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The aim of this study was to investigate the associations among the immunoexpression levels of manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and myeloperoxidase (MPO) in lip squamous cell carcinoma (LSCC) tissues and the clinicopathological characteristics, and prognostic factors in patients with LSCC. The immunoexpression levels of Mn-SOD, GPx, and MPO were examined in 76 LSCC tissue samples using immunohistochemical staining on tissue microarray slides, and compared to those in normal lip mucosa adjacent to venous lakes (normal controls), normal tissue adjacent to corresponding tumors (NTACT), and recurrent tumors. Associations between immunoexpression levels and clinicopathological characteristics were analyzed using the Student's t-test. The prognostic factors were analyzed using Cox regression. The immunoexpression levels of Mn-SOD, GPx, and MPO were significantly different among the normal controls, NTACTs, tumors, and recurrent tumors (Mn-SOD: p = 0.001, GPx: p < 0.001, MPO: p < 0.001). Lower lip cancer was associated with higher Mn-SOD immunoexpression levels (p = 0.04) and probably indicated higher oxidative stress. Lymph node involvement with a lower immunoexpression level of MPO (p = 0.007) indicated compensatory mechanism to attenuate oxidative damage. A low Mn-SOD immunoexpression level was borderline significantly associated with a worse prognosis for disease-specific survival, and it was probably related to a lower capacity for coping with oxidative stress., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

Background: Acetylation and deacetylation are the most studied covalent histone modifications resulting in transcriptional regulation with histone deacetylases (HDAC) and histone acetyltransferases (HAT) as the main associated enzymes. These enzymes overexpression induces abnormal transcription of key genes that regulate important cellular functions, such as proliferation, cell cycle regulation, and apoptosis. Thus, the expression of different HATs and HDACs has been evaluated in various cancers., Objective: To investigate HDAC1, HDAC2 and HAT1 expression in lip squamous cell carcinoma (LSCC) and actinic cheilitis (AC) and to demonstrate their correlation with DNA metyltransferases (DNMTs)., Material and Methods: Thirty cases of lip squamous cell carcinoma (LSCC), thirty cases of actinic cheilitis (AC), and 28 cases of non-neoplastic epithelium as control were selected for immunohistochemical investigation., Results: Nuclear HDAC2 immunopositivity was significantly higher in AC (75.07% ± 29.70) when compared with LSCC (51.06% ± 39.02). HDAC1 and HAT1 nuclear immunostaining were higher in AC, with no statistical significance. When comparing data with our previous study, we found a positive correlation between HDAC1 X DNMT1/DNMT3b, HDAC2 X DNMT3b, and HAT1 X DNMT1/DNMT3b for certain studied groups., Conclusion: This study showed higher levels of nuclear HDAC2 immunopositivity in AC, possibly indicating that this enzyme plays a key role in lip photocarcinogenesis early stages., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Epigenetic modifications, including DNA methylation of tumor suppressor genes carried out by DNA methyltransferases (DNMTs), are important events in carcinogenesis. Although there are studies concerning to its expression in several cancer types, DNMTs expression pattern is not known in photoinduced lip carcinogenesis. The aim of this study was to investigate the immunoexpression of DNMTs 1, 3a, and 3b in lip precancerous lesion (actinic cheilitis) and cancer., Methods: Thirty cases of actinic cheilitis (AC), thirty cases of lip squamous cell carcinoma (LSCC), and twenty cases of non-neoplastic tissue (NNT) were selected for immunohistochemical investigation of DNMTs 1, 3a, and 3b., Results: Nuclear DNMT 1 immunoreactivity was significantly higher in the LSCC group (68.6%) compared with NNT (47%), and nuclear DNMT 3b was higher in LSCC (70.9%) than in NNT (37.9%) and in AC (44%). Only DNMT 3a showed both higher nuclear and cytoplasmic expression in AC (35.9% and 35.5%, respectively) than in NNT (4.4% and 16.1%, respectively) and LSCC (8.8% and 13.2%, respectively) (P < 0.05)., Conclusions: The results suggested that DNMT 3a could play a key role in the methylation process of initial steps of UV carcinogenesis present in AC while DNMT 3b could be responsible for de novo methylation in already established lip cancer., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This study aimed to evaluate apoptosis by assessing cleaved caspase-3 immunoexpression in hyperplastic, potentially malignant disorder (PMD), and malignant tumors in intraoral and lower lip sites., Material and Methods: A retrospective study using paraffin blocks with tissues from patients with inflammatory fibrous hyperplasia (IFH), actinic cheilitis, oral leukoplakia, lower lip and intraoral squamous cell carcinoma (SCC) was performed. The tissues were evaluated by immunohistochemical analysis with anti-cleaved caspase-3 antibody. Apoptotic area index was then correlated with lesion type., Results: From 120 lesions assessed, 55 (46%) were cleaved caspase-3-positive. The SCC samples (n=40) had the highest apoptotic area indices (n=35; 87.5%). Significant differences were detected between SCCs and PMDs (p=0.0003), as well as SCCs and IFHs (p=0.001), regarding caspase-3 immunopositivity. Carcinomas of the lower lip had lower apoptotic area indices than intraoral cancer (p=0.0015)., Conclusions: Cleaved caspase-3 immunoexpression showed differences in oral SCCs and PMDs and demonstrated a distinct role of apoptosis in carcinogenesis of intraoral and lower lip cancer. In future, the expression of cleaved caspase-3 with other target molecules in oral cancer may be helpful in delineating the prognosis and treatment of these tumors.

Background: Matrix metalloproteinase-3 (MMP-3) plays a key role in development of cancer. The purpose of this study was to assess MMP-3 in the serum and saliva of patients with oral lichen planus (OLP) and oral squamous cell carcinoma (OSCC)., Materials and Methods: Thirty patients with OLP (8 reticular and 22 erosive forms), and 20 patients with OSCC (6 in low stage and 14 in advanced stage), were enrolled in this study, conducted at the Cancer Department, Clinic of Oral Medicine, Tehran University of Medical Sciences. The serum and saliva MMP-3 was assayed by ELISA method. Statistical analysis of the Student's t-test, ANOVA and Pearson correlation coefficient was performed. The mean saliva and serum levels of MMP-3 were significantly higher in patients with OSCC compared with OLP., Results: The serum and saliva MMP-3 concentrations increased from reticular form of OLP to erosive form of OLP, and increased further to low stage of OSCC and advanced stage of OSCC. Serum MMP-3 correlated significantly with unstimulated (r = 0.310, p = 0.038) and stimulated (r = 0.365, p < 0.026) saliva MMP-3., Conclusion: Serum and saliva MMP-3 levels appear associated with OLP and OSCC.

Actinic cheilitis exhibits a potential of malignant transformation in 10-20 % of cases. The objective of this study was to compare the expression of MDM2 and SUMO-1 proteins between actinic cheilitis (AC) and squamous cell carcinoma (SCC) of the lip. The sample consisted of lower lip mucosa specimens obtained from cases with a clinical and histopathological diagnosis of AC (n = 26) and SCC (n = 25) and specimens of labial semi-mucosa (n = 15) without clinical alterations or inflammation. The tissue samples were stained with hematoxylin-eosin and anti-MDM2 and anti-SUMO-1 antibodies. Data were analyzed by the Kruskal-Wallis and Dunn's tests (5 %). The median expression of MDM2 (kW = 36.8565; df = 3-1 = 2; p = 0.0001) and SUMO-1 (kW = 32.7080; df = 3-1 = 2; p = 0.0001) was similar in cases of AC and SCC of the lip, but differed significantly from that observed for normal labial semi-mucosa. Despite the limitations of the present study, immunohistochemistry demonstrated the overexpression of important proteins (MDM2 and SUMO-1) related to regulatory mechanisms of apoptosis in AC and SCC of the lip, but further studies are needed.

The prevalence of squamous cell carcinoma of the lower lip (SCC-LL) is increasing worlwide. The expression of the enzyme indoleamine 2,3-dioxygenase (IDO) by antigen-presenting cells and/or tumor cells leads to tumor escape by inhibiting T cell-mediated rejection responses. The aim of this study was to determine the expression of IDO in SCC-LL. IDO-expression was analyzed in 47 SCC-LL, together with the expression of markers of T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), Langerhans cells (CD1a, Langerin (CD207)), plasmacytoid DCs (CD123), and regulatory T cells (Foxp3) by immunohistochemistry and immunofluorescence analysis. Twelve specimens out of 47 LL-SCCs contained cells that expressed IDO. IDO-positivity was strongly associated with the intensity of the cancer-associated infiltrate (P=0.0007). IDO-positive cells are located right along the border between the developing tumor and the inflammatory infiltrate. Immunofluorescence stainings showed that CD11c+S100+CD68- dendritic cells (DCs) express IDO in SCC-LL. IDO expression in LL-SCC may aid immune escape and chronic inflammation to promote cancer progression. Inhibition of IDO might be a therapeutic strategy to increase the anti-tumor immune response in SCC-LL.

Background: Lower lip squamous cell carcinoma (LLSCC) is an oral cancer that has distinct epidemiology and etiopathogenesis. Although risk factors for this neoplasia are acknowledged, few studies have investigated the molecular basis of its development and behavior., Methods: Expression of p53 and p21(WAF1/CIP1) was examined by immunohistochemistry of archived tissue from 21 specimens of LLSCC. Differences in this expression between the whole tumor (WT) and the invasive front (IF) as well as correlation between p53 and p21(WAF1/CIP1) expression were analyzed., Results: p53 and p21(WAF1/CIP1) were overexpressed at the IF of LLSCC. The expression of both proteins was higher at IF than at WT. No correlation was observed between p53 and p21(WAF1/CIP1) expression., Conclusions: Our results indicate that p53 and p21(WAF1/CIP1) overexpression is important in LLSCC pathogenesis, reinforce that IF is the most important area for tumor behavior, and support that p53-independent mechanisms should be involved in the expression of p21(WAF1/CIP1).

Background: Lip squamous cell carcinoma (SCC) is the most common form of oral cancer. Human mast cells (MCs), which are increased in lip SCC, are classified by their protease content in tryptase-positive (MC(T)) and tryptase/chymase-positive (MC(TC)). MC proteases are associated with tumor progression and angiogenesis. The aim of this study was to quantify and characterize MC subpopulations in lip SCC., Methods: Serial sections from lip SCC (n = 21) and normal lip vermilion (n = 8) biopsies were stained immunohistochemically for tryptase and enzymehistochemically for chymase to determine MC subpopulation density and distribution., Results: MC(T) and MC(TC) were increased in lip SCC when compared with normal lip (P < 0.0001), where MC(T) predominated over MC(TC) (P < 0.01). In lip SCC neither subpopulation predominated. Regarding distribution, MC(T) were higher than MC(TC) at the intratumoral stroma, whereas MC(TC) were higher than MC(T) at the peritumoral stroma (P < 0.01)., Conclusions: The results suggest that MC subpopulations may contribute to lip SCC progression. While intratumoral MC(T) may stimulate angiogenesis, peritumoral MC(TC) may promote extracellular matrix degradation and tumor progression at the invasion front.

Background: Actinic cheilitis (AC) is a pre-malignant lesion caused by ultraviolet (UV) radiation and characterized by epithelial and connective tissue alterations. Mast cells (MCs), key contributors to solar elastosis in murine UV-irradiated skin, were characterized in order to assess their potential contribution to connective tissue degeneration in AC., Methods: Actinic cheilitis (n = 15) and normal lip (n = 8) biopsies were stained immunohistochemically for tryptase and enzymehistochemically for chymase to determine MC density and protease content. MC subpopulations (i.e. MC(T) containing only tryptase, and MC(TC) containing chymase and tryptase) and their distribution were also determined., Results: Mast cells and their proteases were increased in AC as compared with normal lip (P < 0.0001), and appeared degranulated especially around elastotic areas. MC(T) predominated over MC(TC) in AC and normal lip (P < 0.05). However, in AC MC(T) were increased in the epithelium/connective junction and connective area (P < 0.05), while in normal lip MC(T) predominated in connective and submucosal areas (P < 0.05)., Conclusion: The results suggest that increased MC density and protease content may contribute to elastosis formation in AC. In addition, changes in MC(T) distribution may favor AC malignization.

Junctional nevi of the oral mucosa are rare and may be precancerous. A patient who had an enlarging junctional nevus of the labial mucosa with an adjacent lentigo simplex was studied by light and electron microscopy. On the basis of morphologic similarities--dentritic appearance, lack of desmonsomes, proliferative melanin production, and lack of cytoplasmic fibrils--it appears that the nevus cell most likely develops from melanocytes. The reason for the transformation from melanocyte to nevus cell or junctional nevus cell hyperplasia is unknown.