Skip to main content

Advertisement

SpringerLink
Log in

Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation

  • Original Paper
  • Published:
Medical Molecular Morphology Aims and scope Submit manuscript

Abstract

Gorlin syndrome (GS) is an autosomal dominant genetic disorder involving Patched 1 (PTCH1) mutations. The PTCH1 is a receptor as well as an inhibitor of hedgehog (Hh) to sequester downstream Hh pathway molecules called Smoothened (SMO). PTCH1 mutations causes a variety of GS conditions including falx calcification, odontogenic keratocytes and basal cell carcinomas (BCC). Because PTCH1 is a major driver gene of sporadic BCC, GS patients are characteristically prone to BCC. In order to elucidate the pathological mechanism of BCC-prone GS patients, we investigated keratinocytes derived from GS patient specific iPS cells (G-OFiPSCs) which were generated and reported previously. We found that keratinocytes derived from G-OFiPSCs (GKCs) have increased expression of Hh target molecules. GKCs were irradiated and those cells showed high resistance to UV induced apoptosis. BCL2, known as anti-apoptotic molecule as well as Hh target, significantly increased in GKCs. Several molecules involved in DNA repair, cell cycle control, senescence, and genotoxic stress such as TP53, BRCA1 and GADD45A increased only in GKCs. GKCs are indicated to be resistant to UV irradiation by upregulating molecules which control DNA repair and genotoxic even under DNA damage caused by UV. The anti-apoptotic properties of GKCs may contribute BCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Gorlin RJ, Goltz RW (1960) Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib—a syndrome. N Engl J Med 262:908–912

    CAS  PubMed  Google Scholar 

  2. Evans DGR, Ladusans EJ, Rimmer S, Burnell LD, Thakker N, Farndon PA (1993) Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet 30:460–464

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet Part A 152:27–32

    Google Scholar 

  4. Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, Martin N, Wicking C, Trench GC (1994) Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet 50:282–290

    CAS  PubMed  Google Scholar 

  5. Endo M, Fujii K, Sugita K, Saito K, Kohno Y, Miyashita T (2012) Nationwide survey of nevoid. Med Genet A. 158:351–357

    Google Scholar 

  6. Bree AF, Shah MR (2011) Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet Part A 155:2091–2097

    Google Scholar 

  7. Pandolfi S, Stecca B (2015) Cooperative integration between HEDGEHOG-GLI signalling and other oncogenic pathways: Implications for cancer therapy. Expert Rev Mol Med 17:1–36

    Google Scholar 

  8. Hahn H, Christiansen J, Wicking C, Zaphiropoulos PG, Chidambaram A, Gerrard B, Vorechovsky I, Bale AE, Toftgard R, Dean M, Wainwright B (1996) A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 271:12125–12128

    CAS  PubMed  Google Scholar 

  9. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr, Scott MP (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671

    CAS  PubMed  Google Scholar 

  10. Fan Z, Li J, Du J, Zhang H, Shen Y, Wang C-Y, Wang S (2008) A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family. J Med Genet 45:303–308

    CAS  PubMed  Google Scholar 

  11. Pastorino L, Ghiorzo P, Nasti S, Battistuzzi L, Cusano R, Marzocchi C, Garre ML, Clementi M, Scarra GB (2009) Identification of a SUFU germline mutation in a family with Gorlin syndrome. Am J Med Genet Part A 149:1539–1543

    Google Scholar 

  12. Onodera S, Saito A, Hasegawa D, Morita N, Watanabe K, Nomura T, Shibahara T, Ohba S, Yamaguchi A, Azuma T (2017) Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype. PLoS ONE. https://doi.org/10.1371/journal.pone.0184702

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sarah CG, Kathryn VA (2010) The primary cilium: a signaling center during vertebrate development. Nat Rev Genet 11:331–344

    Google Scholar 

  14. Briscoe J, Thérond PP (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Bio 15:418–431

    Google Scholar 

  15. Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, Seplyarskiy VB, Sharpe HJ, McKee T, Letourneau A, Ribaux PG, Popadin K, Nicole B-S, Chaabene RB, Santoni FA, Andrianova MA, Guipponi M, Garieri M, Verdan C, Grosdemange K, Sumara O, Eilers M, Aifantis I, Michielin O, Sauvage FJ, Antonarakis SE, Nikolaev SI (2016) Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet 48:398–406

    CAS  PubMed  Google Scholar 

  16. Sekulic A, Von HD (2016) Hedgehog pathway inhibition. Cell 164:831

    CAS  PubMed  Google Scholar 

  17. Peterson SC, Eberl M, Vagnozzi AN, Belkadi A, Veniaminova NA, Verhaegen ME, Bichakjian CK, Ward NL, Dlugosz AA, Wong SY (2015) Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 16:400–412

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Youssef KK, Keymeulen AV, Lapouge G, Beck B, Michaux C, Achouri Y, Sotiropoulou PA, Blanpain C (2010) Identification of the cell lineage at the origin of basal cell carcinoma. Nat Cell Biol 12:299–305

    CAS  PubMed  Google Scholar 

  19. Olsen CM, Wilson LF, Green AC, Bain CJ, Fritschi L, Neale RE, Whiteman DC (2015) Cancers in Australia attributable to exposure to solar ultraviolet radiation and prevented by regular sunscreen use. Aust N Z J Public Health 39:471–476

    PubMed  PubMed Central  Google Scholar 

  20. Karagas MR, Stukel TA, Greenberg ER, Baron JA, Mott LA, Stern RS (1992) Risk of subsequent basal cell carcinoma and squamous cell carcinoma of the skin among patients with prior skin cancer. JAMA J Am Med Assoc 267:3305–3310

    CAS  Google Scholar 

  21. Richmond-Sinclair NM, Pandeya N, Williams GM, Neale RE, Van Der Pols JC, Green AC (2010) Clinical signs of photodamage are associated with basal cell carcinoma multiplicity and site: a 16-year longitudinal study. Int J Cancer 127:2622–2629

    CAS  PubMed  Google Scholar 

  22. Lovatt TJ, Lear JT, Bastrilles J, Wong C, Griffiths CE, Samarasinghe V, Roebuck J, Ramachandran S, Smith AG, Jones PW, Fryer AA, Strange RC (2005) Associations between ultraviolet radiation, basal cell carcinoma site and histology, host characteristics, and rate of development of further tumors. J Am Acad Dermatol 52:468–473

    PubMed  Google Scholar 

  23. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, Low JA, Mackey HM, Yauch RL, Graham RA, Reddy JC, Hauschild A (1997) Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 28:2171–2179

    Google Scholar 

  24. Chang ALS, Oro AE (2012) Initial assessment of tumour regrowth after vismodegib in advanced basal cell carcinoma. Arch Dermatol 148:1324–1325

    PubMed  PubMed Central  Google Scholar 

  25. Kondo T, Imamura K, Funayama M, Tsukita K, Miyake M, Ohta A, Woltjen K, Nakagawa M, Asada T, Arai T, Kawakatsu S, Izumi Y, Kaji R, Iwata N, Inoue H (2017) iPSC-based compound screening and in vitro trials identify a synergistic anti-amyloid β combination for Alzheimer’s disease. Cell Rep 21:2304–2312

    CAS  PubMed  Google Scholar 

  26. Yokoi T, Tanaka T, Matsuzaka E, Tamalu F, Watanabe SI, Nishina S, Azuma N (2017) Effects of neuroactive agents on axonal growth and pathfinding of retinal ganglion cells generated from human stem cells. Sci Rep 7:1–13

    Google Scholar 

  27. Singh VK, Kalsan M, Kumar N, Saini A, Chandra R (2015) Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol 3:1–18

    Google Scholar 

  28. Hasegawa D, Ochiai-Shino H, Onodera S, Nakamura T, Saito A, Onda T, Watanabe K, Nishimura K, Ohtaka M, Nakanishi M, Kosaki K, Yamaguchi A, Shibahara T, Azuma T (2017) Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to hedgehog-mediated osteogenic induction. PLoS ONE. https://doi.org/10.1371/journal.pone.0184702

    Article  PubMed  PubMed Central  Google Scholar 

  29. Onodera S, Saito A, Hojo H, Nakamura T, Zujur D, Watanabe K, Morita N, Hasegawa D, Masaki H, Nakauchi H, Nomura T, Shibahara T,Yamaguchi A, Chung UI, Azuma T, Ohba S (2020) Hedgehog activation regulates human osteoblastogenesis. Stem Cell Reports (in press)

  30. Ochiai-Shino H, Kato H, Sawada T, Onodera S, Saito A, Takato T, Shibahara T, Muramatsu T, Azuma T (2014) A novel strategy for enrichment and isolation of osteoprogenitor cells from induced pluripotent stem cells based on surface marker combination. PLoS ONE. https://doi.org/10.1371/journal.pone.0099534

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kato H, Ochiai-Shino H, Onodera S, Saito A, Shibahara T, Azuma T (2015) Promoting effect of 1,25(OH)2 vitamin D3 in osteogenic differentiation from induced pluripotent stem cells to osteocyte-like cells. Open Biol. https://doi.org/10.1098/rsob.140201

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hayashi K, Ochiai-Shino H, Shiga T, Onodera S, Saito A, Shibahara T, Azuma T (2016) Transplantation of human-induced pluripotent stem cells carried by self-assembling peptide nanofiber hydrogel improves bone regeneration in rat calvarial bone defects. BDJ Open. https://doi.org/10.1038/bdjopen.2015.7

    Article  PubMed  PubMed Central  Google Scholar 

  33. Ono M, Hamada Y, Horiuchi Y, Matsuo-Takasaki M, Imoto Y, Satomi K, Arinami T, Hasegawa M, Fujioka T, Nakamura Y, Noguchi E (2012) Generation of induced pluripotent stem cells from human nasal epithelial cells using a Sendai virus vector. PLoS ONE. https://doi.org/10.1371/journal.pone.0042855

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kajiwara K, Tanemoto T, Wada S, Karibe J, Ihara N, Ikemoto Y, Kawasaki T, Oishi Y, Samura O, Okamura K, Takada S, Akutsu H, Sago H, Okamoto A, Umezawa A (2017) Fetal therapy model of Myelomeningocele with three-dimensional skin using amniotic fluid cell-derived induced pluripotent stem cells. Stem Cell Rep 8:1701–1713

    Google Scholar 

  35. Itoh M, Kiuru M, Cairo MS, Christiano AM (2011) Generation of keratinocytes from normal and recessive dystrophic epidermolysis bullosa-induced pluripotent stem cells. Proc Natl Acad Sci 108:8797–8802

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Raj D, Brash DE, Grossman D (2006) Keratinocyte apoptosis in epidermal development and disease. J Invest Dermatol 126:243–257

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Martin MT, Vulin A, Hendry JH (2016) Human epidermal stem cells: role in adverse skin reactions and carcinogenesis from radiation. Mutat Res 770:349–368

    CAS  Google Scholar 

  38. Kim Y, He Y-Y (2014) Ultraviolet radiation-induced non-melanoma skin cancer: regulation of DNA damage repair and inflammation. Genes Di 1:188–198

    Google Scholar 

  39. Pustisek N, Situm M (2011) UV-radiation, apoptosis and skin. Coll Antropol 35:339–341

    PubMed  Google Scholar 

  40. Fischer JL, Lancia JK, Mathur A, Smith ML (2006) Selenium protection from DNA damage involves a Ref1 / p53 / Brca1 protein complex. Anticancer Res 904:899–904

    Google Scholar 

  41. Navaraj A, Mori T, El-Deiry WS (2005) Cooperation between p53 and BRCA1 in repair of cyclobutane pyrimidine dimers. Cancer Biol Ther 12:1409–1414

    Google Scholar 

  42. Deng CX, Wang RH (2003) Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum Mol Genet 12:113–123

    Google Scholar 

  43. MacLeod RAF, Dirks WG, Matsuo Y, Kaufmann M, Milch H, Drexler HG (1999) Widespread intraspecies cross-contamination of human tumor cell lines arising at source. Int J Cancer 83:555–563

    CAS  PubMed  Google Scholar 

  44. Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34:9–19

    CAS  PubMed  Google Scholar 

  45. Hanahan D, Weinberg R (2000) The Hallmarks of cancer. Cell 100:57–70

    CAS  PubMed  Google Scholar 

  46. Ramezani M, Mohamadzaheri E, Khazaei S, Najafi F, Vaisi-Raygani A, Rahbar M, Sadeghi M (2016) Comparison of EMA, CEA, CD10 and Bcl-2 biomarkers by immunohistochemistry in squamous cell carcinoma and basal cell carcinoma of the skin. Asian Pac J Cancer Prev 17:1379–1383

    PubMed  Google Scholar 

  47. Zheng Z, Kye Y, Zhang X, Kim A (2005) Expression of p63, bcl-2, bcl-6 and p16 in basal cell carcinoma and squamous cell carcinoma of the skin. Korean J Pathol 39:91–98

    Google Scholar 

  48. Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, Philpott MP, Esterbauer H, Hauser-Kronberger C, Frischauf AM, Aberger F (2004) Activation of the BCL2 promoter in response to Hedgehog / GLI signal transduction is predominantly mediated by GLI2. Cancer Res 64:7724–7731

    CAS  PubMed  Google Scholar 

  49. 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 279:1197–1205

    CAS  PubMed  Google Scholar 

  50. Mazumdar T, Devecchio J, Agyeman A, Shi T, Houghton JA (2011) Blocking hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells. Cancer Res 71:5904–5914

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Blackford AN, Jackson SP (2017) ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell 66:801–817

    CAS  PubMed  Google Scholar 

  52. Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429

    CAS  PubMed  Google Scholar 

  53. Zhan Q (2005) Gadd45a, a p53- and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutat Res Mol Mech Mutagen 569:133–143

    CAS  Google Scholar 

  54. Ginsburg OM, Kim-Sing C, Foulkes WD, Ghadirian P, Lynch HT, Sun P (2010) BRCA1 and BRCA2 families and the risk of skin cancer. Fam Cancer 9:489–493

    PubMed  Google Scholar 

  55. Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, Kerkhoven RM, van Vliet MH, Wessels LF, Peterse JL, Berns A, Jonkers J (2007) Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci 12:111–116

    Google Scholar 

  56. Jans J, Schul W, Sert YG, Rijksen Y, Rebel H, Eker AP, Nakajima S, van Steeg H, de Gruijl FR, Yasui A, Hoeijmakers JH, van der Horst GT (2005) Powerful skin cancer protectionby a CPD-photolyase transgene. Curr Biol 15:105–115

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to Ms. Akiko Saito, Ms. Chika Itoh, Dr Katsuhito Watanabe, and Dr. Hiroyuki Ogura for providing technical assistance.

Funding

This study was supported by Japan Society for the Promotion of Science: 18K09753, 18H03007, and Tokyo Dental College Research Branding Project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Oral Medicine and Hospital Dentistry, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba, 272-8513, Japan

    Nana Morita

  2. Department of Biochemistry, Tokyo Dental College, 2-9-18, Kanda-Misaki-chou, Chiyoda, Tokyo, 101-0061, Japan

    Shoko Onodera, Takashi Nakamura & Toshifumi Azuma

  3. Department of Oral Oncology, Oral and Maxillofacial Surgery, Tokyo Dental College, 5-11-13, Sugano, Ichikawa, Chiba, 272-8513, Japan

    Yuriko Nakamura & Takeshi Nomura

  4. Department of Dermatology, Tokyo Dental College Ichikawa General Hospital, 5-11-13, Sugano, Ichikawa, Chiba, 272-8513, Japan

    Shin-ichi Takahashi

Authors
  1. Nana Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoko Onodera
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuriko Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shin-ichi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takeshi Nomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshifumi Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshifumi Azuma.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morita, N., Onodera, S., Nakamura, Y. et al. Keratinocytes from Gorlin Syndrome-induced pluripotent stem cells are resistant against UV radiation. Med Mol Morphol 54, 69–78 (2021). https://doi.org/10.1007/s00795-020-00264-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00795-020-00264-4

Keywords

Search

Navigation