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Wnt signaling and Hedgehog expression in basal cell carcinoma

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Abstract

Basal cell carcinoma (BCC) is the most common skin cancer worldwide, and its incidence is increasing due to the aging population and the cumulative effects of widespread sun exposure. The Wnt gene family is involved in cell growth regulation, differentiation, and organogenesis, and not surprisingly, Wnt genes have been linked to oncogenesis. Specifically, β-catenin, a key signaling regulator of the Wnt pathway, is involved in the genesis of numerous human cancers including BCCs. Dysregulation of the patched/hedgehog intracellular signaling pathway, other important pathways regulating cell growth and regulation, has also been linked to BCCs. In this review, we outline the key mechanisms of the Wnt and patched/hedgehog intracellular signaling pathways and their involvement in the development, homeostasis, and progression of BCCs.

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References

  1. Marzuka AG, Book SE (2015) Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med 88(2):167–179

    PubMed  PubMed Central  Google Scholar 

  2. Tansil Tan S, et al. (2018) Basal cell carcinoma arises from interfollicular layer of epidermis. J Onco

  3. Noubissi FN et al (2018) Cross-talk between wnt and hh signaling pathways in the pathology of basal cell carcinoma. Int J Environ Res Public Health 15(7):1442

    Article  PubMed Central  CAS  Google Scholar 

  4. Zhang Y, Alexander PB, Wang XF (2017) TGF-β family signaling in the control of cell proliferation and survival. Cold Spring Harb Perspect Biol 9(4):a022145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Swarup S, Verheyen E (2012) Wnt/wingless signaling in Drosophila. Cold Spring Harb Perspect Biol 4(6):a007930

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Croce JC,  McClay DR (2008) Evolution of the Wnt pathways. Methods Mol Biol

  7. Houschyar KS et al (2019) Wnt pathway in bone repair and regeneration - what do we know so far. Front Cell Dev Biol 2019(6):170

    Article  Google Scholar 

  8. Miller JR (2002) The Wnts. Genome Biol. 3(1).

  9. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75

    Article  PubMed  PubMed Central  Google Scholar 

  11. Houschyar KS et al (2015) Wnt signaling induces epithelial differentiation during cutaneous wound healing. Organogenesis 11(3):95–104

    Article  PubMed  PubMed Central  Google Scholar 

  12. Prieve MG, RT (2003) Moon, Stromelysin-1 and mesothelin are differentially regulated by Wnt-5a and Wnt-1 in C57mg mouse mammary epithelial cells. BMC Dev Biol. 3(2).

  13. Wong GT, Gavin BJ, McMahon AP (1994) Differential transformation of mammary epithelial cells by Wnt genes. Mol Cell Biol 14(9):6278–6286

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Siar CH et al (2012) Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma. J Oral Pathol Med 41(4):332–339

    Article  PubMed  Google Scholar 

  15. van Amerongen R (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol. 4(10).

  16. Stamos, J.L. and W.I. Weis (2013) The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 5(1).

  17. Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35(3):161–168

    Article  CAS  PubMed  Google Scholar 

  18. Cadigan, K.M. and M.L. Waterman (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 4(11).

  19. Habas, R. and R.B. Dawid (2005) Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol. 4(1).

  20. Lee YN, Gao Y, Wang HY (2008) Differential mediation of the Wnt canonical pathway by mammalian Dishevelleds-1, -2, and -3. Cell Signal 20(2):443–452

    Article  CAS  PubMed  Google Scholar 

  21. Sharma M et al (2018) Dishevelled: a masterful conductor of complex Wnt signals. Cell Signal 47:52–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. MacDonald, B.T. and X. He (2012) Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb Perspect Biol. 4(12).

  23. Ren, Q., J. Chen, and Y. Liu (2021) LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front Cell Dev Biol. 9.

  24. Gray RS, Roszko I, Solnica-Krezel L (2011) Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity. Dev Cell 21(1):120–133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Duchartre Y, Kim YM, Kahn M (2017) Pharmacologic manipulation of Wnt signaling and cancer stem cells. Methods Mol Biol 1613:463–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kishida S, Yamamoto H, Kikuchi A (2004) Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Mol Cell Biol 24(10):4487–4501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lai SL, Chien AJ, Moon RT (2009) Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res 19(5):532–545

    Article  CAS  PubMed  Google Scholar 

  28. Kohn AD, Moon RT (2005) Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 38(3–4):439–446

    Article  CAS  PubMed  Google Scholar 

  29. Kim SY et al (2004) Phospholipase C, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and redox state are involved in epigallocatechin gallate-induced phospholipase D activation in human astroglioma cells. Eur J Biochem 271(17):3470–3480

    Article  CAS  PubMed  Google Scholar 

  30. Habas R, Dawid IB, He D (2003) Coactivation of Rac and Rho by Wnt/Frizzled signaling is required for vertebrate gastrulation. Genes Dev 17(2):295–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim SI, Choi ME (2012) TGF-β-activated kinase-1: New insights into the mechanism of TGF-β signaling and kidney disease. Kidney Res Clin Pract 31(2):94–105

    Article  PubMed  PubMed Central  Google Scholar 

  32. Francis SH et al (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62(3):525–563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kipanyula, M.J., W.H. Kimaro, and P.F. Seke Etet (2016) The emerging roles of the calcineurin-nuclear factor of activated T-lymphocytes pathway in nervous system functions and diseases. J Aging Res.

  34. Kestler HA, Kühl M (2008) From individual Wnt pathways towards a Wnt signalling network. Philos Trans R Soc Lond B Biol Sci 363(1495):1333–1347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nagai H, Kim YH (2017) Cancer prevention from the perspective of global cancer burden patterns. J Thorac Dis 9(3):448–451

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cheng, Y., et al. (2019) Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 4(62).

  37. Yeo SK et al (2020) Single-cell RNA-sequencing reveals distinct patterns of cell state heterogeneity in mouse models of breast cancer. Elife 9:e58810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Willis RE (2012) Human gene control by vital oncogenes: revisiting a theoretical model and its implications for targeted cancer therapy. Int J Mol Sci 13(1):316–335

    Article  CAS  PubMed  Google Scholar 

  39. Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18(1–2):43–73

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lepage CC et al (2019) Detecting chromosome instability in cancer: approaches to resolve cell-to-cell heterogeneity. Cancers (Basel) 11(2):226

    Article  CAS  Google Scholar 

  41. Lee EYH, Muller WJ (2010) Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol 2(10):a003236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Polsky D, Cordon-Cardo C (2003) Oncogenes in melanoma. Oncogene 22(20):3087–3091

    Article  CAS  PubMed  Google Scholar 

  43. Liu Y et al (2015) Targeting tumor suppressor genes for cancer therapy. BioEssays 37(12):1277–1286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Du Z, Lovly CM (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17(1):58

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Potapova T, Gorbsky GJ (2017) The consequences of chromosome segregation errors in mitosis and meiosis. Biology (Basel) 6(1):12

    Google Scholar 

  46. Kwong LN, Dove WF (2009) APC and its modifiers in colon cancer. Adv Exp Med Biol 656(85):106

    Google Scholar 

  47. McCabe MT, Brandes JC, Vertino PM (2009) Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 15(12):3927–3937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38(1):23–38

    Article  CAS  PubMed  Google Scholar 

  49. Guo XE et al (2014) Targeting tumor suppressor networks for cancer therapeutics. Curr Drug Targets 15(1):2–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen J (2016) The cell-cycle arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Biol 6(3):a026104

    Article  CAS  Google Scholar 

  51. Albrechtsen N et al (1999) Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18(53):7706–7717

    Article  CAS  PubMed  Google Scholar 

  52. Riley T et al (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9(5):402–412

    Article  CAS  PubMed  Google Scholar 

  53. Andersson S et al (2006) The carcinogenic role of oncogenic HPV and p53 gene mutation in cervical adenocarcinomas. Med Oncol 23(1):113–119

    Article  CAS  PubMed  Google Scholar 

  54. Ito A et al (2001) p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J 20(6):1331–1340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huibregtse JM, Scheffner M, Howley PM (1993) Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol 13(2):775–784

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Chellappan S et al (1992) Adenovirus E1A, simian virus 40 tumor antigen, and human papillomavirus E7 protein share the capacity to disrupt the interaction between transcription factor E2F and the retinoblastoma gene product. Proc Natl Acad Sci 89(10):4549–4553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rivlin N et al (2011) Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis. Genes Cancer 2(4):466–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Holland AJ, Cleveland DW (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 13(6):501–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Thompson SL, Bakhoum SF, Compton DA (2010) Mechanisms of chromosomal instability. Curr Biol 20(6):R285–R295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vargas-Rondón N, Villegas VE, Rondón-Lagos M (2017) The role of chromosomal instability in cancer and therapeutic responses. Cancers (Basel) 10(1):4

    Article  CAS  Google Scholar 

  61. de la Chapelle A, Hampel H (2010) Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 28(20):3380–3387

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Houschyar KS et al (2020) Molecular mechanisms of hair growth and regeneration: current understanding and novel paradigms. Dermatology 236(4):271–280

    Article  PubMed  Google Scholar 

  63. Polakis, P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 4(5).

  64. Gajos-Michniewicz A, Czyz M (2020) WNT Signaling in Melanoma. Int J Mol Sci 21(14):4852

    Article  CAS  PubMed Central  Google Scholar 

  65. Duchartre Y, Kim YM, Kahn M (2016) The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 99:141–149

    Article  PubMed  Google Scholar 

  66. Hankey W, Frankel WL, Groden J (2018) Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting. Cancer Metastasis Rev 37(1):159–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Martin-Orozco E et al (2019) WNT signaling in tumors: the way to evade drugs and immunity. Front Immunol 10:2854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Goldsberry WN et al (2019) A Review of the Role of Wnt in Cancer Immunomodulation. Cancers (Basel) 11(6):771

    Article  CAS  Google Scholar 

  69. Ayob AZ, Ramasamy TS (2018) Cancer stem cells as key drivers of tumour progression. J Biochem Sci 25(1):20

    Google Scholar 

  70. Mohammed MK et al (2016) Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis 3(1):11–40

    Article  PubMed  PubMed Central  Google Scholar 

  71. Zhang Y et al (2012) Human telomerase reverse transcriptase (hTERT) is a novel target of the Wnt/β-catenin pathway in human cancer. J Biol Chem 287(39):32494–32511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Koyun E et al (2020) Caspase-3, p53 and Bcl-2 expression in basal cell carcinoma of the eyelid. Postepy Dermatol Alergol 37(4):535–539

    Article  PubMed  PubMed Central  Google Scholar 

  73. Valkenburg KC et al (2011) Wnt/β-catenin signaling in normal and cancer stem cells. Cancers (Basel) 3(2):2050–2079

    Article  CAS  Google Scholar 

  74. Koni M, Pinnarò V, Brizzi MF (2020) The Wnt signalling pathway: a tailored target in cancer. Int J Mol Sci 21(20):7697

    Article  CAS  PubMed Central  Google Scholar 

  75. Athar M et al (2014) Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res 74(18):4967–4975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pak E, Segal RA (2016) Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell 38(4):333–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cucchi D et al (2012) Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma. J Exp Pharmacol 4:173–185

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhang H et al (2001) Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol 158(2):381–385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Rishikaysh P et al (2014) Signaling involved in hair follicle morphogenesis and development. Int J Mol Sci 15(1):1647–1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yang SH et al (2008) Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3-catenin signaling. Nat Genet 40(9):1130–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Noubissi FK et al (2014) Role of CRD-BP in the growth of human basal cell carcinoma cells. J Invest Dermatol 134(6):1718–1724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goers ES et al (2010) MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res 38(7):2467–2484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Hautzentrum Köln/Cologne Dermatology, Cologne, Germany

    Khosrow S. Houschyar & Wolfgang G. Philipp-Dormston

  2. Department of Plastic Surgery, Brown University, Rhode Island Hospital, Providence, RI, USA

    Mimi R. Borrelli

  3. Department of Hand, Plastic and Reconstructive Surgery, Burn Trauma Center, BG Trauma Center Ludwigshafen, University of Heidelberg, Heidelberg, Germany

    Christian Tapking

  4. Department of Plastic and Hand Surgery-Burn Center-Clinic St. Georg, Leipzig, Germany/Martin-Luther-University Halle-Wittenberg, Halle, Germany

    Susanne Rein

  5. Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria

    Daniel Popp

  6. Department of Oral and Maxillofacial Surgery, University Hospital RWTH, Aachen, Germany

    Behrus Puladi

  7. Department of Plastic Surgery, BG University Hospital Bergmannsheil, Ruhr University Bochum, Bochum, Germany

    Christoph Wallner

  8. Clinic for Orthopedics, Trauma Surgery and Plastic Surgery, University Hospital, Leipzig, Germany

    Torsten Schulz

  9. Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford School of Medicine, Stanford, CA, 94305, USA

    Zeshaan N. Maan

  10. Department of Hand, Plastic and Reconstructive Surgery, BG Unfallklinik Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany

    Dominik Duscher

  11. Department of Dermatology and Allergology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    David Kluwig & Amir S. Yazdi

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  1. Khosrow S. Houschyar
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Houschyar, K.S., Borrelli, M.R., Tapking, C. et al. Wnt signaling and Hedgehog expression in basal cell carcinoma. Eur J Plast Surg 45, 543–550 (2022). https://doi.org/10.1007/s00238-021-01920-3

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