lithium-chloride and Mouth-Neoplasms

Topics: Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Self Renewal; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Hyaluronan Receptors; Lithium Chloride; Mice; Mouth Neoplasms; Neoplastic Stem Cells; Plant Lectins; Reactive Oxygen Species; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Oral squamous cell carcinoma is a common and lethal malignancy affecting the head and neck region. CCAT2 (colon cancer-associated transcript 2) gene is affiliated with long non-coding RNAs, which are often found to have important regulatory roles in cancers. This study aims to assess the expression and clinical significance of CCAT2 gene, identify its malignant biological behaviors, and explore the possible mechanisms in oral squamous cell carcinoma. CCAT2 expression was detected by quantitative real-time polymerase chain reaction, and its relationship with clinical factors was assayed using the Kaplan-Meier survival curve. The biological behaviors of CCAT2 and its potential mechanisms in oral squamous cell carcinoma were explored by the combined use of CCAT2 knockdown technology and the Wnt/β-catenin pathway agonist lithium chloride (LiCl). Our results showed that CCAT2 functioning as a potential oncogene was upregulated in oral squamous cell carcinoma. CCAT2 with high expression level was correlated with poor differentiation, higher T stage, and clinical stage, which made CCAT2 to be a prognostic biomarker in oral squamous cell carcinoma. LiCl-activated Wnt/β-catenin signaling pathway could partly restore the CCAT2-mediated malignant biological behaviors of oral squamous cell carcinoma cells by suppressing β-catenin, CCND1, and MYC and activating glycogen synthase kinase 3 beta expression. These findings might assist in the discovery of novel potential diagnostic and therapeutic target for oral squamous cell carcinoma, thereby improve the effects of clinical treatment in patients.

Topics: Adult; Aged; beta Catenin; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Proliferation; Cyclin D1; Female; Gene Silencing; Humans; Kaplan-Meier Estimate; Lithium Chloride; Male; Middle Aged; Mouth Neoplasms; Prognosis; RNA, Long Noncoding; Wnt Signaling Pathway

During tumorigenesis, tumor suppressor and tumor-related genes are commonly silenced by aberrant DNA methylation in their promoter regions, which is one of the important determinants of susceptibility to 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) cells. Here, we examine the chemotherapeutic efficacy of epigenetic agents on 5-FU cytotoxicity.. We investigated the effect of a DNA methyltransferase (DNMT) inhibitor, zebularine (Zeb), on the chemosensitivity of 5-FU and cisplatin (CDDP) by MTT and TUNEL methods, and compared the molecular mechanism of action with those of a GSK3beta inhibitor, LiCl, and an Hsp90 inhibitor, 17-AAG.. A significant apoptotic effect by a combination of Zeb or 17-AAG was found in CDDP treatment; however, considerable suppression of 5-FU-induced apoptosis was observed after incubation with Zeb, 17-AAG, or LiCl. Zeb's suppressive effects were associated with activation of the cAMP/PKA/CREB pathway, differing from mechanisms of 17-AAG and LiCl. Suppression of 5-FU-induced apoptosis by Zeb was not associated with increased Bcl-2 and Bcl-xL expressions dependent on transcription factor CREB, and with the expression level of thymidylate synthase.. In the present study, we identified a more detailed mechanism of action by which Zeb suppresses 5-FU-induced apoptosis. These results indicate that combination therapies have to be carefully investigated due to potential harmful effects in the clinical application of DNMT inhibitors.

Topics: Adjuvants, Immunologic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Apoptosis; Benzoquinones; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Cisplatin; Cyclic AMP Response Element-Binding Protein; Cyclic AMP-Dependent Protein Kinases; Cytidine; DNA (Cytosine-5-)-Methyltransferases; Fluorouracil; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; HSP90 Heat-Shock Proteins; Humans; In Situ Nick-End Labeling; Lactams, Macrocyclic; Lithium Chloride; Mouth Neoplasms; NF-kappa B; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Signal Transduction