Pre and Post-high-intensity Interval Training Delays Colon Tumor Onset in a Syngeneic Mouse Model.

BACKGROUND/AIM: High-intensity interval training (HIIT) can trigger transient anti-tumor cytotoxicity through the mobilization of natural killer cells (NK cells) and myokines. Yet, the effects of HIIT on tumor development and microenvironment are unclear. MATERIALS AND METHODS: Male C57/BL6 mice were administered either MC38 of syngeneic colon cancer cells or vehicle in a single subcutaneous injection. Before injection, the training group completed four weeks of the HIIT program (progressive swimming training, 3/week, 10-12 min, 4-6% of body weight for overload). Following injection, trained mice continued to exercise for two additional weeks. RESULTS: Pre and post-HIIT training was effective in preventing tumor onset (p=0.0065), maintaining body weight gain, and counteracting splenomegaly by 40% compared to the tumor group. However, HIIT had no impact on suppressing tumor growth, modifying final tumor volume, or significantly changing tumor proliferation (Ki-67), connective tissue content, or DNA double-strand damage detected by phospho-histone gamma-H2AX (γ-H2AX). CONCLUSION: Pre and post-HIIT program is feasible for mice carrying a subcutaneous syngeneic tumor and effective in delaying tumor burden; however, HIIT did not alter colon tumor endpoints.

ALCAM is a biomarker of tumor aggressiveness and worse prognosis in glottic laryngeal squamous cell carcinoma.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the second most frequent head and neck tumor. Prognosis of patients with LSCC has not improved in recent decades, showing a need for the identification of prognostic biomarkers and new therapeutic targets. Recently, we showed that ALCAM overexpression was associated with glottic LSCC prognosis. OBJECTIVES AND METHODS: Aiming to validate the prognostic value of ALCAM, we evaluate the ALCAM protein levels by immunohistochemistry in 263 glottic LSCC surgically treated with neck dissection. RESULTS: ALCAM was expressed in 48.7% and overexpressed in 36.5% of glottic LSCC samples. ALCAM overexpression was associated with lymph node metastasis (p = 0.030), lymphovascular involvement (p = 0.0002), high-grade tumors (p = 0.025), and tumor relapse (p = 0.043). Multivariate survival analyses showed an overfitting between ALCAM overexpression and lymph node metastasis as a prognostic variable. CONCLUSIONS: High ALCAM expression was associated with an aggressive glottic LSCC profile.

Glucocorticoid Receptor Gene (NR3C1) Polymorphisms and Metabolic Syndrome: Insights from the Mennonite Population.

The regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with polymorphisms and the methylation degree of the glucocorticoid receptor gene (NR3C1) and is potentially involved in the development of metabolic syndrome (MetS). In order to evaluate the association between MetS with the polymorphisms, methylation, and gene expression of the NR3C1 in the genetically isolated Brazilian Mennonite population, we genotyped 20 NR3C1 polymorphisms in 74 affected (MetS) and 138 unaffected individuals without affected first-degree relatives (Co), using exome sequencing, as well as five variants from non-exonic regions, in 70 MetS and 166 Co, using mass spectrometry. The methylation levels of 11 1F CpG sites were quantified using pyrosequencing (66 MetS and 141 Co), and the NR3C1 expression was evaluated via RT-qPCR (14 MetS and 25 Co). Age, physical activity, and family environment during childhood were associated with MetS. Susceptibility to MetS, independent of these factors, was associated with homozygosity for rs10482605*C (OR = 4.74, pcorr = 0.024) and the haplotype containing TTCGTTGATT (rs3806855*T_ rs3806854*T_rs10482605*C_rs10482614*G_rs6188*T_rs258813*T_rs33944801*G_rs34176759*A_rs17209258*T_rs6196*T, OR = 4.74, pcorr = 0.048), as well as for the CCT haplotype (rs41423247*C_ rs6877893*C_rs258763*T), OR = 6.02, pcorr = 0.030), but not to the differences in methylation or gene expression. Thus, NR3C1 polymorphisms seem to modulate the susceptibility to MetS in Mennonites, independently of lifestyle and early childhood events, and their role seems to be unrelated to DNA methylation and gene expression.

Interleukin 6 and Interleukin 1ß hypomethylation and overexpression are common features of apical periodontitis: A case-control study with gingival tissue as control.

OBJECTIVES: Apical periodontitis is a periradicular tissue disorder that usually arises from infection by microorganisms in the root canal system resulting in local bone resorption. This usually involves the dysregulation of inflammatory mediators, which can be mediated by epigenetic mechanisms. Thus, the objective of this study was to evaluate Interleukin 6 (IL6) and Interleukin 1ß (IL1ß) and DNA methylation and gene expression levels in apical periodontitis. METHODS: Gene expression was analyzed in 60 participants using quantitative polymerase chain reaction, while the methylation levels of IL6 and IL1ß promoters were analyzed in 72 patients using pyrosequencing. All statistical analyzes were performed using the GraphPad Prism software version 8.0. The p value was considered statistically significant when < 0.05. RESULTS: A significantly higher IL6 and IL1ß expression levels were observed in cases relative to controls (fold-changes of 27.4 and 11.43, respectively, and p < 0.0001). By comparing the same groups, lower promoter methylation levels were observed for both genes in cases (methylation percentage delta relative to controls of -24.57% and -16.02%, respectively, and p < 0.0001). A significant inverse correlation between gene expression and promoter methylation was observed for both IL6 (p = 0.0002) and IL1ß (p = 0.001). Neither IL6 expression nor promoter methylation were significantly associated with cases' age, smoking history, alcohol consumption history or sex. For IL1ß, alcoholic cases showed lower methylation level relative to non-alcoholic cases (p = 0.01), while females showed higher methylation levels relative to males (p = 0.03). CONCLUSIONS: Our data suggest a role for DNA methylation in IL6 and IL1ß upregulation in apical periodontitis.

Folic Acid and Vitamin B12 Prevent Deleterious Effects of Rotenone on Object Novelty Recognition Memory and Kynu Expression in an Animal Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by a range of motor signs, but cognitive dysfunction is also observed. Supplementation with folic acid and vitamin B12 is expected to prevent cognitive impairment. To test this in PD, we promoted a lesion within the substantia nigra pars compacta of rats using the neurotoxin rotenone. In the sequence, the animals were supplemented with folic acid and vitamin B12 for 14 consecutive days and subjected to the object recognition test. We observed an impairment in object recognition memory after rotenone administration, which was prevented by supplementation (p < 0.01). Supplementation may adjust gene expression through efficient DNA methylation. To verify this, we measured the expression and methylation of the kynureninase gene (Kynu), whose product metabolizes neurotoxic metabolites often accumulated in PD as kynurenine. Supplementation prevented the decrease in Kynu expression induced by rotenone in the substantia nigra (p < 0.05), corroborating the behavioral data. No differences were observed concerning the methylation analysis of two CpG sites in the Kynu promoter. Instead, we suggest that folic acid and vitamin B12 increased global DNA methylation, reduced the expression of Kynu inhibitors, maintained Kynu-dependent pathway homeostasis, and prevented the memory impairment induced by rotenone. Our study raises the possibility of adjuvant therapy for PD with folic acid and vitamin B12.

Oral Lichen Planus and Oral Squamous Cell Carcinoma share key oncogenic signatures.

To investigate similarities in the gene profile of Oral Lichen Planus and Oral Squamous Cell Carcinoma that may justify a carcinogenic potential, we analyzed the gene expression signatures of Oral Lichen Planus and Oral Squamous Cell Carcinoma in early and advanced stages. Based on gene expression data from public databases, we used a bioinformatics approach to compare expression profiles, estimate immune infiltrate composition, identify differentially and co-expressed genes, and propose putative therapeutic targets and associated drugs. Our results revealed gene expression patterns related to processes of keratinization, keratinocyte differentiation, cell proliferation and immune response in common between Oral Lichen Planus and early and advanced Oral Squamous Cell Carcinoma, with the cornified envelope formation and antigen processing cross-presentation pathways in common between Oral Lichen Planus and early Oral Squamous Cell Carcinoma. Together, these results reveal that key tumor suppressors and oncogenes such as PI3, SPRR1B and KRT17, as well as genes associated with different immune processes such as CXCL13, HIF1A and IL1B are dysregulated in OLP.

FBXL7 Body Hypomethylation Is Frequent in Tumors from the Digestive and Respiratory Tracts and Is Associated with Risk-Factor Exposure.

Squamous cell carcinoma is the main histological tumor type in the upper aerodigestive tract (UADT), including the esophagus (ESCC) and the head and neck sites, as well as the oral cavity (OCSCC), larynx (LSCC) and oropharynx (OPSCC). These tumors are induced by alcohol and tobacco exposure, with the exception of a subgroup of OPSCC linked to human papillomavirus (HPV) infection. Few genes are frequently mutated in UADT tumors, pointing to other molecular mechanisms being involved during carcinogenesis. The F-box and leucine-rich repeat protein 7 (FBXL7) is a potential tumor-suppressing gene, one that is frequently hypermethylated in pancreatic cancer and where the encoded protein promotes the degradation of AURKA, BIRC5 and c-SRC. Thus, the aim of this study was to evaluate the methylation and expression profile of FBXL7 in the UADT and the gene's association with the clinical, etiological and pathological characteristics of patients, as well as the expression of its degradation targets. Here we show that the FBXL7 gene's body is hypomethylated in the UADT, independently of histology, but not in virus-associated tumors. FBXL7 body methylation and gene expression levels were correlated in the ESCC, LSCC, OCSCC and OPSCC. Immunohistochemistry analysis showed that FBXL7 protein levels are not correlated with the levels of its degradation targets, AURKA and BIRC5, in the UADT. The high discriminatory potential of FBXL7 body hypomethylation between non-tumor and tumor tissues makes it a promising biomarker.

Head and Neck Cancers Are Not Alike When Tarred with the Same Brush: An Epigenetic Perspective from the Cancerization Field to Prognosis.

Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent types of cancer worldwide and, despite all efforts, are still diagnosed at late stages and show poor overall survival. Furthermore, HNSCC patients often experience relapses and the development of second primary tumors, as a consequence of the field cancerization process. Therefore, a better comprehension of the molecular mechanisms involved in HNSCC development and progression may enable diagnosis anticipation and provide valuable tools for prediction of prognosis and response to therapy. However, the different biological behavior of these tumors depending on the affected anatomical site and risk factor exposure, as well as the high genetic heterogeneity observed in HNSCC are major obstacles in this pursue. In this context, epigenetic alterations have been shown to be common in HNSCC, to discriminate the tumor anatomical subsites, to be responsive to risk factor exposure, and show promising results in biomarker development. Based on this, this review brings together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy.

IL6 and BCL3 Expression Are Potential Biomarkers in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) ranks among the most lethal tumors worldwide, as a consequence of late detection and poor treatment response, evidencing the need for diagnosis anticipation and new therapeutic targets. First, we investigated the IL6 gene and protein expression in the esophagus of individuals without esophageal disorders (healthy), ESCC, and non-tumoral surrounding tissue (NTST). Our results showed that IL6 mRNA and protein expression is upregulated in tumor cells relative to NTST. In the TCGA dataset, we identified a set of genes whose expression was correlated with IL6 mRNA levels, including the antiapoptotic gene BCL3. By using an immortalized esophageal cell line, we confirmed that IL6 was capable of inducing BCL3 expression in esophageal cells. BCL3 mRNA and protein are overexpressed in ESCC and NTST compared to healthy esophagus, and BCL3 mRNA could distinguish the morphologically normal samples (healthy and NTST) with 100% sensitivity and 95.12% specificity. The spatial intratumoral heterogeneity of both IL6 and BCL3 expression was evaluated, corroborating IL6 upregulation throughout the tumor, while tumor and NTST showed a consistent increase of BCL3 expression relative to the healthy esophagus. Our study shows that IL6 overexpression seems to be a key event in ESCC carcinogenesis, contributing to ESCC through a homogeneous antiapoptotic signalling via BCL3 overexpression, thus suggesting anti-IL6 therapies to be further considered for ESCC treatment. Finally, our data support the use of BCL3 mRNA expression as a potential biomarker for ESCC detection.

Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption.

Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected.

DNA Methylation Markers from Negative Surgical Margins Can Predict Recurrence of Oral Squamous Cell Carcinoma.

The identification of molecular markers in negative surgical margins of oral squamous cell carcinoma (OSCC) might help in identifying residual molecular aberrations, and potentially improve the prediction of prognosis. We performed an Infinium MethylationEPIC BeadChip array on 32 negative surgical margins stratified based on the status of tumor recurrence in order to identify recurrence-specific aberrant DNA methylation (DNAme) markers. We identified 2512 recurrence-associated Differentially Methylated Positions (DMPs) and 392 Differentially Methylated Regions (DMRs) which were enriched in cell signaling and cancer-related pathways. A set of 14-CpG markers was able to discriminate recurrent and non-recurrent cases with high specificity and sensitivity rates (AUC 0.98, p = 3 × 10-6; CI: 0.95-1). A risk score based on the 14-CpG marker panel was applied, with cases classified within higher risk scores exhibiting poorer survival. The results were replicated using tumor-adjacent normal HNSCC samples from The Cancer Genome Atlas (TCGA). We identified residual DNAme aberrations in the negative surgical margins of OSCC patients, which could be informative for patient management by improving therapeutic intervention. This study proposes a novel DNAme-based 14-CpG marker panel as a promising predictor for tumor recurrence, which might contribute to improved decision-making for the personalized treatment of OSCC cases.

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements.

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.

Potential Therapeutic Significance of Laminin in Head and Neck Squamous Carcinomas.

Head and neck squamous cell carcinomas (HNSCC) are among the most common and lethal tumors worldwide, occurring mostly in oral cavity, pharynx, and larynx tissues. The squamous epithelia homeostasis is supported by the extracellular matrix (ECM), and alterations in this compartment are crucial for cancer development and progression. Laminin is a fundamental component of ECM, where it represents one of the main components of basement membrane (BM), and data supporting its contribution to HNSCC genesis and progression has been vastly explored in oral cavity squamous cell carcinoma. Laminin subtypes 111 (LN-111) and 332 (LN-332) are the main isoforms associated with malignant transformation, contributing to proliferation, adhesion, migration, invasion, and metastasis, due to its involvement in the regulation of several pathways associated with HNSCC carcinogenesis, including the activation of the EGFR/MAPK signaling pathway. Therefore, it draws attention to the possibility that laminin may represent a convergence point in HNSCC natural history, and an attractive potential therapeutic target for these tumors.

Lipid droplet biogenesis and COX-2 pathway activation are triggered by Barrett's esophagus and adenocarcinoma, but not esophageal squamous cell carcinoma risk factors.

Esophageal cancer (EC) is an aggressive disease, presenting two main histological subtypes: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). The two EC subtypes widely differ concerning virtually all factors. ESCC development is mainly associated with tobacco and alcohol abuse, whereas obesity and chronic gastroesophageal reflux disease (GERD) are important risk factors not only for EAC, but also for for Barrett's esophagus (BE), an intestinal metaplasia that precedes EAC. Obesity triggers ectopic lipid droplets (LD) accumulation in non-adipose tissues. LD are organelles involved in cell metabolism, signaling, proliferation and production of inflammatory mediators. Therefore, the aim of this work was to investigate LD occurrence and role in EC. This study shows progressive LD levels increase along EAC development, in esophageal samples from non-obese through obese individuals, as well as BE, and EAC patients, whereas no significant changes were observed in ESCC samples, when compared to non-tumor samples. Additionally, in order to mimic BE and EAC risk factors exposure, a non-tumor esophageal cell line was incubated with oleic acid (OA) and acidified medium and/or deoxycholic acid (DCA), revealing a significant increment in LD amount as well as in COX-2 and CXCL-8 expression, and in IL-8 secretion. Further, COX-2 expression and LD amount presented a significant positive correlation and were detected co-localized in EAC, but not in ESCC, suggesting that LD may be the site for eicosanoid production in EAC. In conclusion, this study shows that obesity, and BE- and EAC-associated inflammatory stimuli result in a gradual increase of LD, that may be responsible for orchestrating inflammatory mediators' production and/or action, thus contributing to BE and EAC genesis and progression.

Interplay between HMGA and TP53 in cell cycle control along tumor progression.

The high mobility group A (HMGA) proteins are found to be aberrantly expressed in several tumors. Studies (in vitro and in vivo) have shown that HMGA protein overexpression has a causative role in carcinogenesis process. HMGA proteins regulate cell cycle progression through distinct mechanisms which strongly influence its normal dynamics along malignant transformation. Tumor protein p53 (TP53) is the most frequently altered gene in cancer. The loss of its activity is recognized as the fall of a barrier that enables neoplastic transformation. Among the different functions, TP53 signaling pathway is tightly involved in control of cell cycle, with cell cycle arrest being the main biological outcome observed upon p53 activation, which prevents accumulation of damaged DNA, as well as genomic instability. Therefore, the interaction and opposing effects of HMGA and p53 proteins on regulation of cell cycle in normal and tumor cells are discussed in this review. HMGA proteins and p53 may reciprocally regulate the expression and/or activity of each other, leading to the counteraction of their regulation mechanisms at different stages of the cell cycle. The existence of a functional crosstalk between these proteins in the control of cell cycle could open the possibility of targeting HMGA and p53 in combination with other therapeutic strategies, particularly those that target cell cycle regulation, to improve the management and prognosis of cancer patients.

P2Y2 receptor activation promotes esophageal cancer cells proliferation via ERK1/2 pathway.

Esophageal cancer is a prominent worldwide illness that is divided into two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Mortality rates are alarming, and the understanding of the mechanisms involved in esophageal cancer development, becomes essential. Purinergic signaling is related to many diseases and among these various types of tumors. Here we studied the effects of the P2Y2 receptor activation in different types of esophageal cancer. Esophageal tissue samples of healthy controls were used for P2Y2R expression quantification. Two human esophageal cancer cell lines Kyse-450 (squamous cell carcinoma) and OE-33 (adenocarcinoma) were used to perform in vitro analysis of cell proliferation, migration, adhesion, and the signaling pathways involved in P2Y2R activation. Data showed that P2Y2R was expressed in biopsies of patients with ESCC and adenocarcinoma, as well as in the two human esophageal cancer cell lines studied. The RT-qPCR analysis demonstrated that OE-33 cells have higher P2RY2 expression than Kyse-450 squamous cell line. Results showed that P2Y2R activation, induced by ATP or UTP, promoted esophageal cancer cells proliferation and colony formation. P2Y2R blockage with the selective antagonist, AR-C 118925XX, led to decreased proliferation, colony formation and adhesion. Treatments with ATP or UTP activated ERK 1/2 pathway in ESCC and ECA cells. The P2Y2R antagonism did not alter the migration of esophageal cancer cells. Interestingly, the esophageal cancer cell lines presented a distinct profile of nucleotide hydrolysis activity. The modulation of P2Y2 receptors may be a promising target for esophageal cancer treatment.

High infiltration of B cells in tertiary lymphoid structures, TCR oligoclonality, and neoantigens are part of esophageal squamous cell carcinoma microenvironment.

Esophageal squamous cell carcinoma (ESCA) exhibits high intratumoral molecular heterogeneity posing a challenge to cancer therapy. Immune checkpoint blockade therapy has been approved for this disease, but with modest results. RNA-Seq data from paired tumor and surrounding nonmalignant tissue from 14 patients diagnosed with ESCA without previous treatment and from The Cancer Genome Atlas-ESCA cohort were analyzed. Herein, we investigated ESCA immune landscape including mutation-derived neoantigens and immune cell subpopulations. Tumor-associated antigen expression was determined by in silico analyses and confirmed by immunohistochemistry showing that PRAME, CEACAM4, and MAGEA11 proteins are expressed on tumors. Immune checkpoint molecules gene expression was higher in the tumor compared with surrounding nonmalignant tissue, but its expression varies greatly among patients. TCR repertoire and BCR transcripts analysis evidenced low clonal diversity with one TCR clone predicted to be specific for a MAGEA11-derived peptide. A high number of B-cell clones infiltrating the tumors and the abundance of these cells in tertiary lymphoid structures observed in ESCA tumors support B cells as a potential immune modulator in this tumor.

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality rates. PDAC initiation and progression are promoted by genetic and epigenetic dysregulation. Here, we aimed to characterize the PDAC DNA methylome in search of novel altered pathways associated with tumor development. We examined the genome-wide DNA methylation profile of PDAC in an exploratory cohort including the comparative analyses of tumoral and non-tumoral pancreatic tissues (PT). Pathway enrichment analysis was used to choose differentially methylated (DM) CpGs with potential biological relevance. Additional samples were used in a validation cohort. DNA methylation impact on gene expression and its association with overall survival (OS) was investigated from PDAC TCGA (The Cancer Genome Atlas) data. Pathway analysis revealed DM genes in the calcium signaling pathway that is linked to the key pathways in pancreatic carcinogenesis. DNA methylation was frequently correlated with expression, and a subgroup of calcium signaling genes was associated with OS, reinforcing its probable phenotypic effect. Cluster analysis of PT samples revealed that some of the methylation alterations observed in the Calcium signaling pathway seemed to occur early in the carcinogenesis process, a finding that may open new insights about PDAC tumor biology.

Association of DNA sequence-independent genetic regulatory mechanisms with apical periodontitis: A scoping review.

OBJECTIVE: Different studies in the last decade have proposed that gene expression alterations that are independent of the DNA sequence may also play an important role in periapical disease. The present study aimed to assess the available evidence supporting a relationship between these alterations and apical periodontitis through a scoping review. DESIGN: Specific strategies were developed for different databases (MEDLINE via PubMed, Cochrane Library, Scopus, Web of Science, and Virtual Health Library) and a search performed by March 1st, 2019. The evidence sources were selected according to the eligibility criteria and underwent a critical appraisal of methodological quality. RESULTS: The initial search retrieved 212 references, with eight eligible articles after the removal of replicates and application of exclusion criteria. Five studies identified altered DNA methylation on inflammatory response genes (FOXP3, CXCL3, FADD, MMP2, MMP9, IFNG, IL4, IL12) on AP patients. Three others identified the alterations on the expression of several microRNAs (miR-29b, 106b, 125b, 143, 146a, 155, 198) during AP. No evidence was identified regarding mechanisms of histone methylation, or of epigenetic heritability or stability. CONCLUSIONS: There is available evidence for the involvement of different genetic regulatory mechanisms independent of changes in DNA sequence in the development or severity of apical periodontitis. However, due to methodological limitations, further research must be performed before novel therapies and diagnostic tools for AP may arise from these data.