hes1-protein--human and Carcinoma

Overexpression of the transcriptional factor Hes1 (hairy and enhancer of split-1) has been observed in numerous cancers, but the precise roles of Hes1 in epithelial-mesenchymal transition (EMT), cancer invasion and metastasis remain unknown. Our current study firstly revealed that Hes1 upregulation in a cohort of human nasopharyngeal carcinoma (NPC) biopsies is significantly associated with the EMT, invasive and metastatic phenotypes of cancer. In the present study, we found that Hes1 overexpression triggered EMT-like cellular marker alterations of NPC cells, whereas knockdown of Hes1 through shRNA reversed the EMT-like phenotypes, as strongly supported by Hes1-mediated EMT in NPC clinical specimens described above. Gain-of-function and loss-of-function experiments demonstrated that Hes1 promoted the migration and invasion of NPC cells in vitro. In addition, exogenous expression of Hes1 significantly enhanced the metastatic ability of NPC cells in vivo. Chromatin immunoprecipitation (ChIP) assays showed that Hes1 inhibited PTEN expression in NPC cells through binding to PTEN promoter region. Increased Hes1 expression and decreased PTEN expression were also observed in a cohort of NPC biopsies. Additional studies demonstrated that Hes1-induced EMT-like molecular changes and increased motility and invasion of NPC cells were mediated by PTEN. Taken together, our results suggest, for what we believe is the first time, that Hes1 plays an important role in the invasion and metastasis of NPC through inhibiting PTEN expression to trigger EMT-like phenotypes.

Topics: Animals; Carcinoma; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Transcription Factor HES-1

The purpose of this study was to evaluate the expression of Notch-induced transcription factors (NTFs) HEY1, HES1 and SOX9 in colorectal cancer (CRC) patients to determine their clinicopathologic and prognostic significance.. Levels of HEY1, HES1 and SOX9 protein were measured by immunohistochemistry in a nonmalignant and malignant tissue microarray of 441 CRC patients, and the findings correlated with pathologic, molecular and clinical variables.. The NTFs HEY1, HES1 and SOX9 were overexpressed in tumours relative to colonic mucosa (OR=3.44, P<0.0001; OR=7.40, P<0.0001; OR=4.08 P<0.0001, respectively). HEY1 overexpression was a negative prognostic factor for all CRC patients (HR=1.29, P=0.023) and strongly correlated with perineural and vascular invasion and lymph node (LN) metastasis. In 5-fluorouracil (5-FU)-treated patients, the tumour overexpression of SOX9 correlated with markedly poorer survival (HR=8.72, P=0.034), but had no predictive effect in untreated patients (HR=0.70, P=0.29). When HEY1, HES1 and SOX9 expression were combined to predict survival with chemotherapy, in treated patients there was an additive increase in the risk of death with each NTF overexpressed (HR=2.09, P=0.01), but no prognostic import in the untreated patient group (HR=0.74, P=0.19).. The present study is the first to discover that HEY1 overexpression correlates with poorer outcome in CRC, and NTF expression is predictive of CRC patient survival with 5-FU chemotherapy. If confirmed in future studies, testing of NTF expression has the potential to enter routine pathological practice for the selection of patients to undergo chemotherapy alone or in combination with Notch inhibitors.

Topics: Antimetabolites, Antineoplastic; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Carcinoma; Cell Cycle Proteins; Colorectal Neoplasms; Female; Fluorouracil; Homeodomain Proteins; Humans; Male; Prognosis; Proportional Hazards Models; Receptors, Notch; Signal Transduction; SOX9 Transcription Factor; Transcription Factor HES-1; Transcription Factors

Biliary tract cancer (BTC) is a fatal cancer originating from epithelial cells of the intra- and extra-hepatic biliary duct system and the gallbladder. Genes and pathways regulating stem and progenitor cells as well as cell-fate decisions are increasingly recognized in tumorigenesis. We evaluated the expression of Notch1, Notch2, and HES1 (hairy and enhancer of split 1), as well as the biliary cell-fate regulators SOX9 (SRY (sex determining region Y)-box 9) and HNF1β (hepatocyte nuclear factor 1β), in BTC for correlation with clinicopathological parameters.. Tissue microarrays including normal bile ducts and 111 BTCs consisting of 17 intrahepatic cholangiocarcinomas, 58 extrahepatic cholangiocarcinomas, and 36 gallbladder carcinomas were analyzed using immunohistochemistry.. Lack of cytoplasmic SOX9 expression was associated with a higher tumor grade (P=0.010) and a significantly reduced overall survival (P=0.002; median 6 months vs. 24 months) in univariate survival analysis, whereas lack of nuclear SOX9 expression was associated with a higher tumor stage (P=0.003). Notch pathway members showed high expression in BTC. However, no correlation was found between cytoplasmic or nuclear Notch1, Notch2, and HES1, as well as HNF1β expression, and any of the clinicopathological parameters. In multivariate analysis, cytoplasmic SOX9 expression was an independent prognostic factor for overall survival (P=0.031, relative risk=0.571).. We show strong Notch pathway activation and identify SOX9 as a prognostic marker in BTC. These results substantiate diagnostic and therapeutic approaches targeting developmentally active genes and pathways.

Topics: Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Biliary Tract Neoplasms; Carcinoma; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 1-beta; Homeodomain Proteins; Humans; Male; Middle Aged; Receptor, Notch1; Receptor, Notch2; Retrospective Studies; SOX9 Transcription Factor; Transcription Factor HES-1

To investigate the effect of DAPT (gamma-secretase inhibitor) on the growth of human tongue carcinoma cells and to determine the molecular mechanism to enable the potential application of DAPT to the treatment of tongue carcinoma.. Human tongue carcinoma Tca8113 cells were cultured with DAPT. Cell growth was determined using Indigotic Reduction method. The cell cycle and apoptosis were analyzed by flow cytometry. Real-time PCR and Immuno-Fluorescence (IF) were employed to determine the intracellular expression levels.. DAPT inhibited the growth of human tongue carcinoma Tca8113 cells by inducing G0-G1 cell cycle arrest and apoptosis. The mRNA levels of Hairy/Enhancer of Split-1 (Hes-1), a target of Notch activation, were reduced by DAPT in a dose-dependent manner. Coincident with this observation, DAPT induced a dose-dependent promotion of constitutive Caspase-3 in Tca8113 cells.. DAPT may have a therapeutic value for human tongue carcinoma. Moreover, the effects of DAPT in tumor inhibition may arise partly via the modulation of Notch-1 and Caspase-3.

Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Apoptosis; Basic Helix-Loop-Helix Transcription Factors; Carcinoma; Caspase 3; Cell Line, Tumor; Cell Membrane; Cell Nucleus; Cyclin D1; Dipeptides; Dose-Response Relationship, Drug; G1 Phase; Homeodomain Proteins; Humans; Receptor, Notch1; Repressor Proteins; Resting Phase, Cell Cycle; Tongue Neoplasms; Transcription Factor HES-1