NOTCH1

Gene Summary

Gene:NOTCH1; notch receptor 1
Aliases: hN1, AOS5, TAN1, AOVD1
Location:9q34.3
Summary:This gene encodes a member of the NOTCH family of proteins. Members of this Type I 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 signaling is an evolutionarily conserved intercellular signaling pathway that regulates interactions between physically adjacent cells through binding of Notch family receptors to their cognate ligands. The encoded preproprotein is proteolytically processed in the trans-Golgi network to generate two polypeptide chains that heterodimerize to form the mature cell-surface receptor. This receptor plays a role in the development of numerous cell and tissue types. Mutations in this gene are associated with aortic valve disease, Adams-Oliver syndrome, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and head and neck squamous cell carcinoma. [provided by RefSeq, Jan 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:neurogenic locus notch homolog protein 1
Source:NCBIAccessed: 31 August, 2019

Ontology:
What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Contents

Gene Summary

Cancer Overview

Specific Cancers (10)

Useful Links

Latest Publications
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (10)

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

Entity Topic PubMed Papers
Breast CancerNOTCH1 and Breast Cancer View Publications213
-NOTCH1 and Precursor T-Cell Lymphoblastic Leukemia-Lymphoma View Publications181
Chronic Lymphocytic LeukemiaNOTCH1 and Chronic Lymphocytic Leukemia View Publications189
Head and Neck CancersNOTCH1 mutations in Head and Neck Cancers
Agrawal et al (2011) whole-exome sequencing and gene copy number analyses to study 32 primary hesd and neck squamous cell tumors and found that nearly 40% of 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in HNSCC.		 View Publications208
Childhood CancersNOTCH1 and Childhood T-Cell ALL View Publications97
Acute Lymphocytic Leukemia (ALL), childNOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL)
"T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy of thymocytes affecting preferentially children and adolescents. The disease is heterogeneous and characterized by a large set of chromosomal and genetic alterations that deregulate the growth of maturing thymocytes. The identification of activating point mutations in NOTCH1 in more then 50% of all T-ALL cases highlights the NOTCH1 cascade as a central player of T-ALL pathogenesis." (Koch et al, 2011)		 View Publications56
-NOTCH1 / Notch signaling and Drug Resistance
Notch signaling and NOTCH1 expression has been implicated in drug resistance in a number of studies.		 View Publications59
Esophageal CancerNOTCH1 and Esophageal Cancer
In a comparative sequencing study of 11 esophageal adenocarcinomas (EAC) and 12 esophageal squamous cell carcinomas (ESCC) Agrawal (2012) found that 21% of ESCCs had inactivating mutations of NOTCH1, and EAC's did not.		 View Publications28
Thyroid CancerNOTCH1 and Thyroid Cancer View Publications23
Acute Lymphocytic Leukaemia (ALL)t(7;9)(q34;q34) in T-Cell Acute Lymphoblastic Leukaemia View Publications7

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

Latest Publications: NOTCH1 (cancer-related)

Itoh M, Okuhashi Y, Takahashi Y, et al.
Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells.
Anticancer Res. 2019; 39(8):4165-4170 [PubMed] Related Publications
AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow.
MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined.
RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation.
CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.
Related: HIF1A Leukemia AKT1 Signal Transduction MTOR

Naghizadeh S, Mohammadi A, Baradaran B, Mansoori B
Overcoming multiple drug resistance in lung cancer using siRNA targeted therapy.
Gene. 2019; 714:143972 [PubMed] Related Publications
Among cancers, lung cancer is the most morbidity and mortality disease that is remaining the fatalist. Generally, there are multiple treatment procedures for lung cancer, such as surgery, immunotherapy, radiotherapy and chemotherapy. There is, therefore, an urgent need for more specified and efficient methods for treatment of lung cancer such as RNAi, which in combination with traditional therapies could silence genes that are involved in the drug resistance. These genes may either be motivators of apoptosis inhibition, EMT and DNA repair system promoters or a member of intracellular signaling pathways, such as JAK/STAT, RAS/RAF/MEK, PI3K/AKT, NICD, B-catenin/TCF/LEF and their stimulator receptors including IGFR, EGFR, FGFR, VEGFR, CXCR4, MET, INTEGRINS, NOTCH1 and FRIZZLED, so could be considered as appropriate targets. In current review, the results of multiple studies which have employed drug application after one specific gene silencing or more than one gene from distinct pathways also simultaneous drug and RNAi usage in vitro and in vivo in lung cancer were summarized.
Related: Apoptosis Lung Cancer Signal Transduction

Ou J, Guan D, Yang Y
Non-contact co-culture with human vascular endothelial cells promotes epithelial-to-mesenchymal transition of cervical cancer SiHa cells by activating the NOTCH1/LOX/SNAIL pathway.
Cell Mol Biol Lett. 2019; 24:39 [PubMed] Free Access to Full Article Related Publications
Background: The aim of this study was to investigate the effect of human umbilical vein endothelial cells on epithelial-to-mesenchymal transition of the cervical cancer cell line SiHa by studying the Notch1/lysyl oxidase (LOX)/SNAIL1 pathway.
Methods: Monocultures of SiHa cells, SiHa cells containing a control sequence, and
Results: Compared with monocultured SiHa cells, co-cultured SiHa cells showed a significant increase in their invasiveness and expression levels of vimentin, as well as of NOTCH 1, LOX, and SNAIL1, whereas their expression of E-cadherin was significantly reduced and protein activities of MMP-2 and MMP-9 were increased. Compared with SiHa, mono- and co-cultured
Conclusion: Co-culture with human umbilical vein endothelial cells promoted the epithelial-to-mesenchymal transition of SiHa cells by activating the NOTCH1/LOX/SNAIL1 pathway in SiHa cells, which enhanced their invasive and metastatic capacities. The results of this study may provide a new perspective on cervical cancer metastasis and a theoretical basis for clinical treatment.
Related: MMP2 MMP9: matrix metallopeptidase 9 Signal Transduction Cervical Cancer

Yang MH, Chang KJ, Li B, Chen WS
Arsenic Trioxide Suppresses Tumor Growth through Antiangiogenesis via Notch Signaling Blockade in Small-Cell Lung Cancer.
Biomed Res Int. 2019; 2019:4647252 [PubMed] Free Access to Full Article Related Publications
Small-cell lung cancer (SCLC) is a highly malignant type of lung cancer with no effective second-line chemotherapy drugs. Arsenic trioxide (As
Related: Angiogenesis Inhibitors Lung Cancer Signal Transduction Small Cell Lung Cancer

Li JY, Huang WX, Zhou X, et al.
Numb inhibits epithelial-mesenchymal transition via RBP-Jκ-dependent Notch1/PTEN/FAK signaling pathway in tongue cancer.
BMC Cancer. 2019; 19(1):391 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Oral cancer has been estimated as the sixth most frequent solid cancer all over the world, in which tongue squamous cell carcinoma (TSCC) is the most common type of oral cancers. However, the mechanism of TSCC metastasizing to lymph node and distant sites has not been completely understood.
METHODS: In this study, RT-qPCR method was used to detect the mRNA level of Numb, PTEN and Notch1 genes, as well as EMT-associated genes. Western blot assay was utilized to detect protein level of these genes. In addition, we determined cell proliferation by MTT assay and employed transwell invasion assay and wound healing assay to probe the abilities of invasion and migration, respectively. To investigate the role of PTEN, its inhibitor VO-Ohpic trihydrate was used to treat SCC-4 and CAL27 cells.
RESULTS: We found that Numb expression was downregulated in SCC-9 and CAL-27 cells compared to NHOK cells. Instead, Notch1 level in SCC-9 and CAL-27 cells were higher than that in NHOK cells. Furthermore, the results showed that Numb overexpression significantly suppressed proliferation, migration and invasion of SCC-9 and CAL-27 cells via regulating Notch1 signaling and EMT-related genes expression. By contrast, we observed that RBP-Jκ knockdown had an inhibitory role in proliferation, migration and invasion of SCC-9 and CAL-27 cells. In cells with Numb overexpression or RBP-Jκ knockdown, p-FAK and EMT-related genes were remarkably regulated.
CONCLUSIONS: Our findings provide new mechanism of understanding the metastasis of TSCC and help develop therapeutic strategies for treating tongue cancer.
Related: PTEN Signal Transduction

Wu M, Zhong X, Peng Q, et al.
Prediction of molecular subtypes of breast cancer using BI-RADS features based on a "white box" machine learning approach in a multi-modal imaging setting.
Eur J Radiol. 2019; 114:175-184 [PubMed] Related Publications
PURPOSE: To develop and validate an interpretable and repeatable machine learning model approach to predict molecular subtypes of breast cancer from clinical metainformation together with mammography and MRI images.
METHODS: We retrospectively assessed 363 breast cancer cases (Luminal A 151, Luminal B 96, HER2 76, and BLBC 40). Eighty-two features defined in the BI-RADS lexicon were visually described. A decision tree model with the Chi-squared automatic interaction detector (CHAID) algorithm was applied for feature selection and classification. A 10-fold cross-validation was performed to investigate the performance (i.e., accuracy, positive predictive value, sensitivity, and F1-score) of the decision tree model.
RESULTS: Seven of the 82 variables were derived from the decision tree-based feature selection and used as features for the classification of molecular subtypes including mass margin calcification on mammography, mass margin types of kinetic curves in the delayed phase, mass internal enhancement characteristics, non-mass enhancement distribution on MRI, and breastfeeding history. The decision tree model accuracy was 74.1%. For each molecular subtype group, Luminal A achieved a sensitivity, positive predictive value, and F1-score of 79.47%, 75.47%, and 77.42%, respectively; Luminal B showed a sensitivity, positive predictive value, and F1-score of 64.58%, 55.86%, and 59.90%, respectively; HER2 had a sensitivity, positive predictive value, and F1-scores of 81.58%, 95.38%, and 87.94%, respectively; BLBC showed sensitivity, positive predictive value, and F1-scores of 62.50%, 89.29%, and 73.53%, respectively.
CONCLUSIONS: We applied a complete "white box" machine learning method to predict the molecular subtype of breast cancer based on the BI-RADS feature description in a multi-modal setting. By combining BI-RADS features in both mammography and MRI, the prediction accuracy is boosted and robust. The proposed method can be easily applied widely regardless of variability of imaging vendors and settings because of the applicability and acceptance of the BI-RADS.
Related: Breast Cancer

Sprouse ML, Welte T, Boral D, et al.
PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients' blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.
Related: Breast Cancer Melanoma NFE2L2

Wang Y, Zhong Y, Hou T, et al.
PM2.5 induces EMT and promotes CSC properties by activating Notch pathway in vivo and vitro.
Ecotoxicol Environ Saf. 2019; 178:159-167 [PubMed] Related Publications
Fine particulate matter (PM2.5) has been closely linked to increased morbidity and mortality of lung cancer worldwide. However, the role of PM2.5 in the etiology of lung cancer and the mechanism involved in PM2.5 induced lung cancer are largely unknown. In this study, we performed chronic exposure animal model to investigate the carcinogenetic mechanisms of PM2.5 by targeting the induction of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSC) properties through Notch1 signal pathway. The antagonism of Notch1 signal pathway was carried out in vitro cell lines of A549 and BEAS-2B to block EMT and CSC. We found that chronic PM2.5 exposure mice lung tissue pathology showed atypical hyperplasia of bronchiolar epithelium. Then, we discovered that chronic PM2.5 exposure induced notable EMT event and obvious CSC properties indicating the developing process of cell malignant behaviors. EMT characterized with decreased protein expression of E-cadherin and increased protein expression of Vimentin. CSC properties induced by chronic PM2.5 exposure characterized with increased cell-surface markers (ABCG2 and ALDH1A1) and self-renewal genes (SOX2 and OCT4). Furthermore, PM2.5 exposure activate Notch signal pathway by increasing expression of Notch1 and Hes1. At last, we blocked Notch signal pathway by inhibitor RO4929097 in vitro to explore the underlying mechanism mediating PM2.5 induced EMT and CSC. We found that blocking Notch1 could prevent PM2.5 induced malignant behaviors including EMT and CSC in A549 and BEAS-2B. These data revealed that the induction of EMT and CSC properties were involved in the lung cancer risk of PM2.5 in vivo, and blocking-up Notch1 may negatively regulate EMT and CSC to suppress the invasion and migration in vitro, thereby putatively serving as a novel therapeutic target for PM2.5 induced lung cancer.
Related: Lung Cancer Signal Transduction

Yu Y, Blokhuis BR, Garssen J, Redegeld FA
A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal-e.g., TLR2 ligands-may modify their responses in the cancer milieu.
Related: Cytokines MMP2 VEGFA PDGFA

Bilous N, Abramenko I, Chumak A, et al.
Analysis of LPL gene expression in patients with chronic lymphocytic leukemia.
Exp Oncol. 2019; 41(1):39-45 [PubMed] Related Publications
AIM: The IGHV mutational status is one of the most important markers for chronic lymphocytic leukemia (CLL) prognostication. Lipoprotein lipase (LPL) gene expression was found to correlate with IGHV status and was suggested as its surrogate marker. Recent data reported that LPL expression might be influenced by pivotal signalling pathways in CLL. This study aimed to assess LPL gene expression in relation to key immunogenetic and molecular markers of CLL, including IGHV mutational status, B-cell receptor (BCR) stereotypy, TP53, NOTCH1, and SF3B1 gene mutations. Materials and Methods: Expression of LPL mRNA was measured in peripheral blood mononuclear cells of 73 CLL patients by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). IGHV, NOTCH1, TP53, and SF3B1 gene mutation analysis was performed by PCR amplification and direct sequencing.
RESULTS: 44 of 73 (60%) CLL cases were categorized as LPL-positive based on the cut-off value established by ROC (receiver operating characteristic) curve analysis. LPL expression was significantly associated with IGHV mutation status (r = 0.684; p < 0.0001) and tended to correlate with presence of NOTCH1 gene mutations (p = 0.113). BCR stereotyped cases showed higher LPL expression values in comparison to unstereotyped cases in the LPL-positive group of patients (p = 0.041). LPL expression was associated with a shorter overall survival in the entire СLL group (median 107 vs 143, p = 0.048) as well as in Binet A patients, albeit with borderline significance (median 139 vs not reached, p = 0.086).
CONCLUSION: LPL expression was found to be closely correlated with IGHV gene mutational status and overall survival, proving LPL as prognostic marker in CLL. Our results also indicate a possible relationship between aberrant expression of LPL and BCR- and NOTCH1-dependent signalling pathways.
Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Jin M, Wang J, Ji X, et al.
MCUR1 facilitates epithelial-mesenchymal transition and metastasis via the mitochondrial calcium dependent ROS/Nrf2/Notch pathway in hepatocellular carcinoma.
J Exp Clin Cancer Res. 2019; 38(1):136 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Mitochondrial Ca
METHODS: The effect of MCUR1 expression on epithelial-mesenchymal transition (EMT) in HCC cells was first evaluated by immunofluorescent staining and Western blot. Then, in vitro invasion and in vivo metastasis assays were used to evaluate the function of MCUR1 in HCC metastasis. The underlying mechanism has also been explored by investigating the effect of MCUR1 on ROS/Nrf2/Notch1 pathway.
RESULTS: MCUR1 expression was significantly higher in HCC with metastasis and associated with tumor progression. MCUR1 promoted in vitro invasion and in vivo metastasis of HCC cells by promoting EMT via Snail. Mechanistically, MCUR1-mediated mitochondrial Ca
CONCLUSIONS: Our study provides evidence supporting a metastasis-promoting role for MCUR1-dependent mitochondrial Ca
Related: Liver Cancer Mitochondrial Mutations in Cancer NFE2L2 Signal Transduction

Jia Y, Lin R, Jin H, et al.
MicroRNA-34 suppresses proliferation of human ovarian cancer cells by triggering autophagy and apoptosis and inhibits cell invasion by targeting Notch 1.
Biochimie. 2019; 160:193-199 [PubMed] Related Publications
Ovarian cancer is one the prevalent cancers in women and is responsible for 5% of all the cancer related mortalities in women. Owing to late diagnosis, frequent relapses, side effects of chemotherapy, development of drug resistance, there is pressing need to screen out novel and effective treatment options. Accumulating evidences suggest that miRNAs may prove essential therapeutic targets for the treatment of cancer. This study was designed to investigate the role and therapeutic potential of miR-34 in ovarian cancer. It was found that miR-34 is significantly downregulated in ovarian cancer cell lines. Overexpression of miR-34 causes significant decrease in the proliferation of OVACAR-3 ovarian cancer cells via activation of apoptosis and autophagy. The miR-34 overexpression was concomitant with upsurge of apoptosis related proteins (Bax) and the autophagy associated protein (LC3 II and p62). TargetScan analysis showed Notch 1 to be the main target of miR-34 in OVACAR-3 cells which was further validated by luciferase reporter assay. The qRT-PCR results showed Notch 1 to be 3.2-4.1 fold higher in the ovarian cancer cell lines relative to the non-cancerous cells. Nonetheless, miR-34 overexpression in OVACAR-3 cells resulted in the post-transcriptional suppression of Notch 1 expression. Silencing of Notch 1 also caused inhibition of OVACAR-3 cell proliferation via induction of apoptosis and autophagy. Overexpression of Notch 1 could partially rescue the effects of miR-34 overexpression on the proliferation of OVACAR-3 cells. Moreover, overexpression of miR-34 causes significant inhibition of the invasion of the OVACAR-3 cells. The findings of the present study indicate the tumor suppressive role of miR-34 in ovarian cancer and may therefore prove to be a potential therapeutic target.
Related: Apoptosis MicroRNAs Ovarian Cancer

Afshar E, Hashemi-Arabi M, Salami S, et al.
Screening of acetaminophen-induced alterations in epithelial-to-mesenchymal transition-related expression of microRNAs in a model of stem-like triple-negative breast cancer cells: The possible functional impacts.
Gene. 2019; 702:46-55 [PubMed] Related Publications
Current protocols for therapy inefficiently targets triple negative breast cancer and barely eradicate cancer stem cells. Elucidation of the pleiotropic effect of clinically proven therapeutics on cancer cells shed light on novel application of old friends. The pleiotropic effect of acetaminophen (APAP) on breast cancer was previously reported. In a cell model of triple negative breast cancer with stem-like CD44
Related: MicroRNAs

Chen Z, Zuo X, Pu L, et al.
Hypomethylation-mediated activation of cancer/testis antigen KK-LC-1 facilitates hepatocellular carcinoma progression through activating the Notch1/Hes1 signalling.
Cell Prolif. 2019; 52(3):e12581 [PubMed] Related Publications
OBJECTIVES: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK-LC-1 has been on its potential as diagnostic biomarker and immunotherapy target. However, its biological functions and molecular mechanisms in cancer progression remain unknown.
MATERIALS AND METHODS: Expression of KK-LC-1 in HCC was analysed using RT-qPCR, Western blot and immunohistochemistry. The roles of KK-LC-1 on HCC progression were examined by loss-of-function and gain-of-function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK-LC-1 on the downstream Notch signalling. The interaction of KK-LC-1 with presenilin-1 was determined by co-immunoprecipitation. The association of CpG island methylation status with KK-LC-1 reactivation was evaluated by methylation-specific PCR, bisulphite sequencing PCR and 5-Aza-dC treatment.
RESULTS: We identified that HCC tissues exhibited increased levels of KK-LC-1. High KK-LC-1 level independently predicted poor survival outcome. KK-LC-1 promoted cell growth, migration, invasion and epithelial-mesenchymal transition in vitro and in vivo. KK-LC-1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin-1. Upregulation of KK-LC-1 in HCC was attributed to hypomethylated CpG islands.
CONCLUSIONS: This study identified that hypomethylation-induced KK-LC-1 overexpression played an important role in HCC progression and independently predicted poor survival. We defined the KK-LC-1/presenilin-1/Notch1/Hes1 as a novel signalling pathway that was involved in the growth and metastasis of HCC.
Related: Liver Cancer Signal Transduction

Daniele G, L'Abbate A, Turchiano A, et al.
1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia.
Clin Exp Med. 2019; 19(2):261-267 [PubMed] Related Publications
The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.
Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Wang Y, Li M, Dong C, et al.
Linc00152 knockdown inactivates the Akt/mTOR and Notch1 pathways to exert its anti-hemangioma effect.
Life Sci. 2019; 223:22-28 [PubMed] Related Publications
AIMS: Infantile hemangioma (IH) is one of the most common benign vascular tumors occurred in infants. Linc00152 is a kind of long non-coding RNAs (lncRNAs) and acts as a tumor oncogene. Recent study reported that Linc00152 is highly expressed in clinical IH tissues. However, the exact biological roles have not yet been investigated. The aim of the present study was to investigate the oncogenic roles of Linc00152 in IH and the underlying mechanism in vitro.
MAIN METHODS: The expressions of Linc00152 in IH tissues and hemangioma-derived endothelial cells (HemECs) were determined using quantitative real time-PCR (qRT-PCR) analysis. The expressions of Akt/mTOR and Notch1 pathways related proteins were detected using western blot analysis. Cell proliferation was assessed by detecting Ki67 expression and CCK-8 assay. Cell apoptosis was evaluated by detecting apoptotic rate, caspase-3/7 activity, and Bcl-2 and Bax expression.
KEY FINDINGS: The results demonstrated Linc00152 was up-regulated in clinical IH tissues and HemECs. Knockdown of Linc00152 in HemECs suppressed the activation of Akt/mTOR and Notch1 signaling pathways and caused reduction in cell proliferation and Ki67 expression in HemECs. Besides, Linc00152 knockdown resulted in a significant increase in apoptotic rate, caspase-3/7 activity, and Bax expression level, as well as a decrease in Bcl-2 expression level. However, the effects of Linc00152 knockdown on cell proliferation and apoptosis were mitigated by overexpression of Akt or Notch1.
SIGNIFICANCE: Knockdown of Linc00152 suppressed HemECs proliferation and induced apoptosis via inhibiting Akt/mTOR and Notch1 signaling pathways.
Related: AKT1 Signal Transduction MTOR

Wang L, Zhao S, Yu M
Mechanism of Low Expression of miR-30a-5p on Epithelial-Mesenchymal Transition and Metastasis in Ovarian Cancer.
DNA Cell Biol. 2019; 38(4):341-351 [PubMed] Related Publications
Metastasis of ovarian cancer is regulated by microRNAs. This study focused on the effects of miR-30a-5p on ovarian cancer migration and invasion. Our results showed that the miR-30a-5p and mucin type O-glycan biosynthesis are closely related to ovarian cancer, and that miR-30a-5p was downregulated in ovarian cancer cells. miR-30a-5p overexpression reduced cell viability and inhibited migration and invasion in HO-8910 and HO-8910PM cells. S phase kinase-associated protein 2 (SKP2), B cell lymphoma 9 (BCL9), and NOTHC1 are direct target genes of miR-30a-5p. MTDH, SKP2, BCL9, and NOTCH1 genes were overexpressed in ovarian cancer cells, and they are direct target genes of miR-30a-5p. miR-30a-5p overexpression inhibited epithelial-mesenchymal transition (EMT) process, while upregulation of SKP2, BCL9, and NOTCH1 gene expression levels reduced the inhibition of EMT process by miR-30a-5p. miR-30a-5p was lowly expressed in ovarian cancer, and such a phenomenon is related to ovarian cancer metastasis. miR-30a-5p might inhibit the migration and invasion of ovarian cancer cells by downregulating the expression of SKP2, BCL9, and NOTCH1 genes.
Related: MicroRNAs Ovarian Cancer BCL9

Kim TH, Park JH, Woo JS
Resveratrol induces cell death through ROS‑dependent downregulation of Notch1/PTEN/Akt signaling in ovarian cancer cells.
Mol Med Rep. 2019; 19(4):3353-3360 [PubMed] Related Publications
Resveratrol, a natural polyphenol compound, has been reported to exert anticancer activity in various cancer cells. The present study investigated the effect and underlying mechanisms of resveratrol in the human ovarian cancer cell lines, A2780 and SKOV3. Treatment with resveratrol induced apoptotic cell death in dose‑ and time‑dependent manners, as well as a transient increase of reactive oxygen species (ROS) generation. Resveratrol‑induced cell death was attenuated by the antioxidant, N‑acetylcysteine (NAC), suggesting that ROS were involved in the observed cell death. Treatment with resveratrol resulted in a ROS‑dependent decrease of Notch1 signaling. When cells were transfected to overexpress Notch1 using EF.hlCN1.CMV.GFP, resveratrol‑induced cell death was blocked. Western blot analysis demonstrated that resveratrol also upregulated phospho‑phosphatase and tensin homolog (p‑PTEN) and downregulated phospho‑Akt (p‑Akt). Overexpression of p‑Akt by transfection with a constitutively active form (caAkt), and the p‑PTEN inhibitor SF1670 prevented resveratrol‑induced cell death. The caspase‑3 inhibitor z‑DEVD‑FMK significantly attenuated the resveratrol‑induced caspase‑3 cleavage. Taken together, the results of the present study suggest that resveratrol induces caspase‑dependent cell death through suppression of Notch1 and PTEN/Akt signaling and it is mediated by increased ROS generation in human ovarian cancer cells.
Related: Apoptosis Ovarian Cancer PTEN AKT1 Signal Transduction

Sato Y, Yamada T, Hiroyama T, et al.
A robust culture method for maintaining tumorigenic cancer stem cells in the hepatocellular carcinoma cell line Li-7.
Cancer Sci. 2019; 110(5):1644-1652 [PubMed] Free Access to Full Article Related Publications
Cancer tissues contain small populations of highly tumorigenic cells termed cancer stem cells (CSCs). Immortalized cell lines containing CSCs are valuable and powerful experimental tools for research into the characteristics of these stem cells. We previously reported that the hepatocellular carcinoma cell line Li-7 includes abundant CD13
Related: Liver Cancer

He Y, Li J, Ding N, et al.
Combination of Enzastaurin and Ibrutinib synergistically induces anti-tumor effects in diffuse large B cell lymphoma.
J Exp Clin Cancer Res. 2019; 38(1):86 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is the most common form of lymphoma. Although durable remissions can be achieved in more than half of these patients, DLBCL remains a significant clinical challenge, with approximately 30% of patients not being cured. BCR-associated kinases (SYK, BTK, and PI3K) inhibitors have exhibited encouraging pre-clinical and clinical effects, as reported by many researchers. Early studies demonstrated that protein kinase C-β (PKCβ) inhibitors alter phosphorylation level the Bruton's tyrosine kinase (BTK), which leads to enhanced BTK signaling. Here, for the first time, we investigate whether the combination of PKCβ inhibitor enzastaurin and BTK inhibitor ibrutinib has synergistic anti-tumor effects in DLBCL.
METHODS: In vitro cell proliferation was analyzed using Cell Titer-Glo Luminescent Cell Viability Assay. Induction of apoptosis and cell cycle arrest were measured by flow cytometry. Western Blotting analysis was used to detect the essential regulatory enzymes in related signaling pathways. RNA-seq was conducted to evaluate the whole transcriptome changes brought by co-treatment with low doses of enzastaurin and ibrutinib. The synergistic anti-tumor effects of enzastaurin and ibrutinib were also evaluated in vivo.
RESULTS: Combination of enzastaurin and ibrutinib produced a lasting synergistic effect on the survival and proliferation of DLBCL cells, including reduction of proliferation, promoting apoptosis, inducting G1 phase arrest, preventing cell invasion and migration, and down-regulating activation of downstream signaling. More importantly, whole-transcriptome changes results showed that combination therapy worked synergistically to regulate whole-transcriptome expression compared with enzastaurin and ibrutinib alone. Co-treatment with low doses of enzastaurin and ibrutinib could effectively downregulate BCR, NF-κB, JAK and MAPK related signaling pathway. Furthermore, the mRNA expression analysis further indicated that co-treatment significantly decreased the mRNA levels of NOTCH1. The combination effect in inhibiting proliferation of DLBCL cells probably was realized through suppression of NOTCH1 expression. Finally, the anti-tumor activity of co-treatment also was demonstrated in vivo.
CONCLUSIONS: Combination of enzastaurin and ibrutinib had synergistic anti-tumor effects in DLBCL, independent of molecular subtype. These results provided a sound foundation for an attractive therapeutic treatment, and the simultaneous suppression of BTK and PKCβ might be a new treatment strategy for DLBCL.
Related: Apoptosis

Jang W, Park J, Kwon A, et al.
CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.
Exp Mol Med. 2019; 51(1):4 [PubMed] Free Access to Full Article Related Publications
We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.
Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Gao XH, Yu GY, Hong YG, et al.
Clinical significance of multiple gene detection with a 22-gene panel in formalin-fixed paraffin-embedded specimens of 207 colorectal cancer patients.
Int J Clin Oncol. 2019; 24(2):141-152 [PubMed] Related Publications
BACKGROUND: Simultaneous detection of multiple molecular biomarkers is helpful in the prediction of treatment response and prognosis for colorectal cancer (CRC) patients.
METHODS: A 22-gene panel consisting of 103 hotspot regions was utilized in the formalin-fixed paraffin-embedded (FFPE) tissue samples of 207 CRC patients, using the next-generation sequencing (NGS)-based multiplex PCR technique. Those 22 genes included AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53.
RESULTS: Of the 207 patients, 193 had one or more variants, with 170, 20, and 3 having one, two, and three mutated genes, respectively. Of the total 414 variants identified in this study, 384, 25, and 5 were single-nucleotide variants, deletion, and insertion. The top four frequently mutated genes were TP53, KRAS, PIK3CA, and FBXW7. There was high consistency between the results of NGS-PCR technique and routine ARMS-PCR in KRAS and BRAF mutation detection. Univariate and multivariate analyses demonstrated that advanced TNM stage, elevated serum CEA, total variants number ≥ 2, AKT1 and PTEN mutation were independent predictors of shorter DFS; poor differentiation, advanced TNM stage, total variants number ≥ 2, BRAF, CTNNB1 and NRAS mutation were independent predictors of shorter OS.
CONCLUSIONS: It is feasible to detect multiple gene mutations with a 22-gene panel in FFPE CRC specimens. TNM stage and total variants number ≥ 2 were independent predictors of DFS and OS. Detection of multiple gene mutations may provide additional prognostic information to TNM stage in CRC patients.
Related: Colorectal (Bowel) Cancer

Yokoyama A, Kakiuchi N, Yoshizato T, et al.
Age-related remodelling of oesophageal epithelia by mutated cancer drivers.
Nature. 2019; 565(7739):312-317 [PubMed] Related Publications
Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.
Related: Cancer of the Esophagus Esophageal Cancer

Wardhani LO, Matsushita M, Kuwamoto S, et al.
Expression of Notch 3 and Jagged 1 Is Associated With Merkel Cell Polyomavirus Status and Prognosis in Merkel Cell Carcinoma.
Anticancer Res. 2019; 39(1):319-329 [PubMed] Related Publications
BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine skin cancer and most MCCs are related to infection with Merkel cell polyomavirus (MCPyV). Notch signaling modulates cell fate in various tissues including the skin during development and homeostasis, and its aberrant activity relates to onset and progression of various malignancies. Therefore, association of NOTCH1/ NOTCH2/NOTCH3/jagged 1 (JAG1) expression with MCPyV status and prognosis in MCC was investigated.
MATERIALS AND METHODS: A total of 19 MCPyV-positive and 19 MCPyV-negative MCC samples from patients were stained immunohistochemically with antibodies against NOTCH1, NOTCH2, NOTCH3, and JAG1 and analyzed.
RESULTS: Expression of NOTCH1 and NOTCH2 was not associated with MCPyV status or prognosis. However, higher JAG1 expression was found in MCPyV-negative than in MCPyV-positive MCC (p<0.001), and NOTCH3 expression was higher in MCPyV-positive MCC (p=0.062). Kaplan-Meier and multivariate analyses showed that patients with MCC with higher NOTCH3 expression had better overall survival than otherwise (p=0.001 and p=0.033, respectively).
CONCLUSION: Expression of NOTCH3, as a tumor suppressor, is an independent predictor of MCC outcome.
Related: Merkel Cell Carcinoma Merkel Cell Polyomavirus Signal Transduction

Akbarzadeh M, Majidinia M, Fekri Aval S, et al.
Molecular Targeting of Notch Signaling Pathway by DAPT in Human Ovarian Cancer: Possible Anti Metastatic Effects
Asian Pac J Cancer Prev. 2018; 19(12):3473-3477 [PubMed] Free Access to Full Article Related Publications
Background: Ovarian cancer is one of the most important gynecological malignancies, causing significant mortality. Recently, there has been extensive attention to the involvement of signaling cascades in its initiation/progression. In this study, we focused on the possible role of Notch signal transduction in proliferation and metalloproteinase 2 and 9 function in human ovarian cancer OVCAR-3 cells. Methods: MTT proliferation assays were used to evaluate effects of a DAPT inhibitor on cell proliferation. For measurement of Hes-1 mRNA levels, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied following 48 h incubation with the inhibitor. In addition, metalloproteinase (MMPs) activity was assessed by zymography. Results: Inhibition of Notch signaling resulted in a significant reduction in OVCAR-3 cell proliferation. Additionally, DAPT treatment of cells significantly decreased Hes-1 mRNA levels (p < 0.05) as well as activity of MMP-2 and -9 (p < 0.05). Conclusion: Our results suggested that suppression of Notch signaling by a specific inhibitor can effectively decrease proliferation and the potential for metastasis of OVCAR-3 cells via a reduction in the activity of metalloproteinases 2 and 9. Thus, pharmacological targeting of the Notch signaling pathway could be a promising future treatment for ovarian cancer.
Related: MMP2 Ovarian Cancer Signal Transduction

Maciel ALT, Poubel CP, Noronha EP, et al.
CRLF2 expression associates with ICN1 stabilization in T-cell acute lymphoblastic leukemia.
Genes Chromosomes Cancer. 2019; 58(6):396-401 [PubMed] Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy with few molecular alterations showing a consensual prognostic value. CRLF2 overexpression was recently identified in high-risk T-ALL patients. For these cases, no genomic abnormality was found to be associated with CRLF2 overexpression. IKZF1 has been recently shown to be a direct transcriptional regulator of CRLF2 expression. Moreover, it is known that NOTCH1 antagonizes IKZF1 in T-ALL. In light of these pieces of evidence, we reasoned that IKZF1 binding perturbation and CRLF2 upregulation could be associated in T-ALL. We evaluated two independent series of pediatric T-ALL cases (PHOP, n = 57 and TARGET, n = 264) for the presence of common T-ALL molecular abnormalities, such as NOTCH1/FBXW7 mutations. We also assessed CRLF2 and IKZF1 gene expression. CRLF2 overexpression was observed in 14% (PHOP) and 16% (TARGET) of T-ALL patients. No correlation was found between mRNA expression of CRLF2 and IKZF1 in both cohorts. Interestingly, we show that patients with mutations affecting NOTCH1-PEST domain and/or FBXW7 had higher CRLF2 expression (P = .04). In summary, we demonstrate for the first time that only mutations resulting in ICN1 (intracellular domain of NOTCH1) stabilization are associated with CRLF2 overexpression.
Related: Acute Lymphocytic Leukemia (ALL)

Ning F, Zhou Q, Chen X
miR-200b promotes cell proliferation and invasion in t-cell acute Lymphoblastic leukemia through NOTCH1.
J Biol Regul Homeost Agents. 2018 Nov-Dec; 32(6):1467-1471 [PubMed] Related Publications
MicroRNA-200b (miR-200b) functions as an oncogenic regulator in human lung cancer. However, the effect of miRNA-200b on the development and progression of T-Cell acute lymphoblastic leukemia (T-ALL) remains largely unknown. In this study, we evaluated the impact of miR-200b in T-ALL cell proliferation, survival and invasion using gain and loss of function approaches. Human Jurkat cells, a widely used
Related: MicroRNAs

Su H, Wang X, Song J, et al.
MicroRNA-539 inhibits the progression of Wilms' Tumor through downregulation of JAG1 and Notch1/3.
Cancer Biomark. 2019; 24(1):125-133 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Previous studies demonstrated that miR-539 play an important role in the carcinogenesis of some cancers. The aim of the present study was to determine the role of miR-539 in the pathogenesis of Wilms' Tumor (WT).
METHODS: The expression level of miR-539 was measured by qRT-PCR in 42 WT tissues and SK-NEP-1 cell line. Protein expression of genes (E-cadherin, N-cadherin, Vimentin, Notch 1, Notch 3 and JAG1) was assessed by Western blot. The function of miR-539 was investigated in SK-NEP-1 cells by MTT and Transwell assays. The relationship between miR-539 and JAG1 was verified by a dual luciferase assay in SK-NEP-1 cells.
RESULTS: The expression level of miR-539 was significantly decreased in WT tissues. Downregulation of miR-539 was closely related to NWTS-5 stage, lymph node metastasis and histological type of WT patients. Furthermore, low miR-539 expression was associated with a shorter overall survival rate in WT patients. In vitro, overexpression of miR-539 suppressed proliferation, migration and invasion of SK-NEP-1 cells. In addition, JAG1 was a direct target of miR-539. MiR-539 inhibited the development of WT by inhibiting JAG1-Notch1/3 expressing and blocking EMT.
CONCLUSION: MiR-539 inhibited the progression of WT through downregulation of JAG1 and Notch1/3.
Related: MicroRNAs Wilms' Tumour Wilms Tumour NOTCH3

Saltarella I, Frassanito MA, Lamanuzzi A, et al.
Homotypic and Heterotypic Activation of the Notch Pathway in Multiple Myeloma-Enhanced Angiogenesis: A Novel Therapeutic Target?
Neoplasia. 2019; 21(1):93-105 [PubMed] Free Access to Full Article Related Publications
Interactions of multiple myeloma (MM) cells with endothelial cells (ECs) enhance angiogenesis and MM progression. Here, we investigated the role of Notch signaling in the cross talk between ECs and MM cells enabling angiogenesis. MMECs showed higher expression of Jagged1/2 ligands, of activated Notch1/2 receptors, and of Hes1/Hey1 Notch target genes than ECs from monoclonal gammopathy of undetermined significance patients, suggesting that homotypic activation of Notch pathway occurs in MM. MM cells co-cultured with MMECs triggered Notch activation in these cells through a cell-to-cell contact-dependent way via Jagged1/2, resulting in Hes1/Hey1 overexpression. The angiogenic effect of Notch pathway was analyzed through Notch1/2·siRNAs and the γ-secretase inhibitor MK-0752 by in vitro (adhesion, migration, chemotaxis, angiogenesis) and in vivo (Vk12598/C57B/6 J mouse model) studies. Activated Notch1/2 pathway was associated with the overangiogenic MMEC phenotype: Notch1/2 knockdown or MK-0752 treatment reduced Hes1/Hey1 expression, impairing in vitro angiogenesis of both MMECs alone and co-cultured with MM cells. MM cells were unable to restore angiogenic abilities of treated MMECs, proving that MMEC angiogenic activities closely rely on Notch pathway. Furthermore, Notch1/2 knockdown affected VEGF/VEGFR2 axis, indicating that the Notch pathway interferes with VEGF-mediated control on angiogenesis. MK-0752 reduced secretion of proangiogenic/proinflammatory cytokines in conditioned media, thus inhibiting blood vessel formation in the CAM assay. In the Vk12598/C57B/6 J mouse, MK-0752 treatment restrained angiogenesis by reducing microvessel density. Overall, homotypic and heterotypic Jagged1/2-mediated Notch activation enhances MMECs angiogenesis. Notch axis inhibition blocked angiogenesis in vitro and in vivo, suggesting that the Notch pathway may represent a novel therapeutic target in MM.
Related: Myeloma Myeloma - Molecular Biology Angiogenesis and Cancer Signal Transduction VEGFA

Gill BS, Navgeet, Kumar S
Antioxidant potential of ganoderic acid in Notch-1 protein in neuroblastoma.
Mol Cell Biochem. 2019; 456(1-2):1-14 [PubMed] Related Publications
Neuroblastoma is a childhood tumor arising from developing a sympathetic nervous system and causes around 10% of pediatric tumors. Despite advancement in the use of sophisticated techniques in molecular biology, neuroblastoma patient's survivability rate is very less. Notch pathway is significant in upholding cell maintenance and developmental process of organs. Notch-1 proteins are a ligand-activated transmembrane receptor which decides the fate of the cell. Notch signaling leads to transcription of genes which indulged in numerous diseases including tumor progression. Ganoderic acid, a lanosterol triterpene, isolated from fungus Ganoderma lucidum with a wide range of medicinal values. In the present study, various isoforms of the ganoderic acid and natural inhibitors were docked by molecular docking using Maestro 9 in the Notch-1 signaling pathway. The receptor-based molecular docking exposed the best binding interaction of Notch-1 with ganoderic acid A with GScore (- 8.088), kcal/mol, Lipophilic EvdW (- 1.74), Electro (- 1.18), Glide emodel (- 89.944) with the active participation of Arg 189, Arg 199, Glu 232 residues. On the other hand natural inhibitor, curcumin has GScore (- 7.644), kcal/mol, Lipophilic EvdW (- 2.19), Electro (- 0.73), Glide emodel (- 70.957) with Arg 75 residues involved in docking. The ligand binding affinity of ganoderic acid A in Notch-1 is calculated using MM-GBSA (- 76.782), whereas curcumin has (- 72.815) kcal/mol. The QikProp analyzed the various drug-likeness parameters such as absorption, distribution, metabolism, excretion, and toxicity (ADME/T) and isoforms of ganoderic acid require some modification to fall under Lipinski rule. The ganoderic acid A and curcumin were the best-docked among different compounds and exhibits downregulation in Notch-1 mRNA expression and inhibits proliferation, viability, and ROS activity in IMR-32 cells.
Related: Neuroblastoma Signal Transduction

Koch U, Radtke F
Notch in T-ALL: new players in a complex disease.
Trends Immunol. 2011; 32(9):434-42 [PubMed] Related Publications
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy of thymocytes affecting preferentially children and adolescents. The disease is heterogeneous and characterized by a large set of chromosomal and genetic alterations that deregulate the growth of maturing thymocytes. The identification of activating point mutations in NOTCH1 in more then 50% of all T-ALL cases highlights the NOTCH1 cascade as a central player of T-ALL pathogenesis. In this review, we summarize and update more recent findings on the molecular mechanisms of T-ALL with a particular emphasis on the oncogenic properties of aberrant NOTCH1 signaling.
Related: MicroRNAs Signal Transduction

Agrawal N, Frederick MJ, Pickering CR, et al.
Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.
Science. 2011; 333(6046):1154-7 [PubMed] Free Access to Full Article Related Publications
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.
Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology FBXW7

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