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.
Level of Evidence: Not gradable.
Similar content being viewed by others
Data availability
Please contact the author for data requests.
References
Marzuka AG, Book SE (2015) Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management. Yale J Biol Med 88(2):167–179
Tansil Tan S, et al. (2018) Basal cell carcinoma arises from interfollicular layer of epidermis. J Onco
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
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
Swarup S, Verheyen E (2012) Wnt/wingless signaling in Drosophila. Cold Spring Harb Perspect Biol 4(6):a007930
Croce JC, McClay DR (2008) Evolution of the Wnt pathways. Methods Mol Biol
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
Miller JR (2002) The Wnts. Genome Biol. 3(1).
MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26
Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75
Houschyar KS et al (2015) Wnt signaling induces epithelial differentiation during cutaneous wound healing. Organogenesis 11(3):95–104
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).
Wong GT, Gavin BJ, McMahon AP (1994) Differential transformation of mammary epithelial cells by Wnt genes. Mol Cell Biol 14(9):6278–6286
Siar CH et al (2012) Differential expression of canonical and non-canonical Wnt ligands in ameloblastoma. J Oral Pathol Med 41(4):332–339
van Amerongen R (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol. 4(10).
Stamos, J.L. and W.I. Weis (2013) The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 5(1).
Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35(3):161–168
Cadigan, K.M. and M.L. Waterman (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. 4(11).
Habas, R. and R.B. Dawid (2005) Dishevelled and Wnt signaling: is the nucleus the final frontier? J Biol. 4(1).
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
Sharma M et al (2018) Dishevelled: a masterful conductor of complex Wnt signals. Cell Signal 47:52–64
MacDonald, B.T. and X. He (2012) Frizzled and LRP5/6 receptors for Wnt/β-catenin signaling. Cold Spring Harb Perspect Biol. 4(12).
Ren, Q., J. Chen, and Y. Liu (2021) LRP5 and LRP6 in Wnt signaling: similarity and divergence. Front Cell Dev Biol. 9.
Gray RS, Roszko I, Solnica-Krezel L (2011) Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity. Dev Cell 21(1):120–133
Duchartre Y, Kim YM, Kahn M (2017) Pharmacologic manipulation of Wnt signaling and cancer stem cells. Methods Mol Biol 1613:463–478
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
Lai SL, Chien AJ, Moon RT (2009) Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res 19(5):532–545
Kohn AD, Moon RT (2005) Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 38(3–4):439–446
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
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
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
Francis SH et al (2010) cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev 62(3):525–563
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.
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
Nagai H, Kim YH (2017) Cancer prevention from the perspective of global cancer burden patterns. J Thorac Dis 9(3):448–451
Cheng, Y., et al. (2019) Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 4(62).
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
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
Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18(1–2):43–73
Lepage CC et al (2019) Detecting chromosome instability in cancer: approaches to resolve cell-to-cell heterogeneity. Cancers (Basel) 11(2):226
Lee EYH, Muller WJ (2010) Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol 2(10):a003236
Polsky D, Cordon-Cardo C (2003) Oncogenes in melanoma. Oncogene 22(20):3087–3091
Liu Y et al (2015) Targeting tumor suppressor genes for cancer therapy. BioEssays 37(12):1277–1286
Du Z, Lovly CM (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17(1):58
Potapova T, Gorbsky GJ (2017) The consequences of chromosome segregation errors in mitosis and meiosis. Biology (Basel) 6(1):12
Kwong LN, Dove WF (2009) APC and its modifiers in colon cancer. Adv Exp Med Biol 656(85):106
McCabe MT, Brandes JC, Vertino PM (2009) Cancer DNA methylation: molecular mechanisms and clinical implications. Clin Cancer Res 15(12):3927–3937
Moore LD, Le T, Fan G (2013) DNA methylation and its basic function. Neuropsychopharmacology 38(1):23–38
Guo XE et al (2014) Targeting tumor suppressor networks for cancer therapeutics. Curr Drug Targets 15(1):2–16
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
Albrechtsen N et al (1999) Maintenance of genomic integrity by p53: complementary roles for activated and non-activated p53. Oncogene 18(53):7706–7717
Riley T et al (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9(5):402–412
Andersson S et al (2006) The carcinogenic role of oncogenic HPV and p53 gene mutation in cervical adenocarcinomas. Med Oncol 23(1):113–119
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
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
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
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
Holland AJ, Cleveland DW (2012) Losing balance: the origin and impact of aneuploidy in cancer. EMBO Rep 13(6):501–514
Thompson SL, Bakhoum SF, Compton DA (2010) Mechanisms of chromosomal instability. Curr Biol 20(6):R285–R295
Vargas-Rondón N, Villegas VE, Rondón-Lagos M (2017) The role of chromosomal instability in cancer and therapeutic responses. Cancers (Basel) 10(1):4
de la Chapelle A, Hampel H (2010) Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol 28(20):3380–3387
Houschyar KS et al (2020) Molecular mechanisms of hair growth and regeneration: current understanding and novel paradigms. Dermatology 236(4):271–280
Polakis, P (2012) Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 4(5).
Gajos-Michniewicz A, Czyz M (2020) WNT Signaling in Melanoma. Int J Mol Sci 21(14):4852
Duchartre Y, Kim YM, Kahn M (2016) The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 99:141–149
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
Martin-Orozco E et al (2019) WNT signaling in tumors: the way to evade drugs and immunity. Front Immunol 10:2854
Goldsberry WN et al (2019) A Review of the Role of Wnt in Cancer Immunomodulation. Cancers (Basel) 11(6):771
Ayob AZ, Ramasamy TS (2018) Cancer stem cells as key drivers of tumour progression. J Biochem Sci 25(1):20
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
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
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
Valkenburg KC et al (2011) Wnt/β-catenin signaling in normal and cancer stem cells. Cancers (Basel) 3(2):2050–2079
Koni M, Pinnarò V, Brizzi MF (2020) The Wnt signalling pathway: a tailored target in cancer. Int J Mol Sci 21(20):7697
Athar M et al (2014) Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res 74(18):4967–4975
Pak E, Segal RA (2016) Hedgehog signal transduction: key players, oncogenic drivers, and cancer therapy. Dev Cell 38(4):333–344
Cucchi D et al (2012) Hedgehog signaling pathway and its targets for treatment in basal cell carcinoma. J Exp Pharmacol 4:173–185
Zhang H et al (2001) Role of PTCH and p53 genes in early-onset basal cell carcinoma. Am J Pathol 158(2):381–385
Rishikaysh P et al (2014) Signaling involved in hair follicle morphogenesis and development. Int J Mol Sci 15(1):1647–1670
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
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
Goers ES et al (2010) MBNL1 binds GC motifs embedded in pyrimidines to regulate alternative splicing. Nucleic Acids Res 38(7):2467–2484
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethics approval
Ethical approval was not required for this study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00238-021-01920-3