Complexity and heterogeneity are frequently present during the development and progression of carcinogenesis and, in the last 15 years, significant progress made in clinical research underlines the role of
some epigenetic mechanisms. The most important characteristics of the epigenetic concept are that these
events are reversible, not related to modifications in the structure of DNA and may drive fundamental cell
signaling alterations1. Among these systems of communication in normal and pathological conditions,
also microbiome and staminal cells2 seem to be important. These new profiles of pathological communication develop novel diagnostic, prognostic and therapeutic tool

CASU C

CONI P.

ORRU G

SCANO A

English

Archivio istituzionale della ricerca - Università di Cagliari

7318Complexity and heterogeneity are frequently present during the development and progression of car-cinogenesis and, in the last 15 years, significant progress made in clinical research underlines the role of some epigenetic mechanisms. The most important characteristics of the epigenetic concept are that these events are reversible, not related to modifications in the structure of DNA and may drive fundamental cell signaling alterations1. Among these systems of communication in normal and pathological conditions, also microbiome and staminal cells2 seem to be important. These new profiles of pathological communi-cation develop novel diagnostic, prognostic and therapeutic tools. Like other types of cancers, also oral malignancies have been intensely studied and the most interesting results regard specific epigenome modifications like DNA methylation, acetylation and de-acetylation of Histones and non-coding RNA-related modifications, especially miRNAs, start to be proposed (Figure 1). Oral cancer is one of the most common worldwide in terms of both incidence and mortality and epigenetic modifications of specific genes (APC, cadherin, surviving, PTEN, FLT4, KDR, and TFPI2) are frequently founded hyper-methylated in oral cancer samples and also in cell lines. An increasing number of studies provide evidence for the possible use of epigenetic modifications in oral cancer, including DNA methylation, numerous histone modifications, long non-coding RNAs (lncRNA, >200 nt) and small non-coding RNAs like MicroRNAs (<200 nt).These epigenetic mechanisms are in part responsible for abnormal cellular growth, adding not only ad-ditional complexity in terms of cancer heterogeneity but also new diagnostic and therapeutic opportunities.Non-invasive or minimally invasive procedures based on sampling collection from oral brushing, mouth rinsing, or saliva and analysis of epigenetic markers start to be proposed as a diagnostic aid to identify patients at risk of developing oral cancer3. Abnormal DNA methylation status in the initial and late stages of oral carcinogenesis, before any morphological changes, may silence tumor suppressor genes and/or activate oncogene patterns, including hypermethylation of gene promoter regions4. Thus, the iden-tification of gene methylation may provide an appropriate marker useful for more complete classification but also for establishing alternative therapeutic strategies.Histone proteins can be modified in different ways (ubiquitylation, sumoylation, methylation, acetyl-ation, and also phosphorylation), influencing gene transcription and several biologic signaling pathways. In particular, histone deacetylase was found to be increased in oral cancer-derived cell lines and in clinical specimens5. A large volume of evidence has demonstrated that these small non-coding RNAs, containing 20-22 nucleotides, play key roles in oral cancer growth, cell migration and invasion. These small molecules are able to bind the regulatory regions (UTR) of the mRNA and block the translation of the target gene or, can induce complete degradation of the transcript6. Therefore, miRNAs may be used as possible molecules able to modulate the expression of target genes in order to maintain the normal state of the organism and more and may be considered as novel prognostic and therapeutic tools for these diseases7. The cancer-revealing miRNA is often carried from oral neoplastic cells in extracellular lipidic vesi-cles, thus circulating in saliva8. Its detection by molecular tools in salivary fluid, such as real-time PCR or droplet PCR, could be a powerful prognostic tool for follow-up after treatment for oral cancer. This laboratory method appears crucial if used in combination with new promising therapeutic procedures such as photodynamic therapy (PDT). European Review for Medical and Pharmacological Sciences 2022; 26: 7318-7320Corresponding Author: Germano Orrù, Ph.D; e-mail: orru@unica.it; gerorru@unica.itA. SCANO1, C. CASU1,2, G. ORRÙ1,3, P. CONI41Oral Biotechnology Laboratory (OBL), Department of Surgical Sciences, University of Cagliari, Cagliari, Italy2Innovation Sciences and Technologies, University of Cagliari, Cagliari, Italy3National Research Council of Italy CNR, ISPA Sassari, Sassari, Italy4Department of Medical Sciences and Public Health, Division of Pathology, AOU of Cagliari, Cagliari, ItalyEditorial – Epigenetic mechanisms in oral cancer: new diagnostic and therapeutic trategiesEpigenetic mechanisms in oral cancer: new diagnostic and therapeutic strategies7319Photodynamic therapy (PDT) involves the use of a phototoxic drug, called a photosensitizer, which is activated by light irradiation (not only laser) of a specific wavelength that corresponds to an absorbance band of the sensitizer, that destroys selectively neoplastic cells9. A recent meta-analysis on PDT and surgery treatment in early-stage suggests that there was no statistically significant difference in recurrence rates between the two interventions10. Different types of photosensitizers are proposed in the scientific litera-ture in PDT for oral cancer: ALA excited by wavelength (λ) of 635 nm; porphyrin derivative λ = 530 nm; chlorine-mediate λ = 664 nm; curcumin with UVA or visible light11. Despite the promising performance of PDT against oral cancer, the therapeutic strategy in terms of a number of treatments, times, and light power, remains unknown at this time. In this context, a PDT therapy based on salivary mRNAs profile could be a good and innovative clinical path. In addition, the use of conventional therapies does not preclude the use of PDT and the use of PDT does not compromise future surgical interventions, radiation therapy, or new therapeutic strategies12. PDT has already proven efficacy and safety for other oral diseases13. In this contest, new fluorescent receptors can be easily internalized in the tumoral cell and, encapsulated in injectable nanoparticles, could be used as new photosensitizers for targeted delivery14,15.Based on these considerations, even if further research is necessary to expand clinical application, it is now clear that epigenetic mechanisms are part of heterogeneous cancer signaling16-18. These preliminary results in oral cancer are promising and are mandatory to expand the application of new types of thera-peutic agents (epigenetic modifiers) in the clinical practice and in laboratory diagnosis strategies by using procedures and methods already used in other pathologies.Conflict of InterestThe Authors declare that they have no conflict of interests.References   1) Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet 2002; 3: 415-428.  2) Reali A, Puddu M, Pintus MC, Marcialis MA, Pichiri G, Coni P, Manus D, Dessì A, Faa G, Fanos V. Multipotent stem cells of mother’s milk. JPNIM 2016; 5: e050103. Figure 1. Schematic representation of the epigenetic events involved in the regulation of gene expression.A. Scano, C. Casu, G. Orrù, P. Coni7320  3) Rossi R, Gissi DB, Gabusi A, Fabbri VP, Balbi T, Tarsitano A, Morandi L. A 13-Gene DNA Methylation Analysis Using Oral Brushing Specimens as an Indicator of Oral Cancer Risk: A Descriptive Case Report. Diagnostics (Basel) 2022; 12: 284.  4) Schussel J, Zhou XC, Zhang Z, Pattani K, Bermudez F, Jean-Charles G, McCaffrey T, Padhya T, Phelan J, Spivakovsky S, Brait M, Li R, Bowne HY, Goldberg JD, Rolnitzky L, Robbins M, Kerr AR, Sirois D, Califano JA. EDNRB and DCC salivary rinse hypermethylation has a similar performance as expert clinical examina-tion in discrimination of oral cancer/dysplasia versus benign lesions. Clin Cancer Res 2013; 19: 3268-3275.  5) Sakuma T, Uzawa K, Onda T, Shiiba M, Yokoe H, Shibahara T, Tanzawa H. Aberrant expression of histone deacetylase 6 in oral squamous cell carcinoma. Int J Oncol 2006; 29: 117-124.   6) Wang J, Lv N, Lu X, Yuan R, Chen Z, Yu J. Diagnostic and therapeutic role of microRNAs in oral cancer. Oncol Rep 2021; 45: 58-64.   7) Pop-Bica C, Gulei D, Cojocneanu-Petric R, Braicu C, Petrut B, Berindan-Neagoe I. Understanding the Role of Non-Coding RNAs in Bladder Cancer: Dark Matter to Valuable Therapeutic Targets. Int J Mol Sci 2017; 18: 1514.   8) Gai C, Camussi F, Broccoletti R, Gambino A, Cabras M, Molinaro L, Carossa S, Camussi G. Salivary extracel-lular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma. BMC Cancer 2018; 18: 439.  9) Civantos FJ, Karakullukcu B, Biel M, Silver CE, Rinaldo A, Saba NF, Takes RP, Vander Poorten V, Ferlito A. A review of photodynamic therapy for neoplasms of the head and neck. Adv Ther 2018; 35: 324-340. 10) Saini R, Lee NV, Liu KY, Poh CF. Prospects in the application of photodynamic therapy in oral cancer and premalignant lesions. Cancers (Basel) 2016; 8: 83. 11) Olek M, Kasperski J, Skaba D, Wiench R, Cieślar G, Kawczyk-Krupka A. Photodynamic therapy for the treat-ment of oral squamous carcinoma-Clinical implications resulting from in vitro research. Photodiagnosis Photo-dyn Ther 2019; 27: 255-267. 12) Binnal A, Tadakamadla J, Rajesh G, Tadakamadla SK. Photodynamic therapy for oral potentially malignant disorders: A systematic review and meta-analysis. Photodiagnosis Photodyn Ther 2022; 37: 102713. 13) Casu C, Mannu C. Atypical Afta Major Healing after Photodynamic Therapy. Case Rep Dent 2017; 2017: 8517470.  14) Carruth JA. Clinical applications of photodynamic therapy. Int J Clin Pract 1998; 52: 39-42. 15) Lachowicz JI, Picci G, Coni P, Lippolis V, Mamusa M, Murgia S,Pichiri G, Caltagirone C. Fluorescent squara-mide ligands for cellular imaging and their encapsulation in cubosomes. New J Chem 2019; 43: 10336-10342. 16) Scano A, Orrù G, Serafi G, Occhinegro A, Ratto D, Girometta C, Rossi, P. Long non-coding RNAs: possible parallel paths by E-cadherin expression in colon cancer development as well as in Pseudomonas aeruginosa infection. Eur Rev Med Pharmacol Sci 2018; 22: 5053-5055. 17) Scano A, Ratto D, Occhinegro A, Pedroncelli A, Rossi P. MicroRNA-552 in colorectal cancer with poor prognosis. Its role as a novel molecular biomarker. Eur Rev Med Pharmacol Sci 2018; 22: 1171-1174. 18) Mameli A, Murgia MS, Orrù G, Casu C. Correlation between chronic mucosal trauma and oral cancer: a case report and review of the literature. WCRJ 2021; 8: e2039.

Epigenetic mechanisms in oral cancer: new diagnostic and therapeutic strategies

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Epigenetic mechanisms in oral cancer: new diagnostic and therapeutic strategies

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