cyclin-d1 and Ameloblastoma

Ameloblastoma is a locally invasive neoplasm often associated with morbidity and facial deformities, showing increased Epidermal Growth Factor Receptor (EGFR) expression. Inhibition of EGFR was suggested as a treatment option for a subset of ameloblastomas. However, there are resistance mechanisms that impair anti-EGFR therapies. One important resistance mechanism for EGFR-inhibition is the EGFR nuclear localization, which activates genes responsible for its mitogenic effects, such as Cyclin D1.. We assessed EGFR nuclear localization in encapsulated (unicystic, n = 3) and infiltrative (multicystic, n = 11) ameloblastomas and its colocalization with Cyclin D1 by using anti-EGFR and anti-lamin B1 double labeling immunofluorescence analyzed by confocal microscopy. Oral inflammatory fibrous hyperplasia and oral squamous cell carcinoma samples were used for comparison.. Twelve cases of ameloblastoma exhibited nuclear EGFR colocalization with lamin B1. This positive staining was mainly observed in the ameloblast-like cells. The EGFR nuclear localization was also observed in control samples. In addition, nuclear EGFR colocalized with Cyclin D1 in ameloblastomas.. Nuclear EGFR occurs in ameloblastomas in association with Cyclin D1 expression, which is important in terms of tumor biology clarification and raises a concern about anti-EGFR treatment resistance in ameloblastomas.

Topics: Ameloblastoma; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Nucleus; Cyclin D1; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Jaw Neoplasms; Lamin Type B; Microscopy, Confocal; Microscopy, Fluorescence; Mouth Neoplasms

Ameloblastoma is an odontogenic neoplasm with local invasiveness and high recurrence. We previously suggested that growth factors, matrix metalloproteinases (MMPs), and TIMPs influence ameloblastoma invasiveness (Pathol. Res. Pract., 208, 2012, 225; Oral. Surg. Oral. Med. Oral. Pathol. Oral Radiol. Endod., 111, 2011, 474). Signals generated by this molecular network would be transduced by ERK 1/2 pathway (Oral. Surg. Oral. Med. Oral. Pathol. Oral Radiol. Endod., 111, 2011, 474). Others signaling pathways may influence ameloblastoma biology. Here, we studied expression of AKT and related molecules in ameloblastoma.. Fourteen cases of solid/multicystic ameloblastomas were examined. Immunohistochemistry was carried out to detected AKT (phospho-AKT), NF-қB (phospho-NF-қB), β-catenin, cyclin-D1, and COX-2 in ameloblastoma samples. These molecules were evaluated in neoplastic cells and stroma.. All proteins were detected in ameloblastoma. Expression of these markers was quantified and compared. Spearman's rank test was carried out to address positive correlations between proteins (P < 0.05). Ameloblastoma had a significant positive correlation of AKT (phospho-AKT) with β-catenin. β-catenin correlated with Cyclin-D1 and COX-2 in neoplastic cells. AKT (phospho-AKT) correlated with β-catenin; β-catenin with Cyclin-D1; AKT (phospho-AKT) with NF-қB (phospho-NF-қB); and NF-қB (phospho-NF-қB) with COX-2 in stromal cells.. Results suggest that proteins studied are present and probably involved in a functional pathway in neoplastic cells and stroma and may therefore influence the local invasiveness of ameloblastoma.

Topics: Ameloblastoma; beta Catenin; Cell Nucleus; Cyclin D1; Cyclooxygenase 2; Cytoplasm; Humans; Immunohistochemistry; Neoplasm Invasiveness; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction; Stromal Cells

Sonic hedgehog (SHH) pathway activation has been identified as a key factor in the development of many types of tumors, including odontogenic tumors. Our study examined the expression of genes in the SHH pathway to characterize their roles in the pathogenesis of keratocystic odontogenic tumors (KOT) and ameloblastomas (AB).. We quantified the expression of SHH, SMO, PTCH1, SUFU, GLI1, CCND1, and BCL2 genes by qPCR in a total of 23 KOT, 11 AB, and three non-neoplastic oral mucosa (NNM). We also measured the expression of proteins related to this pathway (CCND1 and BCL2) by immunohistochemistry.. We observed overexpression of SMO, PTCH1, GLI1, and CCND1 genes in both KOT (23/23) and AB (11/11). However, we did not detect expression of the SHH gene in 21/23 KOT and 10/11 AB tumors. Low levels of the SUFU gene were expressed in KOT (P = 0.0199) and AB (P = 0.0127) relative to the NNM. Recurrent KOT exhibited high levels of SMO (P = 0.035), PTCH1 (P = 0.048), CCND1 (P = 0.048), and BCL2 (P = 0.045) transcripts. Using immunolabeling of CCND1, we observed no statistical difference between primary and recurrent KOT (P = 0.8815), sporadic and NBCCS-KOT (P = 0.7688), and unicystic and solid AB (P = 0.7521).. Overexpression of upstream (PTCH1 and SMO) and downstream (GLI1, CCND1 and BCL2) genes in the SHH pathway leads to the constitutive activation of this pathway in KOT and AB and may suggest a mechanism for the development of these types of tumors.

Topics: Adolescent; Adult; Ameloblastoma; Ameloblasts; Cyclin D1; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Male; Mandibular Neoplasms; Middle Aged; Mouth Mucosa; Neoplasm Recurrence, Local; Odontogenic Tumors; Patched Receptors; Patched-1 Receptor; Proto-Oncogene Proteins c-bcl-2; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Repressor Proteins; Smoothened Receptor; Transcription Factors; Transcription, Genetic; Young Adult; Zinc Finger Protein GLI1

To clarify the genetic background of ameloblastoma, expression of beta-catenin, and mutational status of genes involved in Wnt signaling pathway were investigated.. We analyzed beta-catenin and cyclin D1 in 18 cases of ameloblastoma by immunohistochemical staining, and searched for mutations in CTNNB1 (gene for beta-catenin), APC, AXIN1, and AXIN2 by polymerase chain reaction (PCR) and direct sequencing method.. We detected membranous and occasionally cytoplasmic expression of beta-catenin in 16 of 18 cases (89%), and nuclear expression of beta-catenin principally in the peripheral columnar cells in 11 of 18 cases (61%). In nine of the 18 cases (50%), we detected the expression of cyclin D1 principally in the peripheral columnar cells. However, there was no correlation between nuclear expressions of beta-catenin and cyclin D1. No missense mutations were found in CTNNB1, APC, AXIN1, and AXIN2 in all cases except for silent mutation and already-known single nucleotide polymorphism.. Mutations in CTNNB1, APC, AXIN1, and AXIN2 are not implicated in nuclear accumulation of beta-catenin, and that the expression of cyclin D1 is accelerated independently of beta-catenin in ameloblastomas. Other Wnt signaling members or alternative pathways involved in the degradation of beta-catenin should be subject of further investigation.

Topics: Ameloblastoma; beta Catenin; Cell Nucleus; Cyclin D1; DNA Mutational Analysis; Gene Expression Regulation, Neoplastic; Humans; Jaw Neoplasms; Mutation, Missense; Signal Transduction; Wnt Proteins

To investigate the expression of human telomerase reverse transcripase (hTERT), cyclin D1 mRNA, p16(INK4), p21(WAF1) mRNA and p27(KIP1) protein in human ameloblastoma (ABs).. The expression of hTERT, cyclin D1, p16(INK4), p21(WAF1) mRNA and p27(KIP1) protein in 54 cases of human ABs were detected by in situ hybridization or immunohistochemistry.. The positive cases of hTERT mRNA, cyclin D1 mRNA was 51, 23, respectively. The positive cases of p16(INK4), p21(WAF1) mRNA and p27(KIP1) protein was 17, 12, 9. Comparing with recurred and transformed malignantly, the expression of hTERT mRNA, cyclin D1 mRNA increased, and the expression of p16(INK4), p21(WAF1) mRNA and p27(KIP1) protein decreased or lost. The expression of hTERT mRNA and pl6(INK4), p21(WAF1) mRNA and p27(KIP1) protein in ABs had middle to high negative relation (r(k) = -0.587, r(k) = -0.652, r(k) = -0.783, P < 0.001).. The hTERT mRNA expression in ABs is related to the reguation of pl6(INK4), p21(WAF1) mRNA and p27(KIP1) protein.

Topics: Ameloblastoma; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Humans; Immunohistochemistry; RNA, Messenger; Telomerase

To determine whether cell cycle regulation or alteration plays a role in oncogenesis and cytodifferentiation of odontogenic epithelium, cell cycle-related factors, including cyclin D1, p16INK4a, p21(WAF1/Cip1) and p27Kip1 proteins, DNA topoisomerase IIalpha and histone H3 mRNA, were examined in 8 tooth germs and 31 ameloblastomas. Cyclin D1 was expressed in epithelial cells near the basement membrane in tooth germs and ameloblastomas, suggesting that this protein participates in cell proliferation in odontogenic epithelium. Immunoreactivity for p16 protein was observed in most epithelial cells in tooth germs and ameloblastomas. Expression of p21 protein was detected in most epithelial cells in tooth germs and ameloblastomas, but not in keratinizing or granular cells in variants of ameloblastomas. Expression of p27 protein was chiefly found in central polyhedral cells and keratinizing cells in tooth germs and ameloblastomas. These cyclin-dependent kinase inhibitors were well preserved in ameloblastomas as compared with tooth germs, suggesting that the odontogenic epithelium is strictly regulated by these factors. The cell cycle phase/cellular proliferation markers, DNA topoisomerase IIalpha and histone H3 mRNA, were localized in scattered epithelial cells attached to the basement membrane in tooth germs and ameloblastomas.

Topics: Ameloblastoma; Antigens, Neoplasm; Biomarkers, Tumor; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; DNA Topoisomerases, Type II; DNA-Binding Proteins; Histones; Humans; Immunohistochemistry; In Situ Hybridization; Isoenzymes; Jaw Neoplasms; RNA, Messenger; Tooth Germ