kim JE, Kim HJ, Choi JM, Lee KH, Kim TY, Cho BK, Jung JY, Chung KY, Cho D and Park HJ: The antimicrobial peptide human cationic antimicrobial protein-18/cathelicidin LL-37 as a putative growth factor for malignant melanoma. Br J Dermatol. 163:959–967. 2010. View Article : Google Scholar : PubMed/NCBI
19	Heilborn JD, Nilsson MF, Jimenez CI, Sandstedt B, Borregaard N, Tham E, Sørensen OE, Weber G and Ståhle M: Antimicrobial protein hCAP18/LL-37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells. Int J Cancer. 114:713–719. 2005. View Article : Google Scholar : PubMed/NCBI
20	Coffelt SB, Waterman RS, Florez L, Höner zu Bentrup K, Zwezdaryk KJ, Tomchuck SL, LaMarca HL, Danka ES, Morris CA and Scandurro AB: Ovarian cancers overexpress the antimicrobial protein hCAP-18 and its derivative LL-37 increases ovarian cancer cell proliferation and invasion. Int J Cancer. 122:1030–1039. 2008. View Article : Google Scholar : PubMed/NCBI
21	von Haussen J, Koczulla R, Shaykhiev R, Herr C, Pinkenburg O, Reimer D, Wiewrodt R, Biesterfeld S, Aigner A, Czubayko F, et al: The host defence peptide LL-37/hCAP-18 is a growth factor for lung cancer cells. Lung Cancer. 59:12–23. 2008. View Article : Google Scholar : PubMed/NCBI
22	Coffelt SB, Tomchuck SL, Zwezdaryk KJ, Danka ES and Scandurro AB: Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells. Mol Cancer Res. 7:907–915. 2009. View Article : Google Scholar : PubMed/NCBI
23	Coffelt SB, Marini FC, Watson K, Zwezdaryk KJ, Dembinski JL, LaMarca HL, Tomchuck SL, Honer zu Bentrup K, Danka ES, Henkle SL and Scandurro AB: The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells. Proc Natl Acad Sci USA. 106:3806–3811. 2009. View Article : Google Scholar : PubMed/NCBI
24	Girnita A, Zheng H, Grönberg A, Girnita L and Ståhle M: Identification of the cathelicidin peptide LL-37 as agonist for the type I insulin-like growth factor receptor. Oncogene. 31:352–365. 2012. View Article : Google Scholar : PubMed/NCBI
25	Choi KY, Napper S and Mookherjee N: Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation. Immunology. 143:68–80. 2014. View Article : Google Scholar : PubMed/NCBI
26	Chuang CM, Monie A, Wu A, Mao CP and Hung CF: Treatment with LL-37 peptide enhances antitumor effects induced by CpG oligodeoxynucleotides against ovarian cancer. Hum Gene Ther. 20:303–313. 2009. View Article : Google Scholar : PubMed/NCBI
27	Li D, Wang X, Wu JL, Quan WQ, Ma L, Yang F, Wu KY and Wan HY: Tumor-produced versican V1 enhances hCAP18/LL-37 expression in macrophages through activation of TLR2 and vitamin D3 signaling to promote ovarian cancer progression in vitro. PLoS One. 8:e566162013. View Article : Google Scholar : PubMed/NCBI
28	Kittaka M, Shiba H, Kajiya M, Ouhara K, Takeda K, Kanbara K, Fujita T, Kawaguchi H, Komatsuzawa H and Kurihara H: Antimicrobial peptide LL37 promotes vascular endothelial growth factor-A expression in human periodontal ligament cells. J Periodontal Res. 48:228–234. 2013. View Article : Google Scholar : PubMed/NCBI
29	Yasen M, Kajino K, Kano S, Tobita H, Yamamoto J, Uchiumi T, Kon S, Maeda M, Obulhasim G, Arii S and Hino O: The up-regulation of Y-box binding proteins (DNA binding protein A and Y-box binding protein-1) as prognostic markers of hepatocellular carcinoma. Clin Cancer Res. 11:7354–7361. 2005. View Article : Google Scholar : PubMed/NCBI
30	Zhang LL, He DL, Li X, Li L, Zhu GD, Zhang D and Wang XY: Overexpression of coxsackie and adenovirus receptor inhibit growth of human bladder cancer cell in vitro and in vivo. Acta Pharmacol Sin. 28:895–900. 2007. View Article : Google Scholar : PubMed/NCBI
31	Guay D, Garand C, Reddy S, Schmutte C and Lebel M: The human endonuclease III enzyme is a relevant target to potentiate cisplatin cytotoxicity in Y-box-binding protein-1 overexpressing tumor cells. Cancer Sci. 99:762–769. 2008. View Article : Google Scholar : PubMed/NCBI
32	Wang GR, Zheng Y, Che XM, Wang XY, Zhao JH, Wu KJ, Zeng J, Pan CE and He DL: Upregulation of human DNA binding protein A (dbpA) in gastric cancer cells. Acta Pharmacol Sin. 30:1436–1442. 2009. View Article : Google Scholar : PubMed/NCBI
33	Koike K, Uchiumi T, Ohga T, Toh S, Wada M, Kohno K and Kuwano M: Nuclear translocation of the Y-box binding protein by ultraviolet irradiation. FEBS Lett. 417:390–394. 1997. View Article : Google Scholar : PubMed/NCBI
34	Arakawa Y, Kajino K, Kano S, Tobita H, Hayashi J, Yasen M, Moriyama M, Arakawa Y and Hino O: Transcription of dbpA, a Y box binding protein, is positively regulated by E2F1: Implications in hepatocarcinogenesis. Biochem Biophys Res Commun. 322:297–302. 2004. View Article : Google Scholar : PubMed/NCBI
35	Bandurska K, Berdowska A, Barczyńska-Felusiak R and Krupa P: Unique features of human cathelicidin LL-37. Biofactors. 41:289–300. 2015.PubMed/NCBI
36	Liu J and Du L: PERK pathway is involved in oxygen-glucose-serum deprivation-induced NF-κB activation via ROS generation in spinal cord astrocytes. Biochem Biophys Res Commun. 467:197–203. 2015. View Article : Google Scholar : PubMed/NCBI