# Electronic Cigarettes' Toxicity: From Periodontal Disease to Oral Cancer
## 2 Effects of Electronic Cigarettes on the Oral Cavity
### Genetic and Epigenetic Alterations  
The transition from a normal cell to a cancer cell is a multistep process and is usually based on the accumulation of genetic alterations. Cancer progression appears when the alterations occur for the genes that regulate cell proliferation and apoptosis, but also angiogenesis and metastasis. Gene function can be altered in different ways: oncogenes can be activated by mutation or amplification and tumor suppressor genes may be inactivated by mutation, deletion, or methylation. In oral cancer, there are some genetic alterations found with a high frequency: the inactivation of TP53 (located at 17p13), the gain of chromosomal material at 3q26, and 11q13, and losses at 3p21, 13q21, and 14q32. In many cases, the tumor suppressor genes or oncogenes still need to be identified. Alterations like allelic losses at 3p, 9q, and 17p were observed in dysplastic lesions and were associated with early markers of carcinogenesis. However, early genetic changes are not necessarily correlated with altered morphology [44]. The initiation and evolution of oral cancer represent a cascade of complex processes, where both coding and non-coding genes are involved. Therefore, the identification of clinically relevant Oral Squamous Cell Carcinoma (OSCC)-specific circRNAs (circular RNAs) and the examination of their function and regulatory effects on OSCC are crucial to understanding the disease. circRNAs can regulate several cancer-associated pathways, and ultimately the malignancy of tumor cells. Understanding these processes can be used for the design of more effective anticancer therapies for patients with OSCC, increasing survival [45]. circRNA expression levels were compared in OSCC and healthy oral mucosa tissues using high-throughput, next-generation RNA sequencing technology, and a circRNA derived from the gene encoding pleckstrin homology domain-interacting protein (circPHIP) was characterized. [PERSON] et al. revealed that circPHIP acts as a ceRNA (competitive endogenous RNAs), regulating OSCC cells by adsorbing microRNA miR-142-5p, which not only displayed strong binding to circPHIP in oral cancer cell lines (SCC15 and CAL27) but also played an important role in the progression and metastasis of oral squamous cell carcinoma. The study indicated that circPHIP is highly expressed in both OSCC tissues and cell lines, and it can act as an oncogene in OSCC, due to its involvement in upregulating the expression of PHIP and alpha-actin 4 (ACTN4), which are driver genes in OSCC development. circPHIP regulated PHIP expression and, in consequence, affected the malignant behavior of OSCC. Moreover, the overexpression of PHIP and ACTN4 is associated with the activation of PI3K/AKT/mTOR signaling. The circPHIP/miR-142-5p/PHIP-ACTN4 axis can be at the basis of developing new strategies for targeted therapies for OSCC [46]. The term epigenetics refers to the analysis of changes in gene function that are mitotically and/or me meiotically heritable and that do not involve a modification in DNA sequence. These modifications directly affect gene expression. MicroRNAs (miRNAs) are small RNA molecules that have the ability to regulate gene expression after transcription, by either inhibiting mRNA translation or by degrading mRNA. These molecules intervene in many cellular, physiological, developmental, and pathological processes, including cancer initiation, progression, apoptosis, invasion, and metastasis. It is appreciated that about 50% of human genes are regulated by miRNAs. Dysregulations of microRNA have been reported in many types of cancers, including oral cancer. They play an important role in human natural killer cell function, epithelial-mesenchymal transition, and suppression of cell migration and invasion in cancer [34; 47]. [PERSON] et al. identified 578 miRNAs dysregulated by e-cigarette exposure (non-vaporized liquids) in human lung epithelial cells, and 125 miRNA affected by vaporized e-cigarette liquids.