jzs-10791

Investigating Expression of Skin Basal Cell Carcinoma Molecular Biomarkers

Chnoor Mohammed Faqe Qadir1 and Karzan Ghafur Khidhir1

1Department of Biology, College of Science, University of Sulaimani, Sulaimani, Kurdistan Region- Iraq

Original: 10 January 2020       Revised: 26 March 2020     Accepted: 5 April 2020        Published online: 20 June 2020  

Doi Link; https://doi.org/10.17656/jzs.10791

Abstract

Basal cell carcinoma (BCC) of skin is the most common type of human cancer. It is strongly linked with exposure to UV radiations and tumors mostly develop on the sun-exposed skin. Although BCC rarely metastasizes or causes mortality, it can result in broad morbidity through local invasion and causing tissue destruction. Hedgehog signaling pathway (Hh) have been linked to the development of BCC. The aim of this study was to investigate the expression level of the SHH, PTCH1, GLI1, P53 and SMO genes in BCC skin tissue in order to identify reliable biomarkers for clinical applications in the diagnosis of skin BCC. BCC and healthy skin samples were collected from patients who had pre-operation pathological verification, RNA extracted, cDNA synthesized and RT-qPCR was carried out to analyze the expression levels of SHH, PTCH1, GLI1, P53 and SMO genes. Results of the RT-qPCR analysis revealed significant statistical difference in relative expression of SHH, PTCH1, GLI1, P53 and SMO genes between the BCC and healthy tissue groups. The RT-qPCR analysis also showed that expressions of the target genes were upregulated in BCC skin compared to the healthy skin tissue: GLI1 by 3.1 folds, P53 by 0.844 folds, PTCH1 by 4.64 folds, SHH by 1.75 folds and SMO by 2.46 folds. Results of this study suggest that PTCH1 gene can be used as a molecular biomarker for diagnosing BCC of skin. Further studies of the BCC development signalling pathway genes may lead to improved methods for diagnosis and treatment of this common cancer.

Key Words: Basal cell carcinoma, Hh signalling, marker genes, skin

 References

[1] Marzuka A. G., Book S. E. "Basal cell carcinoma: pathogenesis, epidemiology, clinical features, diagnosis, histopathology, and management", The Yale Journal of Biology and Medicine. Vol.  88, No. 2. pp. 167-179.  (2015).

[2] Puig, S., Berrocal, A. "Management of high-risk and advanced basal cell carcinoma", Clinical and Translational Oncology. Vol. 17, pp. 497–503. (2015).

[3] Verkouteren, J.A.C., Ramdas, K.H.R., Wakkee, M., Nijsten, T. "Epidemiology of basal cell carcinoma". Scholarly review. Br. J. Dermatol. Vol. 177, pp. 359–372. (2017).

[4] Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, Fleischer AB. "Incidence estimate of non-melanoma skin cancer in the United States, 2006". Archives of dermatology. Vol. 146, pp. 283–

      287. (2010).

[5] Flohil, S.C., Seubring, I., Van Rossum, M.M., Coebergh, J.W., de Vries, E., Nijsten, T. "Trends in basal cell carcinoma incidence rates: A 37-year Dutch observational study". Journal of Investigative Dermatology. Vol. 133, pp. 913–918. (2013).

[6] Deady, S., Sharp, L., Comber, H. "Increasing skin cancer incidence in young, affluent, urban populations: A challenge for prevention". Br. J. Dermatol. Vol. 171, pp. 324–331. (2014).

[7] Barton V., Armeson K., Hampras S., Ferris L. K., Visvanathan K., Rollison D., Alberg A. J. "Nonmelanoma skin cancer and risk of all-cause and cancer-related mortality: a systematic review". Archives of Dermatological Research. Vol. 309, No. 4, pp. 243-251. (2017).

[8] Wong C.S., Strange R.C., Lear J.T. "Basal cell carcinoma". The British Medical Journal. Vol. 327, pp. 794– 798. (2003).

[9] Kemp C. J. "Multistep skin cancer in mice as a model to study the evolution of cancer cells". Seminars in Cancer Biology Journal. Vol. 15, pp. 460-473. (2005).

[10] Dlugosz, A., Agrawal, S., Kirkpatrick, P. "Vismodegib". Journal of Nature Reviews- Drug Discovery. Vol. 11, pp. 437–438. (2012).

[11] Pellegrini C., Maturo M. G., Di Nardo L., Ciciarelli V., Gutiérrez C., Fargnoli M. C. "Understanding the Molecular Genetics of Basal Cell Carcinoma". International Journal of Molecular Sciences. Vol. 18, pii: E2485. (2017).

[12] Bakshi A., Chaudhary S. C., Rana M., Elmets C. A., Athar M. 2017. "Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond". Molecular Carcinogenesis. Vol. 12, pp. 2543-2557. (2017).

[13] Kim S., Kim S., Lee C., Shin S., Kim W., Jang G. "Expression profile of sonic hedgehog signaling-related molecules in basal cell carcinoma". PLoS One. Vol. 11,  e0225511. (2019).

[14] Atwood X., Li M., Lee A., Tang Y., Oro E. "GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas". Nature. Vol. 494, pp. 484-488. (2013).

[15] Li J., Wang J., Liu Y., Wang W. "Analysis of mutation in exon 17 of PTCH in patients with  nevoid basal cell carcinoma syndrome". Molecular Biology Reports. Vol. 37, pp. 359-362. (2010).

[16] Skoda M., Simovic D., Karin V., Kardum V., Vranic S., Serman L. "The role of the Hedgehog signalling pathway in cancer: A comprehensive review". The Bosnian Journal of Basic Medical Sciences. Vol. 18, pp. 8- 20. (2018).

[17] Schmittgen T., Livak K. "Analyzing real-time PCR data by the comparative C(T) method". Nature Protocols. Vol. 3, pp. 1101-1108. (2008).

[18] Hogue L., Harvey V. "Basal Cell Carcinoma, Squamous Cell Carcinoma, and Cutaneous Melanoma in Skin of Color Patients". Dermatologic Clinics. Vol. 37, pp. 519-526. (2019).

[19] Kim D., Kus K., Ruiz E. "Basal Cell Carcinoma Review". Haematology /Oncology Clinics of North America. Vol. 33, pp. 13-24. (2019).

[20] Aszterbaum M., Beech, J., Epstein E. "Ultraviolet Radiation Mutagenesis of Hedgehog Pathway Genes in Basal Cell Carcinomas". Journal of Investigative Dermatology. Vol. 4, pp. 41-45. (1999).

[21] Emmert S., Schön M., Haenssle H. "Molecular biology of basal and squamous cell carcinomas". Advances in Experimental Medicine and Biology. Vol. 810, pp. 234-252. (2014).

[22] Ohki K., Kumamoto H., Ichinohasama R., Sato T., Takahashi N., Ooya K. "PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts". International Journal of Oral and Maxillofacial Surgery. Vol 33, pp. 584-592. (2004).

[23] Aszterbaum M., Rothman A., Johnson R., Fisher M., Xie J., Bonifas J., Zhang X., Scott M., Epstein E. "Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome". Journal of Investigative Dermatology. Vol. 110, pp. 885-888. (1998).

[24] Holíková Z., Massi D., Lotti T., Hercogová J. "Insight into the pathogenesis of sporadic basal cell carcinoma". International Journal of Dermatology. Vol. 43, pp. 865-869. (2004).

[25] Tojo M., Mori T., Kiyosawa H., Honma Y., Tanno Y., Kanazawa K., Yokoya S., Kaneko F., Wanaka A. "Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma". Pathology International. Vol. 49, pp. 687-694. (2002).

[26] Daya-Grosjean L., Couvé-Privat S. "Sonic hedgehog signaling in basal cell carcinomas". Cancer Letters. Vol. 225, pp. 181-192. (2005).

[27] Iwasaki J., Srivastava D., Moy R., Lin H., Kouba D. "The molecular genetics underlying basal cell carcinoma pathogenesis and links to targeted therapeutics". Journal of the American Academy of Dermatology. Vol. 66, e167-e178. (2012).

[28] Velcheti V., Govindan R. "Hedgehog signaling pathway and lung cancer". Journal of Thoracic

        Oncology, (2): 7-10. (2007).

[29] Bodak, N., Queille, S., Avril, M., Bouadjar, B., Drougard, C., Sarasin, A. and Daya-Grosjean, L. "High levels of patched gene mutations in basal-cell carcinomas from patients with xeroderma  pigmentosum". Proc. Natl Acad. Sci. Vol. 96, pp. 5117–5122. (1999).

[30] Cohen P. "Axillary basal cell carcinoma in patients with Goltz-Gorlin syndrome: report of basal cell carcinoma in both axilla of a woman with basal cell nevus syndrome and literature review". Dermatol Online Journal. Vol. 20, pg665b9. (2014).

[31] He C., Zhang X., Wang Y., Sun K., Chen H. "Allele loss on chromosome 9q22.2-22.3 in sporadic basal cell carcinoma in Chinese". Chinese Medical Journal. Vol. 112, pp. 497-500. (1999).

[32] Paret C., Theruvath J., Russo A., Kron B., El Malki K., Lehmann N., Wingerter A., Neu M.A., Gerhold-Ay A., Wagner W., Sommer C., Pietsch T., Seidmann L., Faber J. "Activation of the basal cell carcinoma pathway in a patient with CNS HGNET-BCOR diagnosis: consequences for personalized targeted therapy". Oncotarget. Vol. 50, pp. 83378-83391. (2016).

[33] Xie, J., Murone, M., Luoh, S. M., Ryan, A., Gu, Q., Zhang, C., Rosenthal, A. "Activating Smoothened mutations in sporadic basal-cell carcinoma". Nature. Vol. 391, pp 90. (1998).

[34] Zhang T., Chen M., Lü Y., Xing Q., Chen W. "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. Vol. 409, pp. 166-170. (2011).

[35] Malek R., Matta J., Taylor N., Perry M.E., Mendrysa S.M. "The p53 inhibitor MDM2 facilitates Sonic Hedgehog-mediated tumorigenesis and influences cerebellar foliation". PLoS One. Vol. 18, e17884. (2011).

[36] Romer J., Kimura H., Magdaleno S., Sasai K., Fuller C., Baines H., Connelly M., Stewart C., Gould S., Rubin L., Curran T. "Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/) p53(-/-) mice". Cancer Cell. Vol. 6, pp. 229-240. (2004).

[37] Hafner C., Hartmann A., Knuechel R., Dietmaier W., Landthaler M., Vogt T. "Molecular genetic analysis excludes implantation metastasis of basal cell carcinomas". The Archives of Pathology & Laboratory Medicine. Vol. 127, pp. 1221-1224. (2003).

[38] Giglia-Mari, G., Sarasin, A. "TP53 mutations in human skin cancers". Human Mutation, (21): 217–228.

        (2003).

[39] Rosenstein, B., Phelps, R., Weinstock, M., Bernstein, J., Gordon, M., Rudikoff, D., Kantor, I., Shelton, R., Lebwohl, M. "p53 mutations in basal cell carcinomas arising in routine users of sunscreens". Photochemistry. Photobiology. Vol. 70, pp. 798–806. (1999).

[40] Wang, Y., Huang, Y., Ma, Z., Bu, D., Wang, Y., Tu, P., Li, H. "Frequency and features of TP53 mutation in 30 Chinese patients with sporadic basal cell carcinoma". Clinical & Experimental Dermatology. Vol. 39, pp. 829-834. (2014).

View Full Article