• Nenhum resultado encontrado

HIPÓTESES

6 CONCLUSÃO GERAL

A revisão de literatura que compôs o capítulo 1 do presente trabalho nos permitiu ratificar que o reparo tecidual é um processo biológico finamente regulado por células e moléculas sinalizadoras, entre as quais, destacam-se as proteínas da via Hedgehog. No entanto, há escassez de estudos que abordam a participação desta via sob a influência da laserterapia.

A técnica de imuno-histoquímica contribuiu para a visualização da expressão fenotípica das proteínas estudadas na fase tardia da cicatrização fotobiomodulada.

Observou-se que no modelo experimental de cicatrização cutânea, houve uma diminuição inicial de células T CD8+ no grupo submetido ao laser com posterior aumento destas até o período de 28 dias, o que sugere a sua ação imunoreguladora neste processo biológico, em especial no tocante à sua inter-relação com as células T CD68+.

Na fase de remodelamento do reparo tecidual houve continuidade do processo de neoangiogênese confirmado através da presença de células CD31+, actina alfa de músculo liso e NG2+ no microambiente da área de fibroplasia, tanto para os animais controle quanto os tratados com laser. Contudo, no grupo irradiado, este evento ocorreu mais precocemente.

Os níveis sanguíneos de IL-2 e IL-10 foram indetectáveis em ambos os grupos experimentais e não houve diferenças estatisticamente significativas no perfil de expressão de IL-4 e IFN ɣ entre os grupos de estudo. Tal fato sugere que na etapa tardia da cicatrização, o efeito sistêmico desencadeado pelo TLBP seja atenuado e que as alterações locais sejam mais evidentes e se perpetuem por mais tempo a partir da dosimetria inicial empregada no tecido.

Os eventos que ocorrem no reparo tecidual parecem ser cíclicos e continuam se desenvolvendo no tecido, independente do aspecto clínico da lesão que evidencia o seu fechamento e completa cicatrização.

Houve indícios da ativação da via de sinalização Hedgehog na etapa de remodelamento da matriz, haja vista a presença de células Ptch +, Ihh+ e Gli-2+. Porém, a expressão de Ihh e Ptch parece não ter sido fotobiomodulada, uma

vez que não houve diferenças estatisticamente significativas entre os grupos experimentais.

Em relação à ativação da via de sinalização Hedgehog no estudo realizado em mucosa oral humana, observou-se que esta pareceu influenciar positivamente a transformação neoplásica, uma vez que houve aumento progressivo de células Hedgehog positivas nas lesões pré-cancerizáveis presentes no mesmo indivíduo. Tanto o epitélio quanto a matriz conjuntiva participaram deste processo.

Os resultados preliminares do presente estudo experimental, referentes à via de sinalização Hedgehog, fortalecem a necessidade da realização de investigações que contemplem os períodos iniciais do processo de cicatrização cutânea.

REFERÊNCIAS

Abreu MAMM, Silva OMP, DRN Pimentel, Hirata CHW, Weckx LLM, Alchorne MMA, Michalany NS et al. Actinic cheilitis adjacent to squamous carcinoma of the lips as an indicator of prognosis. Rev Bras Otorrinolaringol

2006;72(6):767-71.

African Journal of Child and Adolescent Psychiatry, 7: 75–88.

Alon R, Nourshargh S. Learning in motion: pericytes instruct migrating innate leukocytes. Nature Immunol 2013;4(1):14-15.

Altaba AR, Sánchez P &Dahmane N. Gli and Hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. 2002; (2):361-72.

Andrade, Z A Double and paradoxical role for angiogenesis Rev Patol Trop 2013; 42 (3): 259-264.

Armulik A, Genove G, Betsholtz C. Pericytes: Developmental, Physiological and Pathological Perspectives, Problems and Promises. Dev Cell 2011;21:193-215. Athar, M; Tang, X; Lee, J L; Kopelovich, L; Kim, A L Hedgehog signalling in skin development and cancer Experimental Dermatology 2006; 15: 667-677. Badylak SF The extracellular matrix as a scaffold for tissue reconstruction. Cell Developm Biol 2002;13:377–383.

Barboul, A; Breslin, R J; Woodyard, J P; Wasserkrug, H L;Efron, G The effect of in vivo T helper and T supressor Lymphocyte depletion on wound healing

Annals of Surgery 1989; 209(4): 479- 483.

Bielefeld, K A; Amini-Nik, S; Alman, B A Cutaneous wound healing: recruiting developmental pathways for regeneration Cellular and Molecular Life Sciences 2013; 70: 2059-2081.

Boyce, D E; Jones, W D; Ruge, F; Harding, K G; Moore, K The role of

lymphocytes in human dermal wound healing British Journal of Dermatology 2000; 143: 59-65.

Buckley C. Why does chronic inflammation persist: na unexpected role of fibroblastos. Immunol Lett. 2011;138:12-14.

Buim MEC, Gurgel CAS, Ramos EAG, Lourenço SV & Soares FA. Activation of sonic Hedgehog signaling in oral squamous cell carcinomas: a preliminary study. Human Pathology 2011;42:1484–90.

Byrd, N & Grabel, L Hedgehog signalling in murine vasculogenesis and angiogenesis Trends Cardiovascular Medicine 2004; 14: 308-313.

Calin MA, Coman T, Calin MR. The effect of low level laser therapy on surgical wound healing. Rom Rep in Phys 2010;62(3):617-627.

Carmeliet P. Angiogenesis in health and disease Nature Med 2003;9(6):653- 660.

Catao, M H C V Os benefícios do laser de baixa intensidade na clínica

odontológica e na estomatologia Revista Bras. de Patol. Oral 2004: 3: 214-8. Cherng, S; Young, J; Ma, H Alpha-smooth muscle actin The Journal of

American Science 2008; 4(4): 7-9.

Choi S, Diehl AM. Epithelial-to-Mesenchymal transitions in liver. Hepatology. 2009;50:2007–2013.

Cohen Jr MM. Hedgehog signaling update. Am J Med Gen 2010;152(8):1875– 1914.

Crocker DJ, Murad TM, Geer JC. Role of the pericyte in wound healing an ultrastructural study. Exp Mol Pathol 1970;13:51-65.

Dahmane N, Lee J, Robins P, Heller P &Altaba AR. Activation of the transcription factor Gli1 and the Sonic Hedgehog signaling pathway in skin tumours. Nature 1997;389(23):878-81.

Dassule HR, Lewis P, Bei M, Maas R & McMahon AP. Sonic Hedgehog regulates growth and morphogenesis of the tooth. Development

2000;127:4775-85.

Dederich DN, Bushick RD. Lasers in dentistry: separating science from hype. Journal Am Dent Assoc 2004; 135(2): 204-212.

Delavary, B M; Veer, W M; Egmond, M; Niessem, F B; Beelen, R H

Macrophages in skin injury and repair Immunobiology 2011; 216: 753-762. DeRouen MC, Oro AE. The primary cillium: a small yet mighty organelle. J Invest Dermatol 2009; 129(2): 264-265.

Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, et al. Sonic Hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993;75(7): 1417–1430.

Eming S, Krieg T, Davidson J. Inflammation in wound repair: molecular and cellular mechanisms. Journal Invest Dermatol 2007;127:514-525.

Enwemeka CS; Parker JC, Dowdy DS, Harkness EE, Sanford LE, Woodruff LD. The efficacy of low-power lasers in tissue repair and pain control. A meta-

analysis study. Photomedicine Laser Surg 2004; 22:323-329.

Fan HX, Wang S, Zhao H, Liu N, Chen D, Sun M et al. Sonic Hedgehog signaling may promote invasion and metastasis of oral squamous cell

carcinoma by activating MMP-9 and E-cadherin expression. Med Oncol 2014; 31(41): 1-8.

Farrington-Rock C, Crofts NJ, Doherty MJ, Ashton BA, Phil D, Griffi-Jones C, Canfield AE. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 2004;110:2226-2232.

Felice, T; Pinheiro, A; Menchik, E; Silva, A; Souza, L; Caires, C; Abel, A; Bartemeyer, C; Oliveira, J; Assis, T; Silva, L; Lopes, T; Felippe, L; Pinheiro A utilização do laser de baixa potência na Cicatrização de feridas Interbio 2009; 3 (2): 42-52.

Fonseca MA, Almeida RR, Reis SRA, Medrado ARAP. Repercussão de doenças sistêmicas no reparo tecidual. Rev Bahian Odont 2012;3(1):63-75. Friedman SL. Mechanisms of hepatic fibrogenesis Gastroenterology

2008;134:1655-1669.

Fung DTC, NG GYF, Leung MCP, Tay DKC. Effects of a therapeutic laser on the ultrastructural morphology of repairing medial collateral ligament on a rat model. Lasers Surg Med 2003; 32:286-293.

Gailani MR, Bale SJ, Leffell DJ, DiGiovanna JJ, Peck GL, et al. Developmental defects in Gorlin Syndrome related to a putative tumor suppressor gene on chromosome 9. Cell 1992; 3(69):11-17.

Gál, P; Vidinsky, B; toporcer, T; Mokry, M; Mozes, S; Longauer, F Histological assessement of the effect of laser irradiation on skin wound healing in rats Photomedicine and Laser Surgery 2006: 24(4): 480-488.

Garavello I, Baranauskas V, da Cruz-Hofling MA. The effects of low laser

irradiation on angiogenesis in injured rat tibiae. Histol Histopathol 2004; 19(1): 43-48.

Gomes APN, Johann JE, Lovato GG, Ferreira AM. Comparative Analysis of the Mast Cell Density in Normal Oral Mucosa, Actinic Cheilitis and Lip Squamous Cell Carcinoma. Braz Dent J 2008;19(3):186-189.

Gonçalves RV, Souza NTA, Silva PH, Barbosa FS, Neves CA. Influência do laser de arseneto de gálio-alumínio em feridas cutâneas de ratos. Fisoter Mov 2010;23(3):381-388.

Gurgel CAS, Buim MEC, Carvalho KC, Sales CBS,Reis MG, Souza RO et al. Transcriptional profiles of SHH pathway genes in keratocystic odontogenic tumor and ameloblastoma. J Oral Pathol Med 2014;43:619–626.

Gurtner GC, Werner S, Barrandon Y, Longaker M. Wound Repair and Regeneration. Nature 2008;453:314-321.

Histological assessement of the effect of laser irradiation on skin wound healing in rats. Photomedicine and Laser Surgery. 2006; 24(4): 480-488. Hoff DD, Lo Russo PM, Rudin CM, Reddy JC, Launch RL, Tibes R, et al.

Inhibition of the Hedgehog Pathway in advanced Basal-Cell Carcinoma. N Engl J Med. 2009;361(9):1164-72.

Houreld, N N; Ayuk, S M; Abrahamse, H Expression of genes in normal fibroblasts cells (WS1) in response to irradiation at 660 nm Journal of Photochemistry and Photobiology B: Biology 2014; 130: 146-152.

Hu X, Zhang S, Chen G, Lin C, Huang Z, Chen Y et al. Expression of SHH signaling molecules in the developing human primary dentition. BMC Developmental Biol. 2013;13(11);1-8.

Hwang J, Kang MH, Yoo YA, Quan YH, Kim HK, Oh SC. The effects of sonic Hedgehog signaling pathway components on non-small-cell lung cancer transformation and clinical outcome. World J Surg Oncol 2014, 12:268. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes & Dev. 2001;15:3059-3087.

Inghan, P W; Nakano, Y; Seger, C Mechanisms and functions of Hedgehog signaling across the metazoan Nature Reviews Genetcs 2011; 12: 393-406. Isaac C, Ladeira PRS, Rego FMP, Aldunate JCB, Ferreira MC. Processo de cura das feridas: Cicatrização Fisiológica. Rev. Med. 2010; 89(3/4):125-131. Isohata N, Aoyagi K, Mabuchi T, Daiko H, Fukaya M, Ohta H et al. Hedgehog and epithelial-mesenchymal transition signaling in normal and malignant epithelial cells of the esophagus. Int J Cancer 2009;125:1212-1221.

King PJ, Guasti L, Laufer E. Hedgehog signalling in endocrine development and disease. J Endocrinol.2008;198(3):439-50.

Kitamoto HN, Nagata M, Nagano S, Kitamoto S, Ishidou Y, Yamamoto T et al. GLI2 is a novel therapeutic target for metastasis of osteosarcoma. Int. J. Cancer 2014;00, 00–00.

Le H, Kleinerman R, Lerman OZ, Gurtner GC, Warren SM, Levine JP et al. Hedgehog signaling is essential for normal wound healing. Wound Rep Reg 2008;16:768–773.

Lee, J S; Semela, D; Iredale, J; Shah, V H Sinusoidal remodeling and angiogenesis: a new function for the liver-specific pericyte? Journal of Hepatology 2007; 45: 817-823.

Li J, Chen J, Kirsner R. Pathophisiology of acute wound healing. Clin Dermatol 2007;25:9-18.

Liu J, Cao J, Zhao X. miR-221 facilitates the TGFbeta1-induced epithelial- mesenchymal transition in human bladder cancer cells by targeting STMN1. BMC Urol 2015;28(15):1-9.

Luo J-D, Hu T-P, Wang L, Chen M-S, Liu S-M, Chen AF. Sonic Hedgehog improves wound healing via enhancing cutaneous nitric oxide function in diabetes. Am J Physiol. Endocrinol Metab 2009;297:525-531.

Maier T, Kulichova D, Ruzicka T &Berking C. Noninvasive monitoring of basal cell carcinomas treated with systemic Hedgehog inhibitors: Pseudocysts as a sign of tumor regression. J Am Acad Dermatol 2014;4(71):725-30.

Markopoulos A, Albanidou-Farmaki E &Kayavis I.Actinic cheilitis: clinical and pathologic characteristics. Oral dis. 2004;10:212–6.

Marques KP, Lorenço VS, Silva LFF, Sotto MN, Carneiro PC. Actinic lesions in fishermen’s lower lip: clinical, cytopathological and histopathologic analysis. CLINICS 2010;65(4):363-7.

Martin P. Wound Healing - Aiming for a perfect skin regeneration. Science 1997;276:75-81.

Mason DE, Mitchell KE, Li Y, Finley MR, Freeman LC. Molecular basis of voltage-dependent potassium currents in porcine granulosa cells. Mol Pharmacol. 2002 Jan;61(1):201-13.

Medrado AP, Costa T, Prado T, Reis SRA, Andrade ZA. Phenotype characterization of pericytes during tissue repair following low-level laser

therapy. Photodermatol Photoimmunol Photomed 2010;26:192-197. Medrado ARAP, Pugliese LS, Reis SRA, Andrade ZA. Influence of low level laser therapy on wound healing and its biological action upon myofibroblasts. Lasers Surg Med 2003;32:239-244.

Medrado ARAP, Trindade E, Reis SRA. Andrade ZA Action of low-level laser therapy on living fatty tissue of rats. Lasers Med Sci 2006; 21:19-23.

Medrado, A P; Soares, A P ; Santos, E T; Reis, S R A; Andrade, Z A Influence of laser photobiomodulation upon connective tissue remodeling during wound healing Journal of Photochemistry and Photobiology B: Biology 2008; 92(3): 144-152.

Medrado, A R A P; Trindade, E; Reis, S R A; Andrade, Z A. Action of low-level laser therapy on living fatty tissue of rats. Lasers Med Sci 2006; 21: 19-23. Mendonça RJ, Coutinho-Netto J. Aspectos celulares da cicatrização. An Bras Dermatol 2009;84(3):257-262.

Mester E, Lúdany G, Sellyei M, Szende B, Tota J. The stimulating effect of low power laser rays on biological systems. Laser Rev 1968; 1:3.

Mester E, Spiry T, Szende B, Tota JG. Effect of laser rays on wound healing. Am J Surg 1971; 122(4):532-535.

Midwood KS, Williams LV, Schwarzbauer JE. Tissue repair and the dynamics of the extracellular matrix. Int J iochem Cell Biol 2004;36:1031–1037.

Mitchel RN, Kumar V,Abbas AK, Fausto N, Aster JC Robbins and Cotran: Pathologic. Basis of disease . 8 ed, Philadelphia; 2012.

Nayac BS, Sandifor S, Maxiwell A. Evaluation of wound healing of ethanolic extract of Morinda cetrifolia L leaf. Evid Based Complement Alternat Med. 2009;6(3):351-356.

Nunes PS, Albuquerque-Junior RLC, Cavalcante DRR, Dantas MDM, Cardoso JC, Bezerra MS et al. Collagen-based films containing liposomes loaded using acid as dressing for dermal burn healing. J Biomed Biotech 2011;2011:01-09. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment and polarity in Drosophila. Nature. 1980; 287 (10): 795-801.

Nybakken K, Perrimon N. Hedgehog signal transduction: recent findings. Curr. Opin. Genet. Dev. 2002;2(5):503-511.

Omenetti A, Choi S, Michelotti G, Diehl AM. Hedgehog signaling in the liver. J. Hepatol 2011; 54(2):336-373.

Paiva MAF, Soares MSM, Figueiredo CRLV, Luna AH, Oliveira VEN, et al. Associação entre displasia e inflamação em queilite actínica. Bras Patol Med Lab 2012;6(48):455-8.

Park, J E & Barbul, A Understanding the role of immune regulation in wound healing The American Journal of Surgery 2004; 187: 11S-16S.

Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, et al. Identification of a palmitic acid-modified form of human Sonic Hedgehog. J Biol Chem. 1998;273(22):14037-45.

Pereira, A N P; Eduardo, C P; Matson, E; Marques, M M. Effect of Low-Power Laser irradiation on cell growth and procolagen synthesis of cultured fibroblasts. Lasers Surg Med 2002; 31:263-267.

Pinter M, Prager G, Sieghart W, Dienes HP, Schmid M, Trauner M et al.

Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF- A expression in hepatocellular carcinoma. United European Gastroenterol J 2013;265-75.

Prockt AP, Takahashi A, Pagnoncelli RM. Uso da terapia com laser de baixa intensidade na cirurgia bucomaxilofacial. Rev Port Estomatol Ci Maxilofac 2008; 49(4): 247-255.

Pugliese LS, Medrado ARAP, Reis SRA, Andrade ZA. The influence of therapy of laser of low level in biomodulation of collagen and elastic fibers. Pesqui Odontol Bras 2003;17(4):307-313.

Raitz, R O papel da matriz extracellular ma cicatrização de feridas bucais Revista Inst Ciênc Saúde 2008; 26 (3): 351-356.

Raphael I, Nalawade S, Eagar TN, Forsthuber TG T cells subsets and theur signature cytokines in autoimmune and inflammatory diseases. Cytokine 2015; 74: 5-17.

Reddy GK. Comparison of the photostimulatory effects of visible He-Ne and infrared Ga-As lasers on healing impaired diabetic rat wounds. Lasers Surg Med 2003; 33(5): 344-351.

Reis SRA, Medrado ARAP, Marchionni AMT, Figueira C, Fracassi LD, Knop LAH. Effect of 670-nm laser therapy and dexamethasone on tissue repair: a histological and ultrastructural study. Photomed Laser Surg 2008; 26:307- 313.

Reis, S R A; Medrado, A P; Marchionni, A M T; Figueira, C; Fracassi, L D; Knop, L A H. Effect of low level laser therapy and dexametasone on tissue repair: a histologic and histologic and ultrastructural study. Lasers Surg Med 2006

Ribatti D, Nico B, Crivelatto E. The role of pericytes in Angiogenesis. Int J Dev Biol 2011; 55: 261-268.

Rocha Jr, A M; Oliveira, R G; Farias, R E; Andrade, L C F; Aarestrup, F M Modulação da proliferação fibroblástica e da resposta inflamatória pela terapia a laser de baixa intensidadeno processo de reparo tecidual Anais Brasileiros de Dermatologia 2006; 81(2): 150-156.

Rodero MP, Khosrotehrani K. Skin wound healing modulation by macrophages. Int J Clin Exp Pathol. 2010;3(7):643–653.

Rodrigo, S M; Cunha, A; Pozza, D H; Blaya, D S; Moraes, J F; Weber, J B B; Oliveira, M G Analysis of the systemic effect of red and infrared laser therapy on wound repair Photomedicine and Laser Surgery 2009; 27(6): 929-935. Rosen LS. Clinical experience with angiogenesis signaling inhibitors:focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control 2002; 9(2):36-44.

Rutter DJ, Schlingemann RO, Westphal JR, Rietveld EJR, de Waal RMW. Angiogenesis in wound healing and tumor metastasis. Behring Inst Mitt, 1993; 92:258-272.

Sampaio SA, Rivitti E. Dermatologia. 2a ed. São Paulo: Artes Médicas; 2001. Schindl A, Schindl L, Jurecka W, Honisgsmann H, Breier F. Increased dermal angiogenesisafter low-intensity laser therapy for a chronic radiation ulcer

determined by a video measuring system. J acad Dermatol 1999; 40:481-484. Schneider S, Thurnher D, Kloimstein P, Leitner V, Petzelbauer P, Pammer J. Expression of the sonic Hedgehog pathway in squamous cell carcinoma of the skin and the mucosa of the head and neck. Inc. Head Neck 2011;33:244–250.

Sekulic A, Mangolda AR, Northfeltb DW &LoRussoc PM. Advanced basal cell carcinoma of the skin: targeting the Hedgehog pathway. Curr Opin Oncol 2013; 25:218–223.

Shaw T, Martin P. Wound repair at a glance. J Cell Sci. 2009;122(18):3209- 13.

Shi Y, Shu B, Yang R, Xu Y, Xing B, Liu J, Chen L, Qi S, Liu X, Wang P, Tang J, Xie J. Wnt and Notch signaling pathway involved in wound healing by targeting separately c-Myc and Hes1. Stem Cell Res Ther 2015;6(1):120. Sicklick J, Li Y, Jayaraman A, Kanngai R, Qi Y, Vivekanadan P, Ludlow JW, Owzar K, et al. Dysregulation of the Hedgehog pathway in human

hepatocarcinogenesis Carcinogenesis 2006;27(4):746-757.

Singer A, Clark R. Cutaneous Wound Healing. N Engl J Med 1999;341(10):738- 746.

Souza, N H C; Ferrari, R A M; Silva, D F T; Nunes, F D; Bussadori, S K; Fernandes, K P S Effect of low-level laser therapy on the modulation of

mitochondrial activity of macrophages Brazilian Journal of Physical Therapy 2014; 18(40: 308-314.

Takakura N. Role of hematopoietic lineage cells as accessory components in blood vessel formation. Cancer Sci 2006;97:568-574.

Tazima MFGS, Vicente YAMV, Moriya T. Biologia da Ferida e

Cicatrização Simpósio – Fundamentos em Clínica Cirúrgica 2008; 4(3): 259- 264.

Teglund S, Toftgard R. Hedgehog beyond medulloblastoma and basal cell carcinoma Biochim. Biophys. Acta 2010;181–208.

Thuraisingam T, Xu YZ, Eadie K. MAPKAPK-2 signaling is critical for cutaneous wound healing. J Invest Dermato 2010: 130:278-278.

Tidball JG. Inflammation process in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 2005;288:345-353.

Tidball, J G Inflammation process in muscle injury and repair American

Journal of Physiology Regulation Integrative and Comparative Physiology 2005; 288: 345-353.

Tome-Garcia J, Ghazaryan S, Shu L, Wu L. ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells. PLoS One 2014;9(6):1-12.

Tonnesen M, Feng X, Clark R. Angiogenesis in wound healing. JID Symp Proc 2000;5(1):40-46.

Velnar, T; Bailley, T; Smrkolj, V The wound healing process: an overview of the cellular and molecular mechanisms The Journal of International Medical Research 2009; 37:1528-1542.

Vilela DDC, Chamusca FV, Andrade JCS, Vallve MLF, Gonzalez AC, Andrade ZA, Medrado ARAP, Reis SRA. Influence of the HPA axis on the inflammatory response in cutaneous wounds with the use of 670-nm laser

photobiomodulation. Journal Photochemistry Photobiology B:Biology 2012; 116: 114-120.

Wang YF, Chang CJ, Lin CP, Chang SY, Chu PY, Tai SK, et al. Expression oh Hedgehog signaling molecules as a prognostic indicator of oral squamous cell carcinoma. Head Neck. 2012; 34(11):1556-61.

Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, et al. Pericytes limit tumor cell metastasis. J Clin Invest 2006;116:642-651.

Yan M, Wang L, Zuo H, Zhang Z, Chen W, Mao L, et al. HH/GLI signaling as a new therapeutic target for patients with oral squamous cell carcinoma. Oral Oncol. 2011;47(6):504-9.

Yasukawa A, Hrui H, Koyama Y, Nagai M, Takakuda K. The effect of low reactive-level laser therapy (LLLT) with helium-neon laser on operative wound healing in a rat model. J Vet Med Sci 2007; 69(8): 799-806.

Zedan W, Robinson A, Markham AF & High AS. Expression of the Sonic Hedgehog receptor ‘PATCHED’. J Pathol 2001;194:473–477.

Zeisberg M, Neilson EG. Biomarkers of epithelial-mesenchymal transitions. J Clin Invest 2009;119(6):142

Zeng C, Wang Y, Lu Q, Chen J, Zhang J, Liu T et al. SPOP suppresses

tumorigenesis by regulating Hedgehog/Gli2 signaling pathway in gastric cancer. J Exp Clin Cancer Res 2014; (75)1-12.

Zhang L, Sun ZL, Chen XM & Chen Z. Immunohistochemical expression of SHH, PTC, SMO and GLI1 in glandular odontogenic cysts and dentigerous cysts. Oral Dis. 2010;16:818–22.

Documentos relacionados