hes1-protein--human and Carcinoma--Squamous-Cell

The Notch signaling pathway has been associated with the regulation of self-renewal capacity, cell cycle exit, and survival. However, the relationship between the Notch signaling pathway and HNSCC remains controversial.. A meta-analysis was conducted to evaluate the role of Notch signaling pathway in HNSCC.. Relevant studies published until March 31, 2015 were identified by searching the PubMed, EMBASE and Ovid database.. A total of 9 articles were eligible for this meta-analysis. The meta-analysis results showed that the expression of Notch1, Notch3 and NICD was significantly higher in HNSCC as compared with control tissue. There was no significant difference in Jagged1 and HES1 expression between HNSCC and control tissue. Stratified analysis results showed that the expression of Notch1 was significantly higher in poor differentiation, III and IV stage and positive lymph node metastasis patients. Additionally, over-expression of Notch1, NICD, HES1 and DLL4 significantly predicted poor OS in HNSCC patients.. The Notch signaling pathway plays an important role in tumor development of HNSCC. Inhibition of the Notch signaling pathway is a potential therapeutic method of HNSCC.

Topics: Adaptor Proteins, Signal Transducing; Calcium-Binding Proteins; Carcinoma, Squamous Cell; Cell Differentiation; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Neoplasm Staging; Odds Ratio; Receptor, Notch1; Receptors, Notch; Risk Factors; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Survival Analysis; Time Factors; Transcription Factor HES-1

Cervical cancer (CC) is the most common cancer affecting women worldwide. Human papillomavirus (HPV) infection is a major contributing factor for the development of CC. The development of CC occurs progressively from precancer stages to cancerous stages (ie, invasive squamous cell carcinoma [ISCC] and adenocarcinoma [ADC]). ADC is a rare form of CC that develops from the mucinous endocervical epithelium. It is believed that the downstream targets of Notch signaling contribute to the etiology of CC. One such target is HES1, whose role in the modulation of ADC is unknown. The purpose of this study is to determine the role of HES1 protein in HPV-associated ADC subtype of CC and also to compare its expression in histologic subtypes of precancer and ISCC.. A total of 148 patients (30 with precancers, 98 with ISCC, and 20 with ADC) and 40 normal control participants were analyzed for the expression of HES1 via immunohistochemistry, with results validated by immunoblotting.. The comparison between HPV-16 and HES1 expression was significant in precancer (cervical intraepithelial neoplasia grades 1 to 3; P = .013), ISCC (International Federation of Gynecology and Obstetrics stages I to IV; P = .001), and ADC ( P = .007). An overall significant mean difference was observed between HES1, JAG1, and Notch-3 proteins in precancer ( P = .001), ISCC ( P = .001), and ADC ( P = .001). Pairwise comparisons between HES1 and JAG1 and HES1 and Notch-3 were also found to be significant.. This study showed that among all HPV-16-positive precancers, the major HES1 positivity signal arises from cervical intraepithelial neoplasia grades 2 and 3 that develops into ISCC. Moreover, HPV-16-positive ADC also showed an association with HES1. The HES1, JAG1, and Notch-3 proteins showed their synergistic role in modulating HPV associated ADC along with histologic subtypes of precancer and ISCC of CC.

Topics: Carcinoma, Squamous Cell; Case-Control Studies; Female; Humans; Immunohistochemistry; Neoplasm Staging; Papillomaviridae; Papillomavirus Infections; Precancerous Conditions; Receptor, Notch3; ROC Curve; Transcription Factor HES-1; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Squamous cell carcinoma of the skin (SCC) represents one of the most common cancers in the general population and is associated with a substantial risk of metastasis. Previous work uncovered the functional role of CYFIP1 in epithelial tumors as an invasion inhibitor. It was down-regulated in some cancers and correlated with the metastatic properties of these malignant cells. We investigated its role and expression mechanisms in SCC. We analyzed the expression of CYFIP1 in patient derived SCC, primary keratinocytes and SCC cell lines, and correlated it to the differentiation and NOTCH1 levels. We analyzed the effects of Notch1 manipulation on CYFIP1 expression and confirmed the biding of Notch1 to the CYFIP1 promoter. CYFIP1 expression was down-regulated in SCC and correlated inversely with histological differentiation of tumors. As keratinocyte differentiation depends on Notch1 signaling, we investigated the influence of Notch1 on CYFIP1 expression. CYFIP1 mRNA was highly increased in human Notch1-overexpressing keratinocytes. Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter. CYFIP1 may be a link between loss of differentiation and invasive potential in malignant keratinocytes of cutaneous squamous cell carcinoma.

Topics: Adaptor Proteins, Signal Transducing; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line; Cell Movement; Chromatin Immunoprecipitation; Down-Regulation; Humans; Keratinocytes; Promoter Regions, Genetic; Protein Binding; Receptor, Notch1; RNA Interference; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Tamoxifen; Transcription Factor HES-1

In squamous cell carcinoma of the pharynx and larynx, NOTCH1 downstream signaling has been shown to be activated. The NOTCH1 signaling pathway has not been examined in detail for sinonasal squamous cell carcinomas (SNSCCs). The aim of this study was to evaluate NOTCH1 signaling by mRNA expression analysis and to examine the occurrence of NOTCH1 mutations in SNSCC.. In a retrospective study, we analyzed tissues from 44 SNSCCs and 56 head and neck squamous cell carcinomas (HNSCCs) at other locations. Expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 mRNA were measured by using quantitative real-time polymerase chain reaction (q-rtPCR). In SNSCC, NOTCH1 mutations were evaluated with sequencing of seven selected exons.. Expression of NOTCH1, HEY1, and JAG1 at the mRNA level were significantly higher in tumor tissue compared with normal tissue. In SNSCC, the subgroup of patients with high expression (5th quintile) of HES1 mRNA was associated with better survival (P = .04); however these patients with high expression of HES1 mRNA had also a more favorable tumor stage and grade and more unfavorable resections representing potential confounders.. Key components of NOTCH1 are upregulated at the mRNA level in HNSCCs. The mechanism, clinical significance, and potential therapeutic options should therefore be further evaluated.

Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Male; Middle Aged; Mutation; Paranasal Sinus Neoplasms; Real-Time Polymerase Chain Reaction; Retrospective Studies; RNA, Messenger; Signal Transduction; Survival Analysis; Transcription Factor HES-1; Up-Regulation

Zfp191 represses differentiation and keeps various cells in the stem/progenitor stage. Here, we report that a Zfp191 homolog protein, ZNF396, is expressed in basal cell carcinoma (BCC) and possibly represses the expression of a Notch system effector molecule, Hes1 (hairy and enhancer of split-1), and prevents BCC cells from undergoing Notch-mediated squamous cell differentiation. ZNF396 immunoreactivity was found in the nucleus of 35 of 38 cutaneous BCC and 4 of 74 squamous cell carcinoma tissue specimens. In non-tumorous epidermal tissues, ZNF396 immunoreactivity was restricted in basal cells. siRNA-mediated silencing of ZNF396 induced the expression of Notch2, Hes1, and involucrin in cultured BCC cells. Finally, we found that siRNA-mediated silencing of ZNF396 gene inhibited the proliferation of TE354.T basal cell carcinoma cells. ZNF396 might repress Notch-Hes1 signaling axis and prevent tumor cells from undergoing squamous differentiation in BCC.

Topics: Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Down-Regulation; HEK293 Cells; Homeodomain Proteins; Humans; Protein Precursors; Receptor, Notch2; RNA Interference; RNA, Small Interfering; Skin Neoplasms; Transcription Factor HES-1; Transcription Factors

Notch signaling is one of the main involved pathways in cell differentiation and organogenesis, and its deregulation may lead to tumorigenesis. In this pathway, targeted to the CSL (CBF1, Suppressor of Hairless or Lag-1) complex, notch intracellular domain (NICD) releases corepressors and recruits MAML1 as coactivator triggering the activation of notch signaling transcription complex. Hairy enhance of split-1 (HES1) is one of the notch signaling target genes which is a basic helix-loop-helix (bHLH) transcription factor acting as a proliferation stimulator through the suppression of cell cycle inhibitors such as p27 and p21.. In this study, we aimed to analyze the role of HES1 in the progression of esophageal squamous cell carcinoma (ESCC).. Messenger RNA (mRNA) expression of HES1 in fresh tumoral tissues and their margin normal samples were assessed in 50 ESCC patients by real-time polymerase chain reaction (RT-PCR).. Thirteen out of 50 cases (26 %) had HES1 underexpression, while HES1 overexpression was observed only in 4 (8 %) samples. HES1 underexpression was significantly correlated with tumor depth of invasion (P = 0.035).. Although we have not observed any significant correlation between the HES1 expression and notch activation in ESCC, this study is the first report that elucidated the HES1 underexpression in ESCC and revealed its correlation with the invasiveness of ESCC.

Topics: Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Biomarkers, Tumor; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Homeodomain Proteins; Humans; Male; Middle Aged; Prognosis; Real-Time Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transcription Factor HES-1

Tumor angiogenesis plays important roles in the pathogenesis and prognosis of lung cancer. Both vascular endothelial growth factor (VEGF) and Dll4/Notch pathways are critical for angiogenesis, whereas their relationship under hypoxia in lung cancer remains unknown. Thus, in the present study, we evaluated the expression of VEGF and Dll4/Notch signaling molecules, and assessed their association with the microvessel density (CD31) and hypoxia (HIF1a) in lung cancer and normal lung tissues using immunohistochemical and Real-time RT-PCR techniques. Then, we investigated the biological function of Dll4 by transfecting Dll4 into HUVECs. In lung cancer tissues, Notch pathway molecules (HES1) and VEGF pathway molecules (VEGFR1 and VEGFR2) were significantly up-regulated, while the ratio of VEGFR1/VEGFR2 was decreased. CD31 and HIF1a were also found to be elevated in lung cancer. VEGFR1 was negatively correlated with Notch1 while positively correlated with Dll4. CD31 was positively correlated with HIF1a but negatively correlated with VEGFR1. Moreover, HIF1a was nearly positively correlated with HES1 in lung cancer tissues. After transfection, Dll4, Notch1 and VEGFR1 were up-regulated while VEGF and VEGFR2 were down-regulated in Dll4-transfected HUVECs compared with controls. Also, our findings suggest that the expression of VEGF and VEGFR2 increased gradually with the disease progression of lung cancer. In summary, VEGF and Notch signaling pathway molecules were overexpressed in lung cancer, which positively correlates with hypoxia (HIF1a) and angiogenesis (CD31). There might be a negative feedback loop between VEGF and Dll4/Notch signaling pathway in lung tumor angiogenesis.

Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Calcium-Binding Proteins; Carcinoma, Squamous Cell; Cells, Cultured; Disease Progression; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Homeodomain Proteins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Signaling Peptides and Proteins; Lung; Lung Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Notch; Retrospective Studies; Signal Transduction; Transcription Factor HES-1; Umbilical Veins; Up-Regulation; Vascular Endothelial Growth Factor A

Cancer stem-like cell (CSC; also known as tumor initiating cell) is defined as a small subpopulation of cancer cells within a tumor and isolated from various primary tumors and cancer cell lines. CSCs are highly tumorigenic and resistant to anticancer treatments. In this study, we found that prolonged exposure to tumor necrosis factor alpha (TNFα), a major proinflammatory cytokine, enhances CSC phenotype of oral squamous cell carcinoma (OSCC) cells, such as an increase in tumor sphere-forming ability, stem cell-associated genes expression, chemo-radioresistance, and tumorigenicity. Moreover, activation of Notch1 signaling was detected in the TNFα-exposed cells, and suppression of Notch1 signaling inhibited CSC phenotype. Furthermore, we demonstrated that inhibition of a Notch downstream target, Hes1, led to suppression of CSC phenotype in the TNFα-exposed cells. We also found that Hes1 expression is commonly upregulated in OSCC lesions compared to precancerous dysplastic lesions, suggesting the possible involvement of Hes1 in OSCC progression and CSC in vivo. In conclusion, inflammatory cytokine exposure may enhance CSC phenotype of OSCC, in part by activating the Notch-Hes1 pathway.

Topics: Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Transformation, Neoplastic; Homeodomain Proteins; Humans; Mouth Neoplasms; Neoplastic Stem Cells; Receptor, Notch1; Transcription Factor HES-1; Tumor Necrosis Factor-alpha

The constitutive activation of the Notch pathway has been demonstrated in various types of malignancies. However, it remains unclear how the Notch pathway is involved in the pathogenesis of oral squamous cell carcinoma (OSCC). We investigated the expression of Notch pathway molecules in OSCC cell lines and biopsy specimens and examined the effect of Notch pathway inhibition. Reverse transcription-polymerase chain reaction revealed upregulation of Notch1, Notch2, Jagged1, HES1 and HEY1 in both OSCC cell lines and biopsy specimens. Immunohistochemical examination showed that the Notch intracellular domain accumulates in the nucleus of cells in OSCC cell lines and biopsy specimens. In addition, Jagged1 is expressed in the cytoplasm of cells in OSCC cell lines and biopsy specimens. Furthermore, Notch pathway inhibition using a gamma-secretase inhibitor prevented the growth of OSCC in vitro. These findings suggest that inhibition of the Notch pathway suppresses OSCC growth and may be a useful approach for the treatment of patients with OSCC.

Topics: Aged; Amyloid Precursor Protein Secretases; Basic Helix-Loop-Helix Transcription Factors; Biopsy; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Female; Homeodomain Proteins; Humans; Immunohistochemistry; Mouth Neoplasms; Protease Inhibitors; Receptor, Notch1; Receptor, Notch2; Receptors, Notch; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transcription Factor HES-1; Up-Regulation

Hairy and enhancer of split 1 (Hes1) and Hes5 are target genes for the mammalian Notch pathway, which are highly expressed in epithelia in the process of embryogenesis or in neural stem cells, inhibit cell differentiation via the Notch-Hes-Hash signaling, and promote the survival of stem cells. Either Hes1 or Hes5 overactivation is likely to affect cell differentiation, thereby resulting in carcinogenesis.. We transfected the diced small interference RNA into SiHa cells and detected cell differentiation and proliferation by immunocytochemistry, Western blot, and methyl thiazolyl tetrazolium assay.. Knockdown of Hes1 and Hes5 would up-regulate the downstream gene Hash1, but not the upstream gene Notch1 in the Notch-Hes-Hash pathway. After Hes1/Hes5 RNA interference, expression of differentiation-associated proteins (including Nanog, stage-specific embryonic antigen 4, and tumor rejection antigen-1-60) was reduced, and the cell differentiation was promoted; meanwhile, the cell proliferation was inhibited, which was verified by detecting proliferation-associated proteins (eg, Ki-67, proliferating cell nuclear antigen) and methyl thiazolyl tetrazolium assay.. Our findings suggest that Hes1/Hes5 gene would inhibit the cell differentiation via down-regulating Hash1 and promote the cell proliferation in cervical carcinoma cells; the cell differentiation and proliferation can be reversed simultaneously by Hes1/Hes5 knockdown using RNA interference.

Topics: Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Carcinoma, Squamous Cell; Cell Differentiation; Cell Proliferation; Down-Regulation; Female; Gene Expression Regulation; Homeodomain Proteins; Humans; Immunoenzyme Techniques; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Transcription Factor HES-1; Transfection; Tumor Cells, Cultured; Uterine Cervical Neoplasms