hes1-protein--human and Microsatellite-Instability

Alterations in the Notch signaling pathway play a role in colorectal cancer (CRC). Hes1, a Notch-induced transcription factor, has recently been reported to show decreased expression by immunohistochemistry in sessile serrated adenomas. Variable staining patterns have been reported in tubular adenomas, and existing data on Hes1 expression in CRC are limited and inconsistent. We therefore sought to investigate the expression of Hes1 by immunohistochemistry in a large and well-characterized cohort of CRC patients to determine clinicopathological associations and prognostic significance. Immunohistochemistry for Hes1 was performed on 2775 consecutive CRCs in tissue microarray format. Hes1 expression was classified into 3 categories: absent, 1302 cases (46.9%); cytoplasmic staining only with loss of nuclear staining, 1002 cases (36.1%); and nuclear with or without cytoplasmic staining, 471 cases (17%). In univariate analysis, loss of nuclear expression of HES1 was significantly associated with older age, female sex, right-sided location, mucinous or medullary histology, higher histological grade, microsatellite instability, BRAFV600E mutation, and larger tumor size. Strong and statistically significant associations with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, and larger size remained in multivariate analysis. Patients with loss of nuclear expression of Hes1 had a significantly worse all-cause 5-year survival in both univariate (P = .002) and multivariate (P = .009) analysis. We conclude that loss of nuclear expression of Hes1 occurs in 83% of CRCs when studied in tissue microarray format and is associated with female sex, right-sided location, BRAFV600E mutation, microsatellite instability, larger tumor size, and significantly worse survival.

Topics: Adenocarcinoma; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Nucleus; Colorectal Neoplasms; Cytoplasm; Down-Regulation; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Microsatellite Instability; Microsatellite Repeats; Middle Aged; Multivariate Analysis; Mutation; Odds Ratio; Predictive Value of Tests; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Risk Factors; Tissue Array Analysis; Transcription Factor HES-1; Treatment Outcome; Tumor Burden; Young Adult

Tea polyphenol has been shown to have anti-colorectal cancer and anti-gene mutation effects, although the mechanism of inhibition of microsatellite instability (MSI) colorectal cancer is not known.. Using LoVo, HCT-116, HT-29, and SW480 cells treated with an aqueous solution of tea polyphenol, cell proliferation was detected by the methyl thiazolyl tetrazolium method, changes in microsatellite sequences by the Genescan method and changes in the gene expression of LoVo cells using Illumina expression arrays.. The proliferation inhibition rate of LoVo, HCT-116, HT-29, and SW480 cells treated with tea polyphenol increased with increasing drug concentration and showed an increasing tendency with time. The proliferation inhibition rate of LoVo and HCT-116 cells with tea polyphenols was higher than that of HT-29 and SW480 cells, and there was a significant difference in the proliferation inhibition rate at 24, 72 h and 1 week. The microsatellite sequence of LoVo cells treated with tea polyphenols remained stable.. The gene expression arrays and quantitative RT-PCR suggested that tea polyphenol inhibited the gene expression of metallothionein 2A (MT2A), transcription factor (MAFA), hairy and enhancer of split 1 (HES1), and jagged1 (JAG1) nearly twofold over controls. It was also found that tea polyphenol inhibited the BAX and p38 genes with a more than twofold difference but did not significantly inhibited the NFκB pathway.. Tea polyphenol significantly inhibited the proliferation of MSI colorectal cancer signals maintained stable at the microsatellite state in MSI colorectal cancer. Tea polyphenol inhibited the gene expression of HES1, JAG1, MT2A, and MAFA but upregulated the gene expression of BAX and downregulated that of (P)38. Further research is required to investigate how these pathways are interrelated.

Topics: Basic Helix-Loop-Helix Transcription Factors; bcl-2-Associated X Protein; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Flavonoids; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Maf Transcription Factors, Large; Membrane Proteins; Metallothionein; Microsatellite Instability; p38 Mitogen-Activated Protein Kinases; Phenols; Polyphenols; Serrate-Jagged Proteins; Tea; Transcription Factor HES-1