hes1-protein--human and Salivary-Gland-Neoplasms

Our previous study demonstrated a close relationship between NOTCH signaling pathway and salivary adenoid cystic carcinoma (SACC). HES1 is a well-known target gene of NOTCH signaling pathway. The purpose of the present study was to further explore the molecular mechanism of HES1 in SACC.. Comparative transcriptome analyses by RNA-Sequencing (RNA-Seq) were employed to reveal NOTCH1 downstream gene in SACC cells. Immunohistochemical staining was used to detect the expression of HES1 in clinical samples. After HES1-siRNA transfected into SACC LM cells, the cell proliferation and cell apoptosis were tested by suitable methods; animal model was established to detect the change of growth ability of tumor. Transwell and wound healing assays were used to evaluate cell metastasis and invasion.. We found that HES1 was strongly linked to NOTCH signaling pathway in SACC cells. The immunohistochemical results implied the high expression of HES1 in cancerous tissues. The growth of SACC LM cells transfected with HES1-siRNAs was significantly suppressed in vitro and tumorigenicity in vivo by inducing cell apoptosis. After HES1 expression was silenced, the SACC LM cell metastasis and invasion ability was suppressed.. The results of this study demonstrate that HES1 is a specific downstream gene of NOTCH1 and that it contributes to SACC proliferation, apoptosis and metastasis. Our findings serve as evidence indicating that HES1 may be useful as a clinical target in the treatment of SACC.

Topics: Adult; Aged; Animals; Apoptosis; Carcinoma, Adenoid Cystic; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Middle Aged; Oncogenes; Receptor, Notch1; Recurrence; RNA, Small Interfering; Salivary Gland Neoplasms; Transcription Factor HES-1; Xenograft Model Antitumor Assays

Truncation of Notch1 has been shown to cause a subtype of acute leukemia, and activation of Notch4 has been associated with mammary and salivary gland carcinomas of mice. Here we identify a new mechanism for disrupting Notch signaling in human tumorigenesis, characterized by altered function of a new ortholog of the Drosophila melanogaster Notch co-activator molecule Mastermind. We cloned the t(11;19) translocation that underlies the most common type of human malignant salivary gland tumor. This rearrangement fuses exon 1 from a novel gene of unknown function at 19p13, termed mucoepidermoid carcinoma translocated 1 (MECT1), with exons 2-5 of a novel member of the Mastermind-like gene family (MAML2) at 11q21 (ref. 3). Similar to D. melanogaster Mastermind and MAML1 (refs. 4,5), full-length MAML2 functioned as a CSL (CBF-1, suppressor of hairless and Lag-1)-dependent transcriptional co-activator for ligand-stimulated Notch. In contrast, MECT1-MAML2 activated transcription of the Notch target gene HES1 independently of both Notch ligand and CSL binding sites. MECT1-MAML2 induced foci formation in RK3E epithelial cells, confirming a biological effect for the fusion product. These data suggest a new mechanism to disrupt the function of a Notch co-activator in a common type of malignant salivary gland tumor.

Topics: Animals; Artificial Gene Fusion; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Mucoepidermoid; Carrier Proteins; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 19; DNA-Binding Proteins; Drosophila melanogaster; Drosophila Proteins; Gene Expression Regulation; Gene Rearrangement; Homeodomain Proteins; Humans; In Situ Hybridization, Fluorescence; Intercellular Signaling Peptides and Proteins; Jagged-2 Protein; Karyotyping; Ligands; Luciferases; Membrane Proteins; Molecular Sequence Data; Mutation; Neoplasms, Glandular and Epithelial; Nuclear Proteins; Promoter Regions, Genetic; Receptors, Notch; Repressor Proteins; Ribonuclease, Pancreatic; Salivary Gland Neoplasms; Signal Transduction; Trans-Activators; Transcription Factor HES-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transfection; Translocation, Genetic; Tumor Cells, Cultured