NOTCH2

Gene Summary

Gene:NOTCH2; notch 2
Aliases: hN2, AGS2, HJCYS
Location:1p13-p11
Summary:This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:neurogenic locus notch homolog protein 2
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Intercellular Signaling Peptides and Proteins
  • Splenic Neoplasms
  • fms-Like Tyrosine Kinase 3
  • Tumor Microenvironment
  • T-Lymphocytes, Helper-Inducer
  • Survival Rate
  • Wnt4 Protein
  • Mutation
  • Cell Proliferation
  • Neoplastic Cell Transformation
  • Molecular Sequence Data
  • Apoptosis
  • Tumor Markers
  • Signal Transduction
  • Transcription Factors
  • Oligonucleotide Array Sequence Analysis
  • Gene Expression Profiling
  • Cancer Gene Expression Regulation
  • Membrane Proteins
  • Base Sequence
  • Xenograft Models
  • Wnt Proteins
  • Translocation
  • Cell Movement
  • Young Adult
  • Immunohistochemistry
  • Breast Cancer
  • Brain and CNS Tumours
  • NOTCH1 Receptor
  • Brain Tumours
  • Stem Cells
  • RNA Interference
  • Proto-Oncogene Proteins
  • Western Blotting
  • Notch Receptors
  • NOTCH2
  • Basic Helix-Loop-Helix Transcription Factors
  • Chromosome 1
  • Messenger RNA
  • Calcium-Binding Proteins
  • Homeodomain Proteins
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NOTCH2 (cancer-related)

Arribas AJ, Rinaldi A, Mensah AA, et al.
DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features.
Blood. 2015; 125(12):1922-31 [PubMed] Free Access to Full Article Related Publications
Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.

Yamaguchi T, Mukai H, Yamashita S, et al.
Comprehensive DNA Methylation and Extensive Mutation Analyses of HER2-Positive Breast Cancer.
Oncology. 2015; 88(6):377-84 [PubMed] Related Publications
OBJECTIVE: Resistance to trastuzumab is a problem that remains to be solved in HER2-positive breast cancer. We aimed to characterize profiles of genetic and epigenetic alterations in cancer-related pathways in HER2-positive breast cancers, using biopsy tissue samples obtained from patients enrolled in a prospective neoadjuvant clinical trial.
METHODS: HER2-positive breast cancer tissue samples were collected and processed with the PAXgene Tissue System. A total of 24 breast cancers were analyzed. Genetic alterations of 409 cancer-related genes were analyzed by a bench-top next-generation sequencer. DNA methylation statuses were analyzed by a bead array with 485,512 probes.
RESULTS: The WNT pathway was potentially activated by aberrant methylation of its negative regulators, such as DKK3 and SFRP1, in 9 breast cancers. The AKT/mTOR pathway was activated by mutations of PIK3CA in 5 breast cancers. The Notch pathway was potentially activated by mutations of NOTCH1 and NOTCH2 in 4 breast cancers. The p53 pathway was inactivated by mutations of TP53 in 13 breast cancers and potentially by aberrant methylation of its downstream genes in 10 breast cancers. Cell adhesion was affected by mutations of CDH1 in 1 breast cancer.
CONCLUSION: Genes involved in cancer-related pathways were frequently affected not only by genetic but also by epigenetic alterations in HER2-positive breast cancer.

Brandt WD, Schreck KC, Bar EE, et al.
Notch signaling activation in pediatric low-grade astrocytoma.
J Neuropathol Exp Neurol. 2015; 74(2):121-31 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in the development, stem cell biology, and pathogenesis of several cancers, but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomic sites compared with non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res186 and Res259 using either RNA interference or a γ-secretase inhibitor resulted in variable, but significant, reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target.

Clipson A, Wang M, de Leval L, et al.
KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype.
Leukemia. 2015; 29(5):1177-85 [PubMed] Related Publications
To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.

Lee H, Kim KR, Cho NH, et al.
MicroRNA expression profiling and Notch1 and Notch2 expression in minimal deviation adenocarcinoma of uterine cervix.
World J Surg Oncol. 2014; 12:334 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
BACKGROUND: MicroRNA (miRNA) expression is known to be deregulated in cervical carcinomas. However, no data is available about the miRNA expression pattern for the minimal deviation adenocarcinoma (MDA) of uterine cervix. We sought to detect deregulated miRNAs in MDA in an attempt to find the most dependable miRNA or their combinations to understand their tumorigenesis pathway and to identify diagnostic or prognostic biomarkers. We also investigated the association between those miRNAs and their target genes, especially Notch1 and Notch2.
METHODS: We evaluated miRNA expression profiles via miRNA microarray and validated them using.real-time PCR assays with 24 formalin-fixed, paraffin-embedded tissue blocks of MDA and 11 normal proliferative endocervical tissues as control. Expression for Notch1 and 2 was assessed by immunohistochemistry.
RESULTS: MiRNA-135a-3p, 192-5p, 194-5p, and 494 were up-regulated, whereas miR-34b-5p, 204-5p, 299-5p, 424-5p, and 136-3p were down-regulated in MDA compared with normal proliferative endocervical tissues (all P<0.05). Considering the second-order Akaike Information Criterion consisting of likelihood ratio and number of parameters, miR-34b-5p showed the best discrimination power among the nine candidate miRNAs. A combined panel of miR-34b-5p and 194-5p was the best fit model to discriminate between MDA and control, revealing 100% sensitivity and specificity. Notch1 and Notch2, respective target genes of miR-34b-5p and miR-204-5p, were more frequently expressed in MDA than in control (63% vs. 18%; 52% vs. 18%, respectively, P<0.05). MiR-34b-5p expression level was higher in Notch1-negative samples compared with Notch1-positive ones (P<0.05). Down-regulated miR-494 was associated with poor patient survival (P=0.036).
CONCLUSIONS: MDA showed distinctive expression profiles of miRNAs, Notch1, and Notch2 from normal proliferative endocervical tissues. In particular, miR-34b-5p and 194-5p might be used as diagnostic biomarkers and miR-494 as a prognostic predictor for MDA. The miR-34b-5p/Notch1 pathway as well as Notch2 might be important oncogenic contributors to MDA.

Minuzzo S, Agnusdei V, Pusceddu I, et al.
DLL4 regulates NOTCH signaling and growth of T acute lymphoblastic leukemia cells in NOD/SCID mice.
Carcinogenesis. 2015; 36(1):115-21 [PubMed] Related Publications
Activation of the NOTCH pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) mainly due to mutations in NOTCH1 or alterations in FBW7 and is involved in the regulation of cell proliferation and survival. Since mutations hit different domains of the receptor, they are predicted to heterogeneously perturb ligand-induced NOTCH1 activity. Moreover, T-ALL cells also co-express NOTCH3 receptors which could be triggered by different ligands. In this study, we aimed to investigate the role of DLL4 in the regulation of NOTCH signaling in T-ALL cells in the context of different types of NOTCH1 mutation or wild-type NOTCH receptor, as well as the effects of DLL4 neutralization on T-ALL engraftment in mice. We found that NOTCH signaling can be stimulated in T-ALL cells in vitro by either human or murine DLL4 with heterogeneous effects, according to NOTCH1/FBW7 mutation status, and that these effects can be blocked by antibodies neutralizing DLL4, NOTCH1 or NOTCH2/3. In vivo, DLL4 is expressed in the spleen and the bone marrow (BM) of NOD/SCID mice bearing T-ALL xenografts as well as the BM of T-ALL patients. Importantly, DLL4 blockade impaired growth of T-ALL cells in NOD/SCID mice and increased leukemia cell apoptosis. These results show that DLL4 is an important component of the tumor microenvironment which contributes to the early steps of T-ALL cell growth.

Yu HP, Qi ST, Feng WF, et al.
Interference of Notch 2 inhibits the progression of gliomas and induces cell apoptosis by induction of the cell cycle at the G0/G1 phase.
Mol Med Rep. 2015; 11(1):734-8 [PubMed] Related Publications
Glioblastoma is the most common type of malignant brain tumor with a poor prognosis. The Notch signaling pathway is often aberrantly activated in glioma cells. In order to determine the expression of Notch 2 and to evaluate its possible prognostic value in malignant glioblastoma, specimens from 32 patients and 20 controls were analyzed using immunohistochemical staining and reverse transcription quantitative polymerase chain reaction. The expression of Notch 2 in the glioma tissues was significantly higher compared with that in the normal brain tissues (P<0.01). Subsequently, endogenous Notch 2 interference was effectively performed by specific small hairpin (sh)RNA in the glioma cancer cell line U251. The results from an MTT assay and from Annexin V-fluorescein isothiocyanate/propidium iodide staining indicated that interference of Notch 2 significantly inhibited the proliferation and induced the apoptosis of U251 cells. In addition, the cell cycle was analyzed using flow cytometry and the results revealed that Notch 2 shRNA induced cell cycle arrest at the G0/G1 phase in U251 cells. Additionally, proteins associated with the cell cycle and cell proliferation were detected using western blot analysis. The data demonstrated that the expression of P21, cyclin D and phosphorylated retinoblastoma was significantly inhibited in the Notch 2 shRNA-transfected U251 cells. The results of the present study provide further insights into the effects of Notch 2 and a molecular reference for brain tumor therapy.

Roy L, Samyesudhas SJ, Carrasco M, et al.
ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature.
Oncotarget. 2014; 5(18):8355-66 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Ovarian cancer is the most deadly gynecological malignancy since most patients have metastatic disease at the time of diagnosis. Therefore, identification of critical pathways that contribute to ovarian cancer progression is necessary to yield novel therapeutic targets. Recently we reported that the DNA binding protein ARID3B is overexpressed in human ovarian tumors. To determine if ARID3B has oncogenic functions in vivo, ovarian cancer cell lines stably expressing ARID3B were injected intraperitoneally into nude mice. Overexpression of ARID3B increased tumor burden and decreased survival. To assess how ARID3B contributes to the increased tumor growth in vivo, we identified ARID3B induced genes in tumor ascites cells. ARID3B induced expression of genes associated with metastasis and cancer stem cells (CD44, LGR5, PROM1 (CD133), and Notch2). Moreover, ARID3B increased the number of CD133+ (a cancer stem cell marker) cells compared to control cells. The increase in CD133+ cells resulting from ARID3B expression was accompanied by enhanced paclitaxel resistance. Our data demonstrate that ARID3B boosts production CD133+ cells and increases ovarian cancer progression in vivo.

Li X, He X, Tian W, Wang J
Short hairpin RNA targeting Notch2 inhibits U87 human glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo.
Mol Med Rep. 2014; 10(6):2843-50 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
Notch signaling has been reported to be oncogenic or tumor suppressive, depending on the tissue context. To investigate the effects of Notch2 knockdown on U87 human glioma cell proliferation in vitro and in vivo, and the associated mechanisms, U87 cells were stably transfected with p green fluorescent protein (GFP)‑V‑RS Notch2 short hairpin (sh) RNA plasmid and pGFP‑V‑RS scramble‑shRNA plasmid. The former was referred to as the Notch2‑shRNA group and the latter as the negative‑shRNA group. mRNA and protein expression, cell proliferation, cell cycle and apoptosis were measured by reverse transcription‑polymerase chain reaction, western blot analysis, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide analysis and flow cytometry using propidium iodide, respectively. Tumor volume, tumor weight and cumulative survival rate were determined in a nude mouse xenograft tumor model. Notch2 mRNA and protein expression in the Notch2‑shRNA group were reduced by 87.6 and 94.5% compared with the negative‑shRNA group (P<0.001). Notch2 knockdown significantly inhibited U87 cell proliferation after three days of culture (P<0.05). Notch2 silencing induced cell cycle arrest at G0/G1 phase by upregulation of p21 protein expression and downregulation of mini chromosome maintenance complex 2 and cyclin‑D1 protein expression. Furthermore, knockdown of Notch2 also induced U87 cell apoptosis. On day 50 after inoculation, tumor weight in the Notch2‑shRNA group was significantly lower than that in the negative‑shRNA group (0.55±0.10 vs. 1.23±0.52 g; P<0.01). The cumulative survival rate was significantly longer in the Notch2‑shRNA group compared with the negative‑shRNA group (log rank test P=0.01). In conclusion, Notch2 silencing inhibited U87 glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo. Thus, Notch2 may be a key therapeutic target for the treatment of glioma.

Zhang X, Shi Y, Weng Y, et al.
The truncate mutation of Notch2 enhances cell proliferation through activating the NF-κB signal pathway in the diffuse large B-cell lymphomas.
PLoS One. 2014; 9(10):e108747 [PubMed] Article available free on PMC after 01/02/2016 Related Publications
The Notch2 is a critical membrane receptor for B-cell functions, and also displays various biological roles in lymphoma pathogenesis. In this article, we reported that 3 of 69 (4.3%) diffuse large B-cell lymphomas (DLBCLs) exhibited a truncate NOTCH2 mutation at the nucleotide 7605 (G/A) in the cDNA sequence, which led to partial deletion of the C-terminal of PEST (proline-, glutamic acid-, serine- and threonine-rich) domain. The truncate Notch2 activated both the Notch2 and the NF-κB signals and promoted the proliferation of B-cell lymphoma cell lines, including DLBCL and Burkitt's lymphoma cell lines. Moreover, the ectopic proliferation was completely inhibited by ammonium pyrrolidinedithiocarbamate (PDTC), an NF-κB inhibitor. Simultaneously, PDTC also reduced the expression level of Notch2. Based on these results, we conclude that the Notch2 receptor with PEST domain truncation enhances cell proliferation which may be associated with the activation of the Notch2 and the NF-κB signaling. Our results are expected to provide a possible target for new DLBCL therapies by suppressing the Notch2 and the NF-κB signaling.

Ortega M, Bhatnagar H, Lin AP, et al.
A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.
Leukemia. 2015; 29(4):968-76 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.

Kato T, Sakata-Yanagimoto M, Nishikii H, et al.
Hes1 suppresses acute myeloid leukemia development through FLT3 repression.
Leukemia. 2015; 29(3):576-85 [PubMed] Related Publications
In leukemogenesis, Notch signaling can be up and downregulated in a context-dependent manner. The transcription factor hairy and enhancer of split-1 (Hes1) is well-characterized as a downstream target of Notch signaling. Hes1 encodes a basic helix-loop-helix-type protein, and represses target gene expression. Here, we report that deletion of the Hes1 gene in mice promotes acute myeloid leukemia (AML) development induced by the MLL-AF9 fusion protein. We then found that Hes1 directly bound to the promoter region of the FMS-like tyrosine kinase 3 (FLT3) gene and downregulated the promoter activity. FLT3 was consequently upregulated in MLL-AF9-expressing immortalized and leukemia cells with a Hes1- or RBPJ-null background. MLL-AF9-expressing Hes1-null AML cells showed enhanced proliferation and ERK phosphorylation following FLT3 ligand stimulation. FLT3 inhibition efficiently abrogated proliferation of MLL-AF9-induced Hes1-null AML cells. Furthermore, an agonistic anti-Notch2 antibody induced apoptosis of MLL-AF9-induced AML cells in a Hes1-wild type but not a Hes1-null background. We also accessed two independent databases containing messenger RNA (mRNA) expression profiles and found that the expression level of FLT3 mRNA was negatively correlated with those of HES1 in patient AML samples. These observations demonstrate that Hes1 mediates tumor suppressive roles of Notch signaling in AML development, probably by downregulating FLT3 expression.

Gao YB, Chen ZL, Li JG, et al.
Genetic landscape of esophageal squamous cell carcinoma.
Nat Genet. 2014; 46(10):1097-102 [PubMed] Related Publications
Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers. We performed exome sequencing on 113 tumor-normal pairs, yielding a mean of 82 non-silent mutations per tumor, and 8 cell lines. The mutational profile of ESCC closely resembles those of squamous cell carcinomas of other tissues but differs from that of esophageal adenocarcinoma. Genes involved in cell cycle and apoptosis regulation were mutated in 99% of cases by somatic alterations of TP53 (93%), CCND1 (33%), CDKN2A (20%), NFE2L2 (10%) and RB1 (9%). Histone modifier genes were frequently mutated, including KMT2D (also called MLL2; 19%), KMT2C (MLL3; 6%), KDM6A (7%), EP300 (10%) and CREBBP (6%). EP300 mutations were associated with poor survival. The Hippo and Notch pathways were dysregulated by mutations in FAT1, FAT2, FAT3 or FAT4 (27%) or AJUBA (JUB; 7%) and NOTCH1, NOTCH2 or NOTCH3 (22%) or FBXW7 (5%), respectively. These results define the mutational landscape of ESCC and highlight mutations in epigenetic modulators with prognostic and potentially therapeutic implications.

Karube K, Martínez D, Royo C, et al.
Recurrent mutations of NOTCH genes in follicular lymphoma identify a distinctive subset of tumours.
J Pathol. 2014; 234(3):423-30 [PubMed] Related Publications
Follicular lymphoma (FL) is one of the most common malignant lymphomas. The t(14;18)(q32;q21) translocation is found in about 80% of cases and plays an important role in lymphomagenesis. However, the molecular mechanisms involved in the development and transformation of this lymphoma are not fully understood. Gain-of-function mutations of NOTCH1 or NOTCH2 have recently been reported in several B cell lymphoid neoplasms but the role of these mutations in FL is not known. In this study we investigated the mutational status of these genes in 112 FLs. NOTCH1 and NOTCH2 mutations were identified in five and two cases, respectively (total 7/112, 6.3%). All mutations predicted for truncated protein in the PEST domain and were identical to those identified in other B cell lymphoid neoplasms. NOTCH-mutated FL cases were characterized by lower frequency of t(14;18) (14% versus 69%, p = 0.01), higher incidence of splenic involvement (71% versus 25%, p = 0.02) and female predominance (100% versus 55%, p = 0.04). A diffuse large B cell lymphoma (DLBCL) component was more frequently identified in NOTCH-mutated FL than in wild-type cases (57% versus 18%, p = 0.03). These results indicate that NOTCH mutations are uncommon in FL but may occur in a subset of cases with distinctive, characteristic, clinicopathological features.

Sehrawat A, Sakao K, Singh SV
Notch2 activation is protective against anticancer effects of zerumbone in human breast cancer cells.
Breast Cancer Res Treat. 2014; 146(3):543-55 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
We showed previously that zerumbone (ZER), a sesquiterpene isolated from subtropical ginger, inhibited in vitro (MCF-7 and MDA-MB-231cells) and in vivo (MDA-MB-231 cells) growth of human breast cancer cells in association with apoptosis induction. Here, we investigated the role of Notch receptors in anticancer effects of ZER (cell migration inhibition and apoptosis induction) using breast cancer cells. Western blotting was performed to determine protein expression changes. Effect of ZER on transcriptional activity of Notch was assessed by luciferase reporter assays. Transfection with small hairpin RNA or small interfering RNA was performed for knockdown of Notch2 or Presenilin-1 protein. Cell migration and apoptosis were quantitated by Boyden chamber assay and flow cytometry, respectively. Exposure of MDA-MB-231, MCF-7, and SUM159 cells to ZER resulted in increased cleavage of Notch2 in each cell line. On the other hand, levels of cleaved Notch1 and Notch4 proteins were decreased following ZER treatment. Increased cleavage of Notch2 in ZER-treated cells was accompanied by induction of Presenilin-1 protein and transcriptional activation of Notch. Inhibition of cell migration as well as apoptosis induction resulting from ZER exposure was significantly augmented by knockdown of Notch2 protein. ZER-mediated cleavage of Notch2 protein in MDA-MB-231 cells was markedly attenuated upon RNA interference of Presenilin-1. Knockdown of Presenilin-1 protein also resulted in escalation of ZER-induced apoptosis. The present study indicates that Notch2 activation by ZER inhibits its proapoptotic and anti-migratory response at least in breast cancer cells.

Moreira MA, Bagni C, de Pinho MB, et al.
Changes in gene expression profile in two multidrug resistant cell lines derived from a same drug sensitive cell line.
Leuk Res. 2014; 38(8):983-7 [PubMed] Related Publications
Resistance to chemotherapy is one of the most relevant aspects of treatment failure in cancer. Cell lines are used as models to study resistance. We analyzed the transcriptional profile of two multidrug resistant (MDR) cell lines (Lucena 1 and FEPS) derived from the same drug-sensitive cell K562. Microarray data identified 130 differentially expressed genes (DEG) between K562 vs. Lucena 1, 1932 between K562 vs. FEPS, and 1211 between Lucena 1 versus FEPS. The NOTCH pathway was affected in FEPS with overexpression of NOTCH2 and HEY1. The highly overexpressed gene in MDR cell lines was ABCB1, and both presented the ABCB1 promoter unmethylated.

Lombardo Y, Faronato M, Filipovic A, et al.
Nicastrin and Notch4 drive endocrine therapy resistance and epithelial to mesenchymal transition in MCF7 breast cancer cells.
Breast Cancer Res. 2014; 16(3):R62 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
INTRODUCTION: Resistance to anti-estrogen therapies is a major cause of disease relapse and mortality in estrogen receptor alpha (ERα)-positive breast cancers. Tamoxifen or estrogen withdrawal increases the dependence of breast cancer cells on Notch signalling. Here, we investigated the contribution of Nicastrin and Notch signalling in endocrine-resistant breast cancer cells.
METHODS: We used two models of endocrine therapies resistant (ETR) breast cancer: tamoxifen-resistant (TamR) and long-term estrogen-deprived (LTED) MCF7 cells. We evaluated the migratory and invasive capacity of these cells by Transwell assays. Expression of epithelial to mesenchymal transition (EMT) regulators as well as Notch receptors and targets were evaluated by real-time PCR and western blot analysis. Moreover, we tested in vitro anti-Nicastrin monoclonal antibodies (mAbs) and gamma secretase inhibitors (GSIs) as potential EMT reversal therapeutic agents. Finally, we generated stable Nicastrin overexpessing MCF7 cells and evaluated their EMT features and response to tamoxifen.
RESULTS: We found that ETR cells acquired an epithelial to mesenchymal transition (EMT) phenotype and displayed increased levels of Nicastrin and Notch targets. Interestingly, we detected higher level of Notch4 but lower levels of Notch1 and Notch2 suggesting a switch to signalling through different Notch receptors after acquisition of resistance. Anti-Nicastrin monoclonal antibodies and the GSI PF03084014 were effective in blocking the Nicastrin/Notch4 axis and partially inhibiting the EMT process. As a result of this, cell migration and invasion were attenuated and the stem cell-like population was significantly reduced. Genetic silencing of Nicastrin and Notch4 led to equivalent effects. Finally, stable overexpression of Nicastrin was sufficient to make MCF7 unresponsive to tamoxifen by Notch4 activation.
CONCLUSIONS: ETR cells express high levels of Nicastrin and Notch4, whose activation ultimately drives invasive behaviour. Anti-Nicastrin mAbs and GSI PF03084014 attenuate expression of EMT molecules reducing cellular invasiveness. Nicastrin overexpression per se induces tamoxifen resistance linked to acquisition of EMT phenotype. Our finding suggest that targeting Nicastrin and/or Notch4 warrants further clinical evaluation as valid therapeutic strategies in endocrine-resistant breast cancer.

Gao SB, Zheng QF, Xu B, et al.
EZH2 represses target genes through H3K27-dependent and H3K27-independent mechanisms in hepatocellular carcinoma.
Mol Cancer Res. 2014; 12(10):1388-97 [PubMed] Related Publications
UNLABELLED: Alterations of polycomb group (PcG) genes directly modulate the trimethylation of histone H3 lysine 27 (H3K27me3) and may thus affect the epigenome of hepatocellular carcinoma (HCC), which is crucial for controlling the HCC cell phenotype. However, the extent of downstream regulation by PcGs in HCC is not well defined. Using cDNA microarray analysis, we found that the target gene network of PcGs contains well-established genes, such as cyclin-dependent kinase inhibitors (CDKN2A), and genes that were previously undescribed for their regulation by PcG, including E2F1, NOTCH2, and TP53. Using chromatin immunoprecipitation assays, we demonstrated that EZH2 occupancy coincides with H3K27me3 at E2F1 and NOTCH2 promoters. Interestingly, PcG repress the expression of the typical tumor suppressor TP53 in human HCC cells, and an increased level of PcG was correlated with the downregulation of TP53 in certain HCC specimens. Unexpectedly, we did not find obvious H3K27me3 modification or an EZH2 binding signal at the TP53 promoters, suggesting that PcG regulates TP53 expression in an H3K27me3-independent manner. Finally, the reduced expression of PcGs effectively blocked the aggressive signature of liver cancer cells in vitro and in vivo.
IMPLICATIONS: Taken together, our results establish the functional and mechanistic significance of certain gene regulatory networks that are regulated by PcGs in HCC.

Chao CH, Chang CC, Wu MJ, et al.
MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis.
J Clin Invest. 2014; 124(7):3093-106 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis.

Gao SB, Xu B, Ding LH, et al.
The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma.
J Hepatol. 2014; 61(4):832-9 [PubMed] Related Publications
BACKGROUND & AIMS: The alterations of histone modification may serve as a promising diagnostic biomarker of hepatocellular carcinoma (HCC), but the clinical and mechanistic relatedness of the histone H3 lysine 27 and 4 trimethylation (H3K27me3 and H3K4me3) in HCC remains poorly understood. Here we propose that the combination of H3K27me3 and H3K4me3 is a more precise predictive/prognostic value for outcome of HCC patients.
METHODS: We used chromatin immunoprecipitation (ChIP) assays and a ChIP-on-chip screen to analyse HCC.
RESULTS: We found that the EZH2 occupancy coincides with the H3K27me3 at promoters and directly silences the transcription of target genes in HCC. The H3K27me3-related gene network of EZH2 contains well-established genes, such as CDKN2A, as well as previously unappreciated genes, including FOXO3, E2F1, and NOTCH2, among others. We further observed independently increasing profiles of H3K27me3 and H3K4me3 at the promoters of certain target genes in HCC specimens. Importantly, Kaplan-Meier analysis reveals that 3-year overall and tumour-free survival rates are dramatically reduced in patients that simultaneously express EZH2 and menin, compared to rates in the EZH2 or menin under expressing patients. Furthermore, an inhibitor of H3K27me3 alone, or in combination with an H3K4me3 inhibitor, effectively blocked the aggressive phenotype of HCC cells.
CONCLUSIONS: Our results indicate that a combined analysis of both H3K27me3 and H3K4me3 may serve as powerful diagnostic biomarkers of HCC, and targeting both might benefit anti-HCC therapy.

Sebastian P, Babu JM, Prathibha R, et al.
Anterior tongue cancer with no history of tobacco and alcohol use may be a distinct molecular and clinical entity.
J Oral Pathol Med. 2014; 43(8):593-9 [PubMed] Related Publications
BACKGROUND: A small, albeit significant, number of head and neck squamous cell carcinoma (HNSCC) patients has no history of tobacco and alcohol use. Such non-habits associated HNSCCs may represent a distinct clinical entity and exhibit increased aggressiveness. The objective of the study was to understand differences in molecular etiology of habits, and non-habits associated tongue carcinomas.
MATERIALS AND METHODS: High-throughput gene expression profiling of 22 tumor samples was carried out. This was followed by quantitative real-time PCR validation of four of the identified differentially expressed genes.
RESULTS AND CONCLUSION: Eighteen genes were identified that correlate strongly with the habits- and non-habits distinction. Among the genes significantly overexpressed in the non-habits group are CCND1, a key cell-cycle regulator, DACT3, a modulator of the Wnt/beta-catenin pathway, and three genes associated with the Notch signaling pathway. CCND1 and DACT3 overexpression in non-habits associated tongue carcinomas were subsequently validated by quantitative real-time PCR in an independent cohort (n = 18) of patient samples. Gene expression data were integrated with publicly available protein interaction data to build a small protein interaction network containing five of 18 differentially expressed genes. This suggested that a functional 'network module' can be implicated in the subgroup distinction. All the tumors analyzed here were human papillomavirus (HPV) negative samples. An association between CCND1 overexpression in oral tumors and poor prognosis has previously been reported. Thus, CCND1 overexpression in non-habits associated anterior tongue carcinomas may contribute to their increased clinical aggressiveness.

Zhang S, Chung WC, Wu G, et al.
Tumor-suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation.
Neoplasia. 2014; 16(2):158-67 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Elevated Notch ligand and receptor expression has been associated with aggressive forms of prostate cancer, suggesting a role for Notch signaling in regulation of prostate tumor initiation and progression. Here, we report a critical role for Lunatic Fringe (Lfng), which encodes an O-fucosylpeptide 3-ß-N-acetylglucosaminyltransferase known to modify epidermal growth factor repeats of Notch receptor proteins, in regulation of prostate epithelial differentiation and proliferation, as well as in prostate tumor suppression. Deletion of Lfng in mice caused altered Notch activation in the prostate, associated with elevated accumulation of Notch1, Notch2, and Notch4 intracellular domains, decreased levels of the putative Notch3 intracellular fragment, as well as increased expression of Hes1, Hes5, and Hey2. Loss of Lfng resulted in expansion of the basal layer, increased proliferation of both luminal and basal cells, and ultimately, prostatic intraepithelial neoplasia. The Lfng-null prostate showed down-regulation of prostatic tumor suppressor gene NKX3.1 and increased androgen receptor expression. Interestingly, expression of LFNG and NKX3.1 were positively correlated in publically available human prostate cancer data sets. Knockdown of LFNG in DU-145 prostate cancer cells led to expansion of CD44(+)CD24(-) and CD49f(+)CD24(-) stem/progenitor-like cell population associated with enhanced prostatosphere-forming capacity. Taken together, these data revealed a tumor-suppressive role for Lfng in the prostate through differential regulation of Notch signaling.

Fiaschetti G, Schroeder C, Castelletti D, et al.
NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma.
Acta Neuropathol Commun. 2014; 2:39 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.

Cordeiro BM, Oliveira ID, Alves MT, et al.
SHH, WNT, and NOTCH pathways in medulloblastoma: when cancer stem cells maintain self-renewal and differentiation properties.
Childs Nerv Syst. 2014; 30(7):1165-72 [PubMed] Related Publications
PURPOSE: Infant medulloblastoma (MB) is a malignant neuroepithelial embryonal tumor of the cerebellum, believed to derive from precursor granule cells with stem or progenitor cells appearance, and caused by a change in expression profile of genes related to the development. This work aims to study the expression profile of these genes in MB tumors, correlating with clinicopathological characteristics.
METHODS: We quantified, by qPCR in 40 MB tumor samples, the expression of genes in HH (PTCH1, PTCH2, and GLI1), WNT (APC, CTNNB1, WIF1, and DKK2), and NOTCH pathways (NOTCH2 and HES1), which have a crucial role in development, and genes as MYCC, MYCN, and TERT, correlating this findings to patient's clinicopathological characteristics.
RESULTS: Considering the universal RNA as our control sample, and considering the median of gene expression in the control samples as our cutoff, we observed that HES1 gene showed decreased expression compared to control (p = 0.0059), but patients with HES1 overexpression were directly related to a shorter survival (p = 0.0165). Individuals with higher GLI1 gene expression had significant shorter survival (p = 0.0469), and high expression was prevalent in patients up to 5 years old (p = 0.0479). Patients showing high PTCH2 expression were related to worse survival (p = 0.0426), and it was correlated with GLI1 high expression (p = 0.0094). We also observed a concomitant overexpression of WIF1 and DKK2 genes in a subgroup of MB samples (n = 11, p = 0.0118).
CONCLUSIONS: Our results suggest the presence of activated developmental signaling pathways in MB, which are important for cell proliferation and maintenance, and that may be targeted for novel therapeutic options.

Sakata-Yanagimoto M, Enami T, Yokoyama Y, Chiba S
Disease-specific mutations in mature lymphoid neoplasms: recent advances.
Cancer Sci. 2014; 105(6):623-9 [PubMed] Related Publications
Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies.

Cao Z, Ding BS, Guo P, et al.
Angiocrine factors deployed by tumor vascular niche induce B cell lymphoma invasiveness and chemoresistance.
Cancer Cell. 2014; 25(3):350-65 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Tumor endothelial cells (ECs) promote cancer progression in ways beyond their role as conduits supporting metabolism. However, it is unknown how vascular niche-derived paracrine factors, defined as angiocrine factors, provoke tumor aggressiveness. Here, we show that FGF4 produced by B cell lymphoma cells (LCs) through activating FGFR1 upregulates the Notch ligand Jagged1 (Jag1) on neighboring ECs. In turn, upregulation of Jag1 on ECs reciprocally induces Notch2-Hey1 in LCs. This crosstalk enforces aggressive CD44(+)IGF1R(+)CSF1R(+) LC phenotypes, including extranodal invasion and chemoresistance. Inducible EC-selective deletion of Fgfr1 or Jag1 in the Eμ-Myc lymphoma model or impairing Notch2 signaling in mouse and human LCs diminished lymphoma aggressiveness and prolonged mouse survival. Thus, targeting the angiocrine FGF4-FGFR1/Jag1-Notch2 loop inhibits LC aggressiveness and enhances chemosensitivity.

Adamia S, Bar-Natan M, Haibe-Kains B, et al.
NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML.
Blood. 2014; 123(18):2816-25 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34(+) bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics.

Pastò A, Serafin V, Pilotto G, et al.
NOTCH3 signaling regulates MUSASHI-1 expression in metastatic colorectal cancer cells.
Cancer Res. 2014; 74(7):2106-18 [PubMed] Related Publications
MUSASHI-1 (MSI-1) is a well-established stem cell marker in both normal and malignant colon cells and it acts by positively regulating the NOTCH pathway through inactivation of NUMB, a NOTCH signaling repressor. To date, the mechanisms of regulation of MSI-1 levels remain largely unknown. Here, we investigated the regulation of MSI-1 by NOTCH signaling in colorectal cancer cell lines and in primary cultures of colorectal cancer metastases. Stimulation by the NOTCH ligand DLL4 was associated with an increase of MSI-1 mRNA and protein levels, and this phenomenon was prevented by the addition of an antibody neutralizing NOTCH2/3 but not NOTCH1. Moreover, forced expression of activated NOTCH3 increased MSI-1 levels, whereas silencing of NOTCH3 by short hairpin RNA reduced MSI-1 levels in both colorectal cancer cells and CRC tumor xenografts. Consistent with these findings, enforced NOTCH3 expression or stimulation by DLL4 increased levels of activated NOTCH1 in colorectal cell lines. Finally, treatment of colorectal cancer cells with anti-NOTCH2/3 antibody increased NUMB protein while significantly reducing formation of tumor cell spheroids. This novel feed-forward circuit involving DLL4, NOTCH3, MSI-1, NUMB, and NOTCH1 may be relevant for regulation of NOTCH signaling in physiologic processes as well as in tumor development. With regard to therapeutic implications, NOTCH3-specific drugs could represent a valuable strategy to limit NOTCH signaling in the context of colorectal cancers overexpressing this receptor.

Baumgart A, Mazur PK, Anton M, et al.
Opposing role of Notch1 and Notch2 in a Kras(G12D)-driven murine non-small cell lung cancer model.
Oncogene. 2015; 34(5):578-88 [PubMed] Related Publications
Lung cancer is the leading cause of cancer-related deaths worldwide. Recently, we have shown that Notch1 inhibition resulted in substantial cell death of non-small cell lung cancer (NSCLC) cells in vitro. New compounds targeting Notch signal transduction have been developed and are now being tested in clinical trials. However, the tumorigenic role of individual Notch receptors in vivo remains largely unclear. Using a Kras(G12D)-driven endogenous NSCLC mouse model, we analyzed the effect of conditional Notch1 and Notch2 receptor deletion on NSCLC tumorigenesis. Notch1 deficiency led to a reduced early tumor formation and lower activity of MAPK compared with the controls. Unexpectedly, Notch2 deletion resulted in a dramatically increased carcinogenesis and increased MAPK activity. These mice died significantly earlier due to rapidly growing tumor burden. We found that Notch1 regulates Ras/MAPK pathway via HES1-induced repression of the DUSP1 promoter encoding a phosphatase specifically suppressing pERK1/2. Interestingly, Notch1 but not Notch2 ablation leads to decreased HES1 and DUSP1 expression. However, Notch2-depleted tumors showed an appreciable increase in β-catenin expression, a known activator of HES1 and important lung cancer oncogene. Characteristically for β-catenin upregulation, we found that the majority of Notch2-deficient tumors revealed an undifferentiated phenotype as determined by their morphology, E-Cadherin and TTF1 expression levels. In addition, these carcinomas showed aggressive growth patterns with bronchus invasion and obstruction. Together, we show that Notch2 mediates differentiation and has tumor suppressor functions during lung carcinogenesis, whereas Notch1 promotes tumor initiation and progression. These data are further supported by immunohistochemical analysis of human NSCLC samples showing loss or downregulation of Notch2 compared with normal lung tissue. In conclusion, this is the first study characterizing the in vivo functions of Notch1 and Notch2 in Kras(G12D)-driven NSCLC tumorigenesis. These data highlight the clinical importance of a thorough understanding of Notch signaling especially with regard to Notch-targeted therapies.

Gogoi D, Dar AA, Chiplunkar SV
Involvement of Notch in activation and effector functions of γδ T cells.
J Immunol. 2014; 192(5):2054-62 [PubMed] Related Publications
Notch signaling plays a pivotal role in cell fate decision and lineage commitment of lymphocytes. Although the role of Notch in CD4(+) and CD8(+) αβ T cells is well documented, there are no reports on how Notch signaling regulates effector functions of γδ T cells. γδ T cells are a minor fraction in the peripheral blood but are known to play a major role in defense against pathogens and tumors. In this study, we show that Notch receptors (mRNA and protein) are expressed in peripheral γδ T cells. Inhibition of Notch signaling by γ-secretase inhibitor inhibited the proliferation and IFN-γ secretion of γδ T cells in response to stimulation with phosphoantigens and anti-CD3 mAb. In the presence of γ-secretase inhibitor, the antitumor cytolytic ability of γδ T cells was inhibited with a decreased CD107a expression. Knockdown of Notch1 and Notch2 genes in γδ T cells using small interfering RNA inhibited their antitumor cytotoxic potential. Our study describes for the first time, to our knowledge, the role of Notch as an additional signal contributing to Ag-specific effector functions of γδ T cells.

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