Abstract
Cytokines involved in inflammatory and immune response have been associated with risk for development of basal cell carcinoma (BCC). In this study, three functional DNA polymorphisms affecting gene expression were investigated in 54 BCC patients and 111 healthy controls: interleukin-1b (IL-1b) +3953C/T, interleukin-10 (IL-10) − 1082G/A and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Significant increase of the variant alleles was observed in IL-10 − 1082G (P = 0.019) and in ACE D (P = 0.003) in BCC patients in comparison to controls. Multivariate logistic regression models evaluated the contribution of homozygous and heterozygous variant polymorphisms to the risk for BCC development. The studied polymorphisms influencing the expression of IL-10 and ACE genes were recognized as potential predictive factors for BCC. These findings suggest a possible molecular mechanism leading to BCC development that is likely to involve the activation of angiotensin receptors in combination with increased plasma levels of IL-10 in patients.
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References
Ager EI, Neo J, Christophi C (2008) The renin-angiotensin system and malignancy. Carcinogenesis 29:1675–1684
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545
Barber MD, Powell JJ, Lynch SF, Fearon KC, Ross JA (2000) A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer. Br J Cancer 83:1443–1447
Benndorf R, Boger RH, Ergun S, Steenpass A, Wieland T (2003) Angiotensin II type 2 receptor inhibits vascular endothelial growth factor-induced migration and in vitro tube formation of human endothelial cells. Circ Res 93:438–447
Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE (2011) Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci 121:297–303
Boulland M-L, Meignin V, Leroy-Viard K, Copie-Bergman C, Brière J, Touitou R et al (1998) Human interleukin-10 expression in T/natural killer-cell lymphomas: association with anaplastic large cell lymphomas and nasal natural killer-cell lymphomas. Am J Pathol 153:1229–1237
Burke F, Relf M, Negus R, Balkwill F (1996) A cytokine profile of normal and malignant ovary. Cytokine 8:578–585
Carter DM, Lin AN (1993) Basal cell carcinoma. In: Fitzpatrick TM, Eisen AZ, Wolff K, et al. (eds) Dermatology in General Medicine, 4th edn. McGraw-Hill, New York, pp 840–847
Chow L, Rezmann L, Catt KJ, Louis WJ, Frauman AG, Nahmias C, Louis SN (2009) Role of the renin-angiotensin system in prostate cancer. Mol Cell Endocrinol 302:219–229
Chung FM, Yang YH, Chen CH, Lin CC, Shieh TY (2005) Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers. Br J Cancer 93:602–606
Ma C-y, Lin Yin MD (2016) Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion. Neural Regen Res 11:1102–1107
Crowson AN (2006) Basal cell carcinoma: biology, morphology and clinical implications. Mod Pathol 19(Suppl 2):127–147
Crowson AN, Magro CM, Kadin M et al (1996) Differential expression of bcl-2 oncogene in human basal cell carcinoma. Hum Pathol 27:355–359
Curato C, Slavic S, Dong J, Skorska A, Altarche-Xifró W, Miteva K, Kaschina E, Thiel A, Imboden H, Wang J, Steckelings U, Steinhoff G, Unger T, Li J (2010) Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury. J Immunol 185:6286–6293
Dhande I, Ma W, Hussain T (2015) Angiotensin AT2 receptor stimulation is anti-inflammatory in lipopolysaccharide-activated THP-1 macrophages via increased interleukin-10 production. Hypertens Res 38:21–29
Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77:1627–1652
Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147
Elamin I, Zecević RD, Vojvodić D, Medenica L, Pavlović MD (2008) Cytokine concentrations in basal cell carcinomas of different histological types and localization. Acta Dermatovenerol Alp Pannonica Adriat 17(2):55–59
Elaraj DM, Weinreich DM, Varghese S, Puhlmann M, Hewitt SM, Carroll NM, Feldman ED, Turner EM, Alexander HR (2006) The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clin Cancer Res 12:1088–1096
Freitas-Silva M, Pereira D, Coelho C, Bicho M, Lopes C, Medeiros R (2004) Angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women. Cancer Genet Cytogen 155:42–46
Friis S, Sorensen HT, Mellemkjaer L, McLaughlin JK, Nielsen GL, Blot WJ, Olsen JH (2001) Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark. Cancer 92:2462–2470
Fujita M, Hayashi I, Yamashina S, Itoman M, Majima M (2002) Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem Biophys Res Commun 294:441–447
Gastl GA, Abrams JS, Nanus DM, Oosterkamp R, Silver J, Liu F et al (1993) Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer 55:96–101
Goldberg LH (1996) Basal cell carcinoma. Lancet 347:663–667
Goldstein AM, Bale SJ, Peck GL et al (1993) Sun exposure and basal cell carcinoma in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 29:34–41
Goto Y, Ando T, Nishio K, Ishida Y, Kawai S, Goto H, Hamajima N (2005) The ACE gene polymorphism is associated with the incidence of gastric cancer among H. pylori seropositive subjects with atrophic gastritis. Asian Pac J Cancer Prev 6:464–467
Haiman C, Henderson S, Bretsky P, Kolonel L, Henderson B (2003) Genetic variation in angiotensin I-converting enzyme (ACE) and breast cancer risk: The multiethnic cohort. Cancer Res 63:6984–6987
Itakura E, Huang R-R, Wen D-R, Paul E, Wünsch PH, Cochran AJ (2011) IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. Mod Pathol 24:801–809
Kaijzel EL, Dongen H, Bakker AM, Breedveld FC, Huizinga TWJ, Verweij CL (2002) Relationship of polymorphisms of the interleukin-1 gene cluster to occurrence and severity of rheumatoid arthritis. Tissue Antigens 59:122–126
Khorooshi R, Tofte-Hansen EU, Tygesen C, Montanana-Rosell R, Limburg HL, Marczynska J, Asgari N, Steckelings UM, Owens T (2019) Angiotensin AT2 receptor-induced interleukin-10 attenuates neuromyelitis optica spectrum disorder-like pathology. Mult Scler 9:1352458519860327
Komori A, Yatsunami J, Suganuma M, Okabe S, Abe S, Sakai A, Sasaki K, Fujiki H (1993) Tumor necrosis factor acts as a tumor promoter in BALB/3T3 cell transformation. Cancer Res 53:1982–1985
Krüger-Krasagakes S, Krasagakis K, Garbe C, Schmitt E, Hüls C, Blankenstein T et al (1994) Expression of interleukin 10 in human melanoma. Br J Cancer 70:1182–1185
Kuper H, Adami HO, Trichopoulos D (2000) Infections as a major preventable cause of human cancer. J Intern Med 248:171–183
Lacour JP (2002) Carcinogenesis of basal cell carcinomas: genetics and molecular mechanisms. Br J Dermatol 146(Suppl 61):17–19
Li C, Li H, Jiang K, Li J, Gai X (2014) TLR4 signaling pathway in mouse Lewis lung cancer cells promotes the expression of TGF-β1 and IL-10 and tumor cells migration. Biomed Mater Eng 24:869–875
Lin MT, Storer B, Martin PJ, Tseng LH, Gooley T, Chen PJ, Hansen JA (2003) Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 349:2201–2210
Mantovani A, Muzio M, Garlanda C, Sozzani S, Allavena P (2001) Macrophage control of inflammation: negative pathways of regulation of inflammatory cytokines. Novartis Found Symp 234:120–131 (discussion 131-5)
Medeiros R, Vasconcelos A, Costa S, Pinto D, Lobo F, Morais A, Oliveira J, Lopes C (2004) Linkage of angiotensin I-converting enzyme gene insertion/deletion polymorphism to the progression of human prostate cancer. J Pathol 202:330–335
Meenagh A, Williams F, Ross OA, Patterson C, Gorodezky C, Hammond M, Leheny WA, Middleton D (2002) Frequency of cytokine polymorphisms in populations from Western Europe, Africa, Asia, the Middle East and South America. Hum Immunol 63:1055–1061
Miller SJ (1991) Biology of basal cell carcinoma (Part I). J Am Acad Dermatol 24:1–13
Miller SJ (1991) Biology of basal cell carcinoma (Part II). J Am Acad Dermatol 24:161–175
Olbryt M (2012) Role of tumor microenvironment in the formation and progression of skin melanoma. Postepy Hig Med Dosw (Online) 67:413–432
Palli D, Saieva C, Luzzi I, Masala G, Topa S, Sera F, Gemma S, Zanna I, Errico MD, Zini E, Guidotti S, Valeri A, Fabbrucci P, Moretti R, Testai E, Giudice G, Ottini L, Matullo G, Dogliotti E, Gomez-Miguel MJ (2005) Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population. Am J Gastroenterol 100:1941–1948
Papaggelopoulos J, Angelopoulou A, Avgoustidis D, Koronellos N, Derka S, Vassiliou S, Yapijakis C (2019) Association of polymorphisms in the genes of angiotensinogen and angiotensin receptors with risk for basal cell carcinoma. Anticancer Res 39:5525–5530
Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J (1992) A Taq I polymorphism in the human interleukin-1 beta (1L–1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 22:396–402
Porrello ER, Pfleger KD, Seeber RM, Qian H, Oro C, Abogadie F, Delbridge LM, Thomas WG (2011) Heteromerization of angiotensin receptors changes trafficking and arrestin recruitment profiles. Cell Signal 23:1767–1776
Rocken C, Lendeckel U, Dierkes J, Westphal S, Carl-McGrath S, Peters B, Krüger S, Malfertheiner P, Roessner A, Ebert MP (2005) The number of lymph node metastases in gastric cancer correlates with the angiotensin I-converting enzyme gene insertion/deletion polymorphism. Clin Cancer Res 11:2526–2530
Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR (2011) Interleukin-10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol Res 51:170–182
Snoussi K, Strosberg AD, Bouaouina N, Ben Ahmed S, Chouchane L (2005) Genetic variation in pro-inflammatory cytokines (interleukin-1 beta, interleukin-1 alpha and interleukin-6) associated with the aggressive forms, survival, and relapse prediction of breast carcinoma. Eur Cytokine Netw 16:253–260
Sobjanek M, Zabłotna M, Bień E, Gleń J, Sokołowska-Wojdyło M, Ruckemann-Dziurdzińska K, Nowicki R (2016) Clinical significance of IL-2 and IL-10 gene polymorphisms and serum levels in patients with basal-cell carcinoma. Biomark Med 10:185–195
Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C (1994) Macrophages and angiogenesis. J Leukoc Biol 55:410–422
Takamatsu M, Yamauchi M, Maezawa Y, Saito S, Maeyama S, Uchikoshi T (2000) Genetic polymorphisms of interleukin-1, in association with the development of alcoholic liver disease in Japanese patients. Am J Gastrenterol 95:1305–1311
Thomas WG (1999) Regulation of angiotensin II type 1 (AT1) receptor function. Regul Pept 79:9–23
Vairaktaris E, Yiannopoulos A, Vylliotis A, Yapijakis C, Derka S, Vassiliou S, Nkenke E, Serefoglou Z, Ragos V, Tsigris C, Vorris E, Critselis E, Avgoustidis D, Neukam FW, Patsouris E (2006) Strong association of interleukin-6 -174 G[C promoter polymorphism with increased risk of oral cancer. Int J Biol Markers 21:246–250
Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, Spyridonidou S, Vylliotis A, Vorris E, Ragos V, Neukam FW, Patsouris E (2007) A) Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with increased risk for oral cancer. Acta Oncol 46:1097–1102
Vairaktaris E, Serefoglou Z, Yapijakis C, Stathopoulos P, Vassiliou S, Derka S, Nkenke E, Vylliotis A, Ragos V, Neukam FW, Patsouris E (2007) B) The interleukin-1 beta gene polymorphism +3953 C/T is not associated with risk for oral cancer. Anticancer Res 27:3981–3986
Vairaktaris E, Yapijakis C, Serefoglou Z, Derka S, Vassiliou S, Nkenke E, Vylliotis A, Wiltfang J, Avgoustidis D, Critselis E, Neukam FW, Patsouris E (2007) C) The interleukin-8 (-251A/T) polymorphism is associated with increased risk for oral squamous cell carcinoma. Eur J Surg Oncol 33:504–507
Vairaktaris E, Yannopoulos A, Vassiliou S, Serefoglou Z, Vylliotis A, Nkenke E, Critselis E, Avgoustidis D, Yapijakis C, Neukam FW, Patsouris E (2007) D) Strong association of interleukin-4 (-590 C/T) polymorphism with increased risk for oral squamous cell carcinoma in Europeans. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 104:796–802
Vairaktaris E, Yapijakis C, Serefoglou Z, Avgoustidis D, Critselis E, Spyridonidou S, Vylliotis A, Derka S, Vassiliou S, Nkenke E, Patsouris E (2008) A) Gene expression polymorphisms of interleukins-1 beta, -4, -6, -8, -10, and tumor necrosis factors-alpha, -beta: regression analysis of their effect upon oral squamous cell carcinoma. J Cancer Res Clin Oncol 134:821–832
Vairaktaris E, Yapijakis C, Serefoglou Z, Derka S, Vassiliou S, Nkenke E, Vylliotis A, Spyridonidou S, Neukam FW, Schlegel KA, Patsouris E (2008) B) The interleukin-10 (-1082A/G) polymorphism is strongly associated with increased risk for oral squamous cell carcinoma. Anticancer Res 28:309–314
Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 100:2645–2650
Wilkening S, Hemminki K, Rudnai P, Gurzau E, Koppova K, Kumar R, Försti A (2006) Case control study in basal cell carcinoma of the skin: single nucleotide polymorphisms in three interleukin promoters pre-analysed in pooled DNA. Br J Dermatol 155:1139–1144
Wu L, Chen X, Zhao J, Martin B, Zepp JA, Ko JS, Gu C, Cai G, Ouyang W, Sen G, Stark GR, Su B, Vines CM, Tournier C, Hamilton TA, Vidimos A, Gastman B, Liu C, Li X (2015) A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4-ERK5 axis. J Exp Med 212:1571–1587
Wu N, Sun H, Sun Q, Cui M, Jiang R, Cong X (2018) Associations between IL-10 polymorphisms and susceptibility to melanoma, basal cell carcinoma, and squamous cell carcinoma: a meta-analysis. Genet Test Mol Biomarkers. https://doi.org/10.1089/gtmb.2018.0172
Yapijakis C, Koronellos N, Spyridonidou S, Vylliotis A, Avgoustidis D, Goutas N, Vlachodimitropoulos D, Vairaktaris E (2013) Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with decreased risk for basal cell carcinoma. Arch Dermatol Res 305:333–339
Yilmaz V, Yentur SP, Saruhan-Direskeneli G (2005) IL-12 and IL-10 polymorphisms and their effects on cytokine production. Cytokine 30:188–194
Yoshiji H, Yoshii J, Ikenaka Y, Noguchi R, Yanase K, Tsujinoue H, Imazu H, Fukui H (2002) Suppression of the renin-angiotensin system attenuates vascular endothelial growth factor-mediated tumor development and angiogenesis in murine hepatocellular carcinoma cells. Int J Oncol 20:1227–1231
Zhang Z, Liu W, Jia X, Gao Y, Hemminki K, Lindholm B (2004) Use of pyrosequencing to detect clinically relevant polymorphisms of genes in basal cell carcinoma. Clin Chim Acta 342:137–143
Zhu X, McKenzie CA, Forrester T, Nickerson DA, Broeckel U, Schunkert H, Doering A, Jacob HJ, Cooper RS, Rieder MJ (2000) Localization of a small genomic region associated with elevated ACE. Am J Hum Genet 67:1144–1153
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Koronellos, N., Yapijakis, C., Katoulis, A. et al. Association study indicates combined effect of interleukin-10 and angiotensin-converting enzyme in basal cell carcinoma development. Arch Dermatol Res 313, 373–380 (2021). https://doi.org/10.1007/s00403-020-02113-x
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DOI: https://doi.org/10.1007/s00403-020-02113-x