Aim: Ultraviolet (UV) B irradiation induces gene expression that leads to skin cancer. Among the transcription factors induced by UVB radiation exposure, the cyclic AMP response element-binding protein (CREB) is significant. Since several factors downstream of CREB signaling are known to be involved in pterygium pathogenesis, we investigated CREB expression in pterygial and human conjunctival tissues to evaluate if a similar expression pattern is present. Moreover, we analyzed the correlation with CREB expression and other known pterygium markers. Methods: Primary pterygium samples and normal bulbar conjunctivas surgically removed were analyzed. Formalin-fixed, paraffin-embedded tissues were stained by immunohistochemistry with anti-CREB, anti-vimentin, anti-ki-67, anti-survivin, anti-MMP7, anti-p63, anti-cyclin D1, or anti-p53 antibodies. Results: 94.4% of pterygium samples were positive for CREB with a significant difference compared to the control group (p = 0.002). The staining was localized in the epithelium and absent in the stroma. An increased expression was found for cyclin D1 (p = 0.019), ki-67 (p = 0.005), vimentin (p = 0.003), survivin (p < 0.001), p63 (p = 0.003), and MMP7 (p = 0.002). CREB expression showed a significant correlation with cyclin D1 (ρ = 0.49; p = 0.035), ki-67 (ρ = 0.61; p = 0.007), and p53 (ρ = 0.57; p = 0.013) in pterygium. Conclusions: These results permit to hypothesize that CREB is involved in pterygium pathogenesis. Since various molecules have been discovered to inhibit CREB, these data could be of interest for pterygium treatment.

Coroneo MT, Di Girolamo N, Wakefield D: The pathogenesis of pterygia. Curr Opin Ophthalmol 1999;10:282-288.
Elliot R: The aetiology of pterygium. Trans Ophthalmol Soc NZ 1961;13:22-41.
Einspahr JG, Bowgen GT, Alberts DS, McKenzie N, Saboda K, Warneke J, Salasche S, Ranger-Moore J, Curiel-Lewandrowski C, Nagle RB, Nickoloff BJ, Brooks C, Dong Z, Stratton SP: Cross-validation of murine UV signal transduction pathways in human skin. Photochem Photobiol 2008;84:463-476.
Torres J, Enriquez-de-Salamanca A, Fernandez I, Rodriguez-Ares MT, Quadrado MJ, Murta J, Benitez del Castillo JM, Stern ME, Calonge M, et al: Activation of MAPK signaling pathway and NF-kappaB activation in pterygium and ipsilateral pterygium-free conjunctival specimens. IOVS 2011;52:5842-5852.
Coroneo MT: Pterygium as an early indicator of ultraviolet insolation: a hypothesis. Br J Ophthalmol 1993;77:734-739.
Coroneo MT, Di Girolamo N, Wakefield D: The pathogenesis of pterygia. Curr Opin Ophthalmol 1999;10:282-288.
Di Girolamo N, Chui J, Coroneo MT, Wakefield D: Pathogenesis of pterygia: role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004;23:195-228.
Dushku N, Reid TW: Immunohistochemical evidence that human pterygia originate from an invasion of vimentin-expressing altered limbal epithelial basal cells. Curr Eye Res 1994;13:473-481.
Tong L: Expression of p27(KIP1) and cyclin D1, and cell proliferation in human pterygium. Br J Ophthalmol 2008;92:157.
Sakoonwatanyoo P, Tan DT, Smith DR: Expression of p63 in pterygium and normal conjunctiva. Cornea 2004;23:67-70.
Maxia C, Perra M, Demurtas P, Minerba L, Murtas D, Piras F, Cabrera R, Ribatti D, Sirigu P: Relationship between the expression of cyclossigenase-2 and survivin in primary pterygium. Mol Vis 2009;15:458-463.
Liang K, Jiang Z, Ding B, Cheng P, Huang DK, Tao LM: Expression of cell proliferation and apoptosis biomarkers in pterygia and normal conjunctiva. Mol Vis 2011;17:1687-1693.
Seifert P, Eckert J, Spitznas M: Topological-histological investigation of pterygium. Graefes Arch Clin Exp Ophthalmol 2001;239:288-293.
Seifert P, Sekundo W: Capillaries in the epithelium of pterygium. Br J Ophthalmol 1998;83:219-224.
Tseng SH, Chen YT, Cheng HC, Huang FC, Lee SC, Chen FK: Impression cytology study of conjunctival epithelial phenotypes on the healing ocular surface after pterygium excision. Cornea 2001;20:244-250.
Wang IJ, Lai WT, Liou SW, Chiu CZ, Hu FR, Kao WW, Hung PT: Impression cytology of pterygium. J Ocul Pharmacol Ther 2000;16:519-528.
Austin P, Jakobiec FA, Iwamoto T, Hornblass A: Elastofibroma oculi. Arch Ophthalmol 1983;101:1575-1579.
Di Girolamo N, Coroneo MT, Wakefield D: UVB-elicited induction of MMP-1 expression in human ocular surface epithelial cells is mediated through the ERK1/2 MAPK-dependent pathway. IOVS 2003;44:4705-4714.
Petersen MJ, Hansen C, Craig S: Ultraviolet A irradiation stimulates collagenase production in cultured human fibroblasts. J Invest Dermatol 1992;99:440-444.
Ng J, Coroneo MT, Wakefield D, Di Girolamo N: Ultraviolet radiation and the role of matrix metalloproteinases in the pathogenesis of ocular surface squamous neoplasia. IOVS 2003;44:4705-4714.
Kinjo K, Sandoval S, Sakamoto KM, Shankar DB: The role of CREB as a proto-oncogene in hematopoiesis. Cell Cycle 2005;9:1134-1135.
Conkright M, Montminy M: CREB: the unindicated cancer co-conspirator. Trends Cell Biol 2005;15:457-459.
Mayr B, Montminy M: Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2001;2:599-609.
Bland JM, Altman DG: Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;8:307-310.
Jaworski CJ, Aryankalayil-John M, Campos MM, Fariss RN, Rowey J, Agarwalla N, Reid TW, Dushku N, Cox CA, Carper D, Wistow G: Expression analysis of human pterygium shows a predominance of conjunctival and limbal markers and genes associated with cell migration. Mol Vis 2009;15:2421-2434.
Coroneo M: Ultraviolet radiation and the anterior eye. Eye Contac Lens 2011;37:214-224.
Cho EC, Mitton B, Sakamoto KM: CREB and leukemogenesis. Crit Rev Oncog 2011;16:37-46.
Ionov Y, Matsui S, Cowell JK: A role for p300/CREB binding protein genes in promoting cancer progression in colon cancer cell lines with microsatellite instability. Proc Natl Acad Sci USA 2004;101:1273-1278.
Fan CF, Mao XY, Wang EH: Elevated p-CREB-2 (ser 245) expression is potentially associated with carcinogenesis and development of breast carcinoma. Mol Med Report 2012;5:357-362.
Gulani A, Dastur YK: Simultaneous pterygium and cataract surgery. J Postgrad Med 1995;41:8-11.
Chen YT, Tseng SH, Tsai YY, Huang FC, Tseng SY: Distribution of vimentin-expressing cells in pterygium: an immunocytochemical study of impression cytology specimens. Cornea 2009;28:547-552.
Aziz MH, Ghotra AS, Shukla Y, Ahmad N: Ultraviolet-B radiation causes an upregulation of survivin in human keratinocytes and mouse skin. Photochem Photobiol 2004;80:602-608.
Reid TW, Dushku N: What a study of pterygia teaches us about the cornea? Molecular mechanisms of formation. Eye Contact Lens 2010;36:290-295.
Detorakis E, Spandidos D: Pathogenic mechanisms and treatment options for ophthalmic pterygium: trends and perspectives. Int J of Mol Med 2009;23:439-447.
Chui J, Coroneo MT, Tat LT, Crouch R, Wakefield D, Di Girolamo N: Ophthalmic pterygium: a stem cell disorder with premalignant features. Am J Pathol 2011;178:817-827.
Ramalho FS, Maestri C, Ramalho LN, Ribeiro-Silva A, Romao E: Expression of p63 and p16 in primary and recurrent pterygia. Graefes Arch Clin Exp Ophthalmol 2006;244:1310-1314.
Weinstein O, Rosenthal G, Zirkin H, Monos T, Lifshitz T, Argov S: Overexpression of p53 tumor suppressor gene in pterygia. Eye 2002;16:619-621.
Tan DT, Tang WY, Liu YP, Goh HS, Smith DR: Apoptosis and apoptosis related gene expression in normal conjunctiva and pterygium. Br J Ophthalmol 2000;84:212-216.
Tan DT, Lim AS, Goh HS, Smith DR: Abnormal expression of the p53 tumor suppressor gene in the conjunctiva of patients with pterygium. Am J Ophthalmol 1997;123:404-405.
Shimmura S, Ishioka M, Hanada K, Shimazaki J, Tsubota K: Telomerase activity and p53 expression in pterygia. Invest Ophthalmol Vis Sci 2000;41:1364-1369.
Chowers I, Pe'er J, Zamir E, Livni N, Ilsar M, Frucht Pery J: Proliferative activity and p53 expression in primary and recurrent pterygia. Ophthalmology 2001;108:985-988.
Holli AG, Lemasson I, Nyborg JK: p53 recruitment of CREB binding protein mediated through phosphorylated CREB: a novel pathway of tumor suppressor regulation. Mol Cell Biol 2000;20:4849-4858.
Tung JN, Chiang CC, Tsai YY, Chou YY, Yeh KT, Lee H, Cheng YW: CyclinD1 protein expressed in pterygia is associated with β-catenin protein localization. Mol Vis 2010;16:2733-2738.
Liang K, Jiang Z, Ding BQ, Cheng P, Huang DK, Tao LM: Expression of cell proliferation and apoptosis biomarkers in pterygia and normal conjunctiva. Mol Vis 2011;17:1687-1693.
Di Girolamo N, Wakefield D, Coroneo MT: UVB-mediated induction of cytokines and growth factors in pterygium epithelial cells involves cell surface receptors and intracellular signaling. IOVS 2006;47:2430-2437.
Di Girolamo N, Kumar RK, Coroneo MT, Wakefield D: UVB-mediated induction of interleukin-6 and -8 in pterygia and cultured human pterygium epithelial cells. IOVS 2002;43:3430-3437.
Gebhardt M, Recker K, Mentlein R, Nölle B, Paulsen FP, Schaudig U, Al-Samir K, Pufe T, Geerling G: Differential expression of vascular endothelial growth factor implies the limbal origin of pterygia. Ophthalmology 2005;112:1023-1030.
Jin J, Guan M, Sima J, Gao G, Zhang M, Liu Z, Fant J, Ma JX: Decreased pigment epithelium-derived factor and increased vascular endothelial growth factor levels in pterygia. Cornea 2003;22:473-477.
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