Expression profile of sonic hedgehog signaling-related molecules in basal cell carcinoma


Autoři: Hye Sung Kim aff001;  Young Sil Kim aff001;  Chul Lee aff002;  Myung Soo Shin aff003;  Jae Wang Kim aff004;  Bo Gun Jang aff001
Působiště autorů: Department of Pathology, Jeju National University College of medicine, Jeju, South Korea aff001;  Department of Pathology, Seoul National University College of medicine, Seoul, South Korea aff002;  Department of Plastic Surgery, Jeju National University College of medicine, Jeju, South Korea aff003;  Department of Dermatology, Jeju National University College of medicine, Jeju, South Korea aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225511

Souhrn

Basal cell carcinoma (BCC) is the most common human cancer, characterized by aberrant activation of the hedgehog (HH) signaling pathway resulting from mutations in the patched 1 (PTCH1) or smoothened (SMO) genes. In the present study, to uncover the expression profile of HH signaling-related molecules, we thoroughly examined the mRNA and protein expression levels of six molecules including GLI1, GLI2, PTCH1, PTCH2, SHH, and SMO in BCC and various other cutaneous tumors. Real-time PCR analysis demonstrated that BCC showed remarkably enhanced mRNA expression of all HH molecules, except SMO compared to other skin tumors. However, immunohistochemical analysis revealed that only GLI1 protein was specifically upregulated in BCC, while the other HH-related proteins did not show any significant differences between the tumors. Notably, other skin malignancies such as squamous cell carcinoma, sebaceous carcinoma, and malignant melanoma showed no GLI1 expression and there was no difference in GLI1 expression between the BCC subtypes. In addition, GLI1 and GLI2 expression were strongly associated with the hair follicle stem cell markers, LGR4 and LGR5, which are known target genes of the Wnt pathway. Our results suggest that GLI1 has the potential to be a diagnostically useful marker for differentiating BCC from other skin malignancies and an interaction between the HH and Wnt signaling pathways may be involved in the development of BCCs.

Klíčová slova:

Gene expression – Hair follicles – Hedgehog signaling – Immunohistochemistry techniques – Protein expression – Skin tumors – Squamous cell carcinomas – Basal cell carcinomas


Zdroje

1. Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nature reviews Cancer. 2008;8(10):743. doi: 10.1038/nrc2503 18813320

2. Perez-Losada J, Balmain A. Stem-cell hierarchy in skin cancer. Nature Reviews Cancer. 2003;3(6):434. doi: 10.1038/nrc1095 12778133

3. Owens DM, Watt FM. Contribution of stem cells and differentiated cells to epidermal tumours. Nature Reviews Cancer. 2003;3(6):444. doi: 10.1038/nrc1096 12778134

4. Hahn H, Wicking C, Zaphiropoulos PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51. doi: 10.1016/s0092-8674(00)81268-4 8681379

5. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668–71. doi: 10.1126/science.272.5268.1668 8658145

6. Xie J, Murone M, Luoh S-M, Ryan A, Gu Q, Zhang C, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391(6662):90. doi: 10.1038/34201 9422511

7. di Magliano MP, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nature reviews cancer. 2003;3(12):903. doi: 10.1038/nrc1229 14737121

8. Rimkus T, Carpenter R, Qasem S, Chan M, Lo H-W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers. 2016;8(2):22.

9. Niewiadomski P, Niedziółka SM, Markiewicz Ł, Uśpieński T, Baran B, Chojnowska K. Gli Proteins: Regulation in Development and Cancer. Cells. 2019;8(2):147.

10. Infante P, Faedda R, Bernardi F, Bufalieri F, Severini LL, Alfonsi R, et al. Itch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis. Nature communications. 2018;9(1):976. doi: 10.1038/s41467-018-03339-0 29515120

11. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes & development. 2008;22(18):2454–72.

12. Dahmane N, Lee J, Robins P, Heller P, i Altaba AR. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature. 1997;389(6653):876–81. doi: 10.1038/39918 9349822

13. Ghali L, Wong ST, Green J, Tidman N, Quinn AG. Gli1 protein is expressed in basal cell carcinomas, outer root sheath keratinocytes and a subpopulation of mesenchymal cells in normal human skin. Journal of investigative dermatology. 1999;113(4):595–9. doi: 10.1046/j.1523-1747.1999.00729.x 10504446

14. Tanese K, Emoto K, Kubota N, Fukuma M, Sakamoto M. Immunohistochemical visualization of the signature of activated Hedgehog signaling pathway in cutaneous epithelial tumors. The Journal of dermatology. 2018;45(10):1181–6. doi: 10.1111/1346-8138.14543 30035333

15. Peterson SC, Eberl M, Vagnozzi AN, Belkadi A, Veniaminova NA, Verhaegen ME, et al. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell stem cell. 2015;16(4):400–12. doi: 10.1016/j.stem.2015.02.006 25842978

16. Wang GY, Wang J, Mancianti M-L, Epstein EH Jr. Basal cell carcinomas arise from hair follicle stem cells in Ptch1+/− mice. Cancer cell. 2011;19(1):114–24. doi: 10.1016/j.ccr.2010.11.007 21215705

17. Kasper M, Jaks V, Are A, Bergström Å, Schwäger A, Svärd J, et al. Wounding enhances epidermal tumorigenesis by recruiting hair follicle keratinocytes. Proceedings of the National Academy of Sciences. 2011;108(10):4099–104.

18. Jang BG, Lee BL, Kim WH. Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis. PLoS One. 2013;8(12):e82390. doi: 10.1371/journal.pone.0082390 24340024

19. Schepeler T, Page ME, Jensen KB. Heterogeneity and plasticity of epidermal stem cells. Development. 2014;141(13):2559–67. doi: 10.1242/dev.104588 24961797

20. Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development. 2014;141(18):3445–57. doi: 10.1242/dev.083691 25183867

21. Bonifas JM, Epstein EH Jr, Pennypacker S, Chuang P-T, McMahon AP, Williams M, et al. Activation of expression of hedgehog target genes in basal cell carcinomas. Journal of investigative dermatology. 2001;116(5):739–42. doi: 10.1046/j.1523-1747.2001.01315.x 11348463

22. Regl G, Neill GW, Eichberger T, Kasper M, Ikram MS, Koller J, et al. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. Oncogene. 2002;21(36):5529. doi: 10.1038/sj.onc.1205748 12165851

23. Tojo M, Kiyosawa H, Iwatsuki K, Kaneko F. Expression of a sonic hedgehog signal transducer, hedgehog‐interacting protein, by human basal cell carcinoma. British Journal of Dermatology. 2002;146(1):69–73. doi: 10.1046/j.1365-2133.2002.04583.x 11841368

24. Martinez MF, Romano MV, Martinez AP, González A, Muchnik C, Stengel FM, et al. Nevoid Basal Cell Carcinoma Syndrome: PTCH1 Mutation Profile and Expression of Genes Involved in the Hedgehog Pathway in Argentinian Patients. Cells. 2019;8(2):144.

25. Kasper M, Jaks V, Hohl D, Toftgård R. Basal cell carcinoma—molecular biology and potential new therapies. The Journal of clinical investigation. 2012;122(2):455–63. doi: 10.1172/JCI58779 22293184

26. Jaks V, Barker N, Kasper M, Van Es JH, Snippert HJ, Clevers H, et al. Lgr5 marks cycling, yet long-lived, hair follicle stem cells. Nature genetics. 2008;40(11):1291–9. doi: 10.1038/ng.239 18849992

27. Vidal VP, Chaboissier M-C, Lützkendorf S, Cotsarelis G, Mill P, Hui C-C, et al. Sox9 is essential for outer root sheath differentiation and the formation of the hair stem cell compartment. Curr Biol. 2005;15(15):1340–51. doi: 10.1016/j.cub.2005.06.064 16085486

28. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, et al. Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science. 2010;327(5971):1385–9. doi: 10.1126/science.1184733 20223988

29. Jang BG, Lee C, Kim HS, Shin MS, Cheon MS, Kim JW, et al. Distinct expression profile of stem cell markers, LGR5 and LGR6, in basaloid skin tumors. Virchows Archiv. 2017;470(3):301–10. doi: 10.1007/s00428-016-2061-3 28070642

30. Barker N, Van Es J, Jaks V, Kasper M, Snippert H, Toftgård R, et al., editors. Very long-term self-renewal of small intestine, colon, and hair follicles from cycling Lgr5+ ve stem cells. Cold Spring Harbor symposia on quantitative biology; 2008: Cold Spring Harbor Laboratory Press.

31. Silva-Vargas V, Celso CL, Giangreco A, Ofstad T, Prowse DM, Braun KM, et al. β-catenin and Hedgehog signal strength can specify number and location of hair follicles in adult epidermis without recruitment of bulge stem cells. Developmental cell. 2005;9(1):121–31. doi: 10.1016/j.devcel.2005.04.013 15992546


Článek vyšel v časopise

PLOS One


2019 Číslo 11