ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is altered in several epithelial cancers and represents a potential therapeutic target. Here, STAT3 expression, activity and cellular functions were examined in two main histotypes of esophageal carcinomas. In situ, immunohistochemistry for STAT3 and STAT3-Tyr705 phosphorylation (P-STAT3) in esophageal squamous cell carcinomas (ESCC, n=49) and Barrett's adenocarcinomas (BAC, n=61) revealed similar STAT3 expression in ESCCs and BACs (P=0.109), but preferentially activated P-STAT3 in ESCCs (P=0.013). In vitro, strong STAT3 activation was seen by epidermal growth factor (EGF) stimulation in OE21 (ESCC) cells, whereas OE33 (BAC) cells showed constitutive weak STAT3 activation. STAT3 knockdown significantly reduced cell proliferation of OE21 (P=0.0148) and OE33 (P=0.0243) cells. Importantly, STAT3 knockdown reduced cell migration of OE33 cells by 2.5-fold in two types of migration assays (P=0.073, P=0.015), but not in OE21 cells (P=0.1079, P=0.386). Investigation of transcriptome analysis of STAT3 knockdown revealed a reduced STAT3 level associated with significant downregulation of cell cycle genes in both OE21 (P<0.0001) and OE33 (P=0.01) cells. In contrast, genes promoting cell migration (CTHRC1) were markedly upregulated in OE21 cells, whereas a gene linked to tight-junction stabilization and restricted cell motility (SHROOM2) was downregulated in OE21 but upregulated in OE33 cells. This study shows frequent, but distinct, patterns of STAT3 expression and activation in ESCCs and BACs. STAT3 knockdown reduces cell proliferation in ESCC and BAC cells, inhibits migration of BAC cells and may support cell migration of ESCC cells. Thereby, novel STAT3-regulated genes involved in ESCC and BAC cell proliferation and cell migration were identified. Thus, STAT3 may be further exploited as a potential novel therapeutic target, however, by careful distinction between the two histotypes of esophageal cancers.
Subject(s)
Adenocarcinoma/metabolism , Barrett Esophagus/metabolism , Carcinoma, Squamous Cell/metabolism , Esophageal Neoplasms/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/biosynthesis , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Barrett Esophagus/genetics , Barrett Esophagus/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Cell Cycle/genetics , Cell Growth Processes/genetics , Cell Line, Tumor , Cell Movement/genetics , Down-Regulation , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophageal Squamous Cell Carcinoma , Gene Knockdown Techniques , Humans , Phosphorylation , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction , Up-RegulationABSTRACT
The three DNA methyltransferase (DNMT)-inhibiting cytosine nucleoside analogues, azacitidine, decitabine and zebularine, which are currently studied as nonintensive therapy for myelodysplastic syndromes and acute myeloid leukemia (AML), differ in structure and metabolism, suggesting that they may have differential molecular activity. We investigated cellular and molecular effects of the three substances relative to cytarabine in Kasumi-1 AML blasts. Under in vitro conditions mimicking those used in clinical trials, the DNMT inhibitors inhibited proliferation and triggered apoptosis but did not induce myeloid differentiation. The DNMT inhibitors showed no interference with cell-cycle progression whereas cytarabine treatment resulted in an S-phase arrest. Quantitative methylation analysis of hypermethylated gene promoters and of genome-wide LINE1 fragments using bisulfite sequencing and MassARRAY suggested that the hypomethylating potency of decitabine was stronger than that of azacitidine; zebularine showed no hypomethylating activity. In a comparative gene expression analysis, we found that the effects of each DNMT inhibitor on gene transcription were surprisingly different, involving several genes relevant to leukemogenesis. In addition, the gene methylation and expression analyses suggested that the effects of DNMT-inhibiting cytosine nucleoside analogues on the cellular transcriptome may, in part, be unrelated to direct promoter DNA hypomethylation, as previously shown by others.
Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Cytidine/analogs & derivatives , DNA Modification Methylases/antagonists & inhibitors , Gene Expression Regulation, Neoplastic/drug effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Apoptosis , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Cell Differentiation , Cell Line, Tumor , Cell Proliferation , Cytidine/pharmacology , DNA Methylation , Decitabine , Enzyme Inhibitors/pharmacology , Gene Expression Profiling , Humans , Leukemia, Myeloid, Acute/pathologyABSTRACT
The nonremovable reconstruction of the atrophic mandible is possible with basal osseointegrated implants in an immediate-load procedure. Between 4 and 5 implants are necessary to form a reliable foundation for a fixed bridge. The vertical dimension and the aesthetic appearance may be reconstructed in the desired way.
Subject(s)
Alveolar Bone Loss/surgery , Dental Implantation, Endosseous/methods , Denture, Partial, Fixed , Mandible/surgery , Mandibular Diseases/surgery , Alveolar Bone Loss/rehabilitation , Dental Implants , Dental Prosthesis Design , Dental Prosthesis, Implant-Supported , Denture, Partial, Temporary , Humans , Mandibular Diseases/rehabilitation , OsseointegrationABSTRACT
Today, prognathism in the partially or completely edentulous jaw can be treated with endosteal implants and fixed prostheses. The preferred procedure uses basal osseointegration. If the distribution of available bone is favorable, the prosthodontic suprastructures can be loaded early, taking the various phases of bone regeneration into account. Invasive surgical interventions, specifically iliac crest transplants, are rarely indicated and can be avoided in most cases. Patients are able to return to their everyday lives within a few days.
