nach oben

Erschienen in:

17.10.2018 | Original Article

Hedgehog signaling pathway and vitamin D receptor gene variants as potential risk factors in odontogenic cystic lesions

verfasst von: Marko Magic, Katarina Zeljic, Stevo Jovandic, Jelena Stepic, Marko Pejovic, Snjezana Colic, Zvonko Magic, Gordana Supic

Erschienen in: Clinical Oral Investigations | Ausgabe 6/2019

Einloggen, um Zugang zu erhalten

Abstract

Objectives

Genetic variants in the hedgehog signaling pathway and VDR gene are involved in inflammatory responses and neoplastic transformation. Current study investigated whether single-nucleotide polymorphisms in the hedgehog pathway genes PTCH1, GLI1, SMO, and VDR contribute to susceptibility to odontogenic cystic lesions, odontogenic keratocysts, or inflammatory radicular cysts.

Material and methods

Current study examined polymorphisms of PTCH1 (rs357564) and PTCH1 insertion (IVS1-83), GLI1 (rs2228224, rs2228226), SMO (rs2228617), and VDR (rs2228570, rs731236, rs7975232). A case-control study was conducted on 41 keratocyst cases, 43 radicular cyst cases, and control group of 93 healthy individuals without cystic lesions, radiographically confirmed. Single-nucleotide polymorphisms were assessed by real-time and TaqMan SNP genotyping assays, while PTCH1 insertion 18 bp IVS1-83 polymorphism was determined by PCR.

Results

The difference in genotype distribution between keratocyst cases and control group was observed for PTCH1 IVS1-83 and GLI1 rs2228224 polymorphism (p = 0.022, p = 0.030, respectively). Homozygous mutant GG genotype within GLI1 rs2228224 is associated with increased susceptibility for odontogenous keratocysts, with adjusted odds ratio of 4.098 (confidence interval of 1.482–11.328, p = 0.007).

Conclusion

GLI1 rs2228224 and PTCH1 polymorphisms could predispose to odontogenic keratocysts.

Clinical relevance

Variants in hedgehog signaling pathway genes, such as GLI1 and PTCH1, and vitamin D receptor gene, might be considered as molecular risk factors in odontogenic cystic lesions and potential targets for novel therapeutic approaches.

Nur mit Berechtigung zugänglich

Bilodeau EA, Collins BM (2017) Odontogenic cysts and neoplasms. Surg Pathol Clin 10(1):177–222. https://doi.org/10.1016/j.path.2016.10.006

Nayak MT, Singh A, Singhvi A, Sharma R (2013) Odontogenic keratocyst: what is in the name? J Nat Sci Biol Med 4(2):282–285. https://doi.org/10.4103/0976-9668.116968

Speight PM, Takata T (2017) New tumour entities in the 4th edition of the World Health Organization classification of head and neck tumours: odontogenic and maxillofacial bone tumours. Virchows Arch 472:331–339. https://doi.org/10.1007/s00428-017-2182-3

Grachtchouk M, Liu J, Wang A, Wei L, Bichakjian CK, Garlick J, Paulino AF, Giordano T, Dlugosz AA (2006) Odontogenic keratocysts arise from quiescent epithelial rests and are associated with deregulated hedgehog signaling in mice and humans. Am J Pathol 169(3):806–814. https://doi.org/10.2353/ajpath.2006.060054 CrossRefPubMedPubMedCentral

Shimada Y, Katsube K, Kabasawa Y, Morita K, Omura K, Yamaguchi A, Sakamoto K (2013) Integrated genotypic analysis of hedgehog-related genes identifies subgroups of keratocystic odontogenic tumor with distinct clinicopathological features. PLoS One 8(8):e70995. https://doi.org/10.1371/journal.pone.0070995 CrossRefPubMedPubMedCentral

Gorlin RJ, Goltz RW (1960) Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. New Engl J Med 262:908–912. https://doi.org/10.1056/NEJM196005052621803 CrossRefPubMed

Aiello NM, Stanger BZ (2016) Echoes of the embryo: using the developmental biology toolkit to study cancer. Dis Model Mech 9(2):105–114. https://doi.org/10.1242/dmm.023184 CrossRefPubMedPubMedCentral

Rahnama F, Shimokawa T, Lauth M, Finta C, Kogerman P, Teglund S, Toftgard R, Zaphiropoulos PG (2006) Inhibition of GLI1 gene activation by Patched1. The Biochem J 394(Pt 1):19–26. https://doi.org/10.1042/BJ20050941

Zhang T, Chen M, Lu Y, Xing Q, Chen W (2011) A novel mutation of the PTCH1 gene activates the Shh/Gli signaling pathway in a Chinese family with nevoid basal cell carcinoma syndrome. Biochem Biophys Res Commun 409(2):166–170. https://doi.org/10.1016/j.bbrc.2011.04.047 CrossRefPubMed

10.

Ohki K, Kumamoto H, Ichinohasama R, Sato T, Takahashi N, Ooya K (2004) PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. Int J Oral Maxillofac Surg 33(6):584–592. https://doi.org/10.1016/j.ijom.2004.01.013 CrossRefPubMed

11.

Mizuochi H, Fujii K, Shiohama T, Uchikawa H, Shimojo N (2015) Hedgehog signaling is synergistically enhanced by nutritional deprivation and ligand stimulation in human fibroblasts of Gorlin syndrome. Biochem Biophys Res Commun 457(3):318–323. https://doi.org/10.1016/j.bbrc.2014.12.108 CrossRefPubMed

12.

Jacob J, Briscoe J (2003) Gli proteins and the control of spinal-cord patterning. EMBO Rep 4(8):761–765. https://doi.org/10.1038/sj.embor.embor896 CrossRefPubMedPubMedCentral

13.

Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone P (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277(7):5548–5555. https://doi.org/10.1074/jbc.M105708200 CrossRefPubMed

14.

Bigelow RL, Chari NS, Unden AB, Spurgers KB, Lee S, Roop DR, Toftgard R, McDonnell TJ (2004) Transcriptional regulation of bcl-2 mediated by the sonic hedgehog signaling pathway through gli-1. J Biol Chem 279(2):1197–1205. https://doi.org/10.1074/jbc.M310589200 CrossRefPubMed

15.

Louro ID, Bailey EC, Li X, South LS, McKie-Bell PR, Yoder BK, Huang CC, Johnson MR, Hill AE, Johnson RL, Ruppert JM (2002) Comparative gene expression profile analysis of GLI and c-MYC in an epithelial model of malignant transformation. Cancer Res 62(20):5867–5873PubMed

16.

Vered M, Peleg O, Taicher S, Buchner A (2009) The immunoprofile of odontogenic keratocyst (keratocystic odontogenic tumor) that includes expression of PTCH, SMO, GLI-1 and bcl-2 is similar to ameloblastoma but different from odontogenic cysts. J Oral Pathol Med 38(7):597–604. https://doi.org/10.1111/j.1600-0714.2009.00778.x

17.

Hadden MK (2016) Hedgehog and vitamin D signaling pathways in development and disease. Vitam Horm 100:231–253. https://doi.org/10.1016/bs.vh.2015.10.006 CrossRefPubMed

18.

Bandera Merchan B, Morcillo S, Martin-Nunez G, Tinahones FJ, Macias-Gonzalez M (2017) The role of vitamin D and VDR in carcinogenesis: through epidemiology and basic sciences. J Steroid Biochem Mol Biol 167:203–218. https://doi.org/10.1016/j.jsbmb.2016.11.020 CrossRefPubMed

19.

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265. https://doi.org/10.1093/bioinformatics/bth457 CrossRefPubMed

20.

Lou XY, Chen GB, Yan L, Ma JZ, Mangold JE, Zhu J, Elston RC, Li MD (2008) A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies. Am J Hum Genet 83(4):457–467. https://doi.org/10.1016/j.ajhg.2008.09.001 CrossRefPubMedPubMedCentral

21.

Chen GB, Xu Y, Xu HM, Li MD, Zhu J, Lou XY (2011) Practical and theoretical considerations in study design for detecting gene-gene interactions using MDR and GMDR approaches. PLoS One 6(2):e16981. https://doi.org/10.1371/journal.pone.0016981 CrossRefPubMedPubMedCentral

22.

Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC (2006) A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 241(2):252–261. https://doi.org/10.1016/j.jtbi.2005.11.036 CrossRefPubMed

23.

Fu X, Wang Q, Chen X, Huang X, Cao L, Tan H, Li W, Zhang L, Bi J, Su Q, Chen L (2008) Expression patterns and polymorphisms of PTCH in Chinese hepatocellular carcinoma patients. Exp Mol Pathol 84(3):195–199. https://doi.org/10.1016/j.yexmp.2008.04.002 CrossRefPubMed

24.

Lees CW, Zacharias WJ, Tremelling M, Noble CL, Nimmo ER, Tenesa A, Cornelius J, Torkvist L, Kao J, Farrington S, Drummond HE, Ho GT, Arnott ID, Appelman HD, Diehl L, Campbell H, Dunlop MG, Parkes M, Howie SE, Gumucio DL, Satsangi J (2008) Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways. PLoS Med 5(12):e239. https://doi.org/10.1371/journal.pmed.0050239 CrossRefPubMedPubMedCentral

25.

Yadav A, Gupta A, Yadav S, Rastogi N, Agrawal S, Kumar A, Kumar V, Misra S, Mittal B (2016) Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival. Tumour Biol 37(6):8083–8095. https://doi.org/10.1007/s13277-015-4728-9 CrossRefPubMed

26.

Li YY, Tian T, Zhang R, Wang L, Xu J, Fan L, Li JY, Xu W (2014) Association between polymorphism of GLI1 gene SNP rs2228226 and chronic lymphocytic leukemia in Chinese population. Med Oncol (Northwood, London, England) 31(12):294. https://doi.org/10.1007/s12032-014-0294-z CrossRef

27.

Lim CB, Prele CM, Cheah HM, Cheng YY, Klebe S, Reid G, Watkins DN, Baltic S, Thompson PJ, Mutsaers SE (2013) Mutational analysis of hedgehog signaling pathway genes in human malignant mesothelioma. PLoS One 8(6):e66685. https://doi.org/10.1371/journal.pone.0066685 CrossRefPubMedPubMedCentral

28.

Rukin NJ, Strange RC (2007) What are the frequency, distribution, and functional effects of vitamin D receptor polymorphisms as related to cancer risk?. Nutr Rev 65 (8 Pt 2):S96–101

29.

Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP (2004) Genetics and biology of vitamin D receptor polymorphisms. Gene 338(2):143–156. https://doi.org/10.1016/j.gene.2004.05.014 CrossRefPubMed

30.

Zeljic K, Supic G, Stamenkovic Radak M, Jovic N, Kozomara R, Magic Z (2012) Vitamin D receptor, CYP27B1 and CYP24A1 genes polymorphisms association with oral cancer risk and survival. J Oral Pathol Med 41(10):779–787. https://doi.org/10.1111/j.1600-0714.2012.01164.x CrossRefPubMed

31.

Kujundzic B, Zeljic K, Supic G, Magic M, Stanimirovic D, Ilic V, Jovanovic B, Magic Z (2016) Association of vdr, cyp27b1, cyp24a1 and mthfr gene polymorphisms with oral lichen planus risk. Clin Oral Investig 20(4):781–789. https://doi.org/10.1007/s00784-015-1572-7 CrossRefPubMed

32.

Zhu H, Lo HW (2010) The human glioma-associated oncogene homolog 1 (GLI1) family of transcription factors in gene regulation and diseases. Curr Genomics 11(4):238–245. https://doi.org/10.2174/138920210791233108

33.

Balding DJ (2006) A tutorial on statistical methods for population association studies. Nat Rev Genet 7(10):781–791. https://doi.org/10.1038/nrg1916 CrossRefPubMed

34.

Cordell HJ (2009) Detecting gene-gene interactions that underlie human diseases. Nat Rev Genet 10(6):392–404. https://doi.org/10.1038/nrg2579 CrossRefPubMedPubMedCentral

35.

Liboutet M, Portela M, Delestaing G, Vilmer C, Dupin N, Gorin I, Saiag P, Lebbe C, Kerob D, Dubertret L, Grandchamp B, Basset-Seguin N, Soufir N (2006) MC1R and PTCH gene polymorphism in French patients with basal cell carcinomas. J Invest Dermatol 126(7):1510–1517. https://doi.org/10.1038/sj.jid.5700263

36.

Guo YY, Zhang JY, Li XF, Luo HY, Chen F, Li TJ (2013) PTCH1 gene mutations in Keratocystic odontogenic tumors: a study of 43 Chinese patients and a systematic review. PLoS One 8(10):e77305. https://doi.org/10.1371/journal.pone.0077305 CrossRefPubMedPubMedCentral

37.

Gu XM, Zhao HS, Sun LS, Li TJ (2006) PTCH mutations in sporadic and Gorlin-syndrome-related odontogenic keratocysts. J Dent Res 85(9):859–863. https://doi.org/10.1177/154405910608500916 CrossRefPubMed

38.

Yoon JW, Liu CZ, Yang JT, Swart R, Iannaccone P, Walterhouse D (1998) GLI activates transcription through a herpes simplex viral protein 16-like activation domain. J Biol Chem 273(6):3496–3501CrossRefPubMed

39.

Huntzicker EG, Estay IS, Zhen H, Lokteva LA, Jackson PK, Oro AE (2006) Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 20(3):276–281. https://doi.org/10.1101/gad.1380906 CrossRefPubMedPubMedCentral

40.

Szkandera J, Pichler M, Absenger G, Stotz M, Weissmueller M, Samonigg H, Asslaber M, Lax S, Leitner G, Winder T, Renner W, Gerger A (2014) A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients. Clin Cancer Res 20(6):1687–1697. https://doi.org/10.1158/1078-0432.ccr-13-1517 CrossRefPubMed

41.

Albert B, Hahn H (2014) Interaction of hedgehog and vitamin D signaling pathways in basal cell carcinomas. Adv Exp Med Biol 810:329–341PubMed

42.

Alimirah F, Peng X, Gupta A, Yuan L, Welsh J, Cleary M, Mehta RG (2016) Crosstalk between the vitamin D receptor (VDR) and miR-214 in regulating SuFu, a hedgehog pathway inhibitor in breast cancer cells. Exp Cell Res 349(1):15–22. https://doi.org/10.1016/j.yexcr.2016.08.012 CrossRefPubMed

43.

DeBerardinis AM, Banerjee U, Hadden MK (2013) Identification of vitamin d3-based hedgehog pathway inhibitors that incorporate an aromatic a-ring isostere. ACS Med Chem Lett 4(7):590–595. https://doi.org/10.1021/ml400014t CrossRefPubMedPubMedCentral

44.

DeBerardinis AM, Banerjee U, Miller M, Lemieux S, Hadden MK (2012) Probing the structural requirements for vitamin D3 inhibition of the hedgehog signaling pathway. Bioorg Med Chem Lett 22(14):4859–4863. https://doi.org/10.1016/j.bmcl.2012.05.037 CrossRefPubMed

45.

Uhmann A, Niemann H, Lammering B, Henkel C, Hess I, Rosenberger A, Dullin C, Schraepler A, Schulz-Schaeffer W, Hahn H (2012) Calcitriol inhibits hedgehog signaling and induces vitamin d receptor signaling and differentiation in the patched mouse model of embryonal rhabdomyosarcoma. Sarcoma 2012:357040. https://doi.org/10.1155/2012/357040 CrossRefPubMedPubMedCentral

46.

Ettl T, Gosau M, Sader R, Reichert TE (2012) Jaw cysts - filling or no filling after enucleation? A review. J Craniomaxillofac Surg 40(6):485–493. https://doi.org/10.1016/j.jcms.2011.07.023 CrossRefPubMed

47.

Ihan Hren N, Miljavec M (2008) Spontaneous bone healing of the large bone defects in the mandible. Int J Oral Maxillofac Surg 37(12):1111–1116. https://doi.org/10.1016/j.ijom.2008.07.008 CrossRefPubMed

48.

Chiapasco M, Rossi A, Motta JJ, Crescentini M (2000) Spontaneous bone regeneration after enucleation of large mandibular cysts: a radiographic computed analysis of 27 consecutive cases. J Oral Maxillofac Surg 58(9):942–948; discussion 949. https://doi.org/10.1053/joms.2000.8732 CrossRefPubMed

49.

Motamedi MH, Talesh KT (2005) Management of extensive dentigerous cysts. Br Dent J 198(4):203–206. https://doi.org/10.1038/sj.bdj.4812082 CrossRefPubMed

50.

Pejovic M, Stepic J, Markovic A, Dragovic M, Milicic B, Colic S (2016) Retrospective study of spontaneous bone regeneration after decompression of large odontogenic cystic lesions in children. Vojnosanit Pregl 73(2):129–134CrossRefPubMed

51.

Wang J, Peng Y, Liu Y, Yang J, Ding N, Tan W (2015) Berberine, a natural compound, suppresses hedgehog signaling pathway activity and cancer growth. BMC Cancer 15:595. https://doi.org/10.1186/s12885-015-1596-z CrossRefPubMedPubMedCentral

Titel: Hedgehog signaling pathway and vitamin D receptor gene variants as potential risk factors in odontogenic cystic lesions
verfasst von: Marko Magic
Katarina Zeljic
Stevo Jovandic
Jelena Stepic
Marko Pejovic
Snjezana Colic
Zvonko Magic
Gordana Supic
Publikationsdatum: 17.10.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Clinical Oral Investigations / Ausgabe 6/2019
Print ISSN: 1432-6981
Elektronische ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-018-2686-5

Neu im Fachgebiet Zahnmedizin

19.04.2024 | Vorhofflimmern | Nachrichten

Newsletter bestellen

Springer Medizin

Hedgehog signaling pathway and vitamin D receptor gene variants as potential risk factors in odontogenic cystic lesions

Abstract

Objectives

Material and methods

Results

Conclusion

Clinical relevance

Neu im Fachgebiet Zahnmedizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Invasive Zahnbehandlung: Wann eine Antibiotikaprophylaxe vor infektiöser Endokarditis schützt

Zell-Organisatoren unter Druck: Mechanismen des embryonalen Zahnwachstums aufgedeckt

Die Oralprophylaxe & Kinderzahnheilkunde umbenannt

Newsletter

Springer Medizin

Abstract

Objectives

Material and methods

Results

Conclusion

Clinical relevance

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 6/2019

Psychological symptoms and self-image of patients with complaints attributed to dental restorative materials

Cell sheets of human dental pulp stem cells for future application in bone replacement

Novel low-dose protocols using cone beam computed tomography in dental medicine: a review focusing on indications, limitations, and future possibilities

Influence of static forces on the expression of selected parameters of inflammation in periodontal ligament cells and alveolar bone cells in a co-culture in vitro model

In vivo and in vitro assessment of the bleaching effectiveness of a brush-off patch containing 3.0% hydrogen peroxide

Clinical performance of precoated brackets and self-etch bonding technique: a prospective comparative study

Neu im Fachgebiet Zahnmedizin

Parodontalbehandlung verbessert Prognose bei Katheterablation

Invasive Zahnbehandlung: Wann eine Antibiotikaprophylaxe vor infektiöser Endokarditis schützt

Zell-Organisatoren unter Druck: Mechanismen des embryonalen Zahnwachstums aufgedeckt

Die Oralprophylaxe & Kinderzahnheilkunde umbenannt

Newsletter