Gene Summary

Gene:NOS2; nitric oxide synthase 2
Summary:Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:nitric oxide synthase, inducible
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
Show (40)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 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.

  • Up-Regulation
  • T-Lymphocytes
  • Sweden
  • Immunohistochemistry
  • NF-kappa B
  • Tyrosine
  • Young Adult
  • Vascular Cell Adhesion Molecule-1
  • Sequence Alignment
  • Radiopharmaceuticals
  • Colorectal Cancer
  • Transcription
  • Nitric Oxide Synthase
  • Oxidative Stress
  • Rectum
  • Sex Distribution
  • Bladder Cancer
  • p53 Protein
  • Nitric Oxide
  • Messenger RNA
  • Chromosome 17
  • Stomach Cancer
  • Apoptosis
  • COX2 (PTGS2)
  • Nitric Oxide Synthase Type II
  • Viral Nonstructural Proteins
  • ras Proteins
  • Statistics, Nonparametric
  • Enzymologic Gene Expression Regulation
  • Vascular Endothelial Growth Factors
  • Breast Cancer
  • bcl-2-Associated X Protein
  • Virus Diseases
  • Tumor Stem Cell Assay
  • Weight Loss
  • Promoter Regions
  • Pancreatic Cancer
  • Polymorphism
  • Cancer Gene Expression Regulation
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: NOS2 (cancer-related)

Kielbik M, Szulc-Kielbik I, Klink M
The Potential Role of iNOS in Ovarian Cancer Progression and Chemoresistance.
Int J Mol Sci. 2019; 20(7) [PubMed] Free Access to Full Article Related Publications
Inducible nitric oxide synthase (iNOS), the enzyme responsible for nitric oxide (NO) production, is not present in most cells under normal conditions. The expression of its mRNA, as well as its protein synthesis and full enzymatic activity, undergoes multilevel regulation including transcriptional and posttranscriptional mechanisms, the availability of iNOS substrate and cofactors and oxygen tension. However, in various malignant diseases, such as ovarian cancer, the intracellular mechanisms controlling iNOS are dysregulated, resulting in the permanent induction of iNOS expression and activation. The present review summarizes the multistaged processes occurring in normal cells that promote NO synthesis and focuses on factors regulating iNOS expression in ovarian cancer. The possible involvement of iNOS in the chemoresistance of ovarian cancer and its potential as a prognostic/predictive factor in the course of disease development are also reviewed. According to the available yet limited data, it is difficult to draw unequivocal conclusions on the pros and cons of iNOS in ovarian cancer. Most clinical data support the hypothesis that high levels of iNOS expression in ovarian tumors are associated with a greater risk of disease relapse and patient death. However, in vitro studies with various ovarian cancer cell lines indicate a correlation between a high level of iNOS expression and sensitivity to cisplatin.

Tsagozis P, Augsten M, Zhang Y, et al.
An immunosuppressive macrophage profile attenuates the prognostic impact of CD20-positive B cells in human soft tissue sarcoma.
Cancer Immunol Immunother. 2019; 68(6):927-936 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Immune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized.
METHODS: Marker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics.
RESULTS: B cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10
CONCLUSIONS: Analysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages.

Suh SS, Hong JM, Kim EJ, et al.
Antarctic freshwater microalga,
Int J Med Sci. 2019; 16(2):189-197 [PubMed] Free Access to Full Article Related Publications
Inflammation triggered by the innate immune system is a strategy to protect organisms from the risk of environmental infection. However, it has recently become clear that inflammation can cause a variety of human diseases, including cancer. In this study, we investigated the effects of an ethanol extract of the Antarctic freshwater microalgae,

Kamarádová K, Vošmiková H, Rozkošová K, et al.
Morphological, immunohistochemical and molecular features of inflammatory bowel disease associated colorectal carcinoma and associated mucosal lesions - Single institution experience.
Pathol Res Pract. 2019; 215(4):730-737 [PubMed] Related Publications
BACKGROUND: Patients with inflammatory bowel disease (IBD) - ulcerative colitis (UC) and Crohn's disease (CD) have an elevated risk of developing colorectal carcinoma (CRC). Major risk factor in IBD patients is the continuous chronic inflammation leading to development of dysplasia and carcinoma. Nevertheless, other types of non-conventional but suspicious mucosal changes serrated change/dysplasia, NOS and villous hypermucinous change, have also been reported in IBD patients. Preneoplastic potential of these lesions is still not well elucidated.
AIMS: The aim of this study was identification of IBD-associated CRCs focusing on finding related precursor lesions in the surgical specimen or in archival biopsy samples followed by a detailed morphological, immunohistochemical and molecular evaluation. For the purpose of the study the mucosal lesions were divided into conventional IBD-associated dysplasia and non-conventional lesions that were merged under a provisory term of putative preneoplastic lesions (PPL).
METHODS: A total of 309 consecutive IBD colectomy specimens diagnosed during a 10-year period were reviewed. Detailed morphological evaluation, immunohistochemical analysis of mismatch repair (MMR) proteins, p53 and O
RESULTS: We identified 11 cases of morphologically heterogenous IBD-associated CRCs, occurring in 5 males and 6 females, aged 26-79 years (mean 44 years). A total of 22 mucosal lesions were revealed in 8 CRC patients comprising conventional IBD-associated dysplasia (4 lesions), PPLs as serrated change/dysplasia NOS (11 lesions), villous hypermucinous change (5 lesions), and two true serrated lesions (one sessile serrated adenoma and one traditional serrated adenoma). More than one type of lesion was found in 6 patients. Seven CRC cases harbored mutation of KRAS/NRAS and one case of BRAF. Two patients with KRAS-mutated CRC showed the same mutation in PPL in the same specimen (one serrated change NOS and one TSA with high-grade dysplasia). Similarly, one BRAF-mutated carcinoma case presented the same mutation in serrated change/dysplasia, NOS in the same specimen. Of the CRCs, two showed deficient MMR system profile, six presented with loss of MGMT expression, and six showed aberrant p53 expression. PPLs showed deficient MGMT expression (14 cases) and aberrant p53 (10 cases) as well.
CONCLUSION: IBD-associated CRCs are very heterogeneous entities. Besides conventional IBD-related dysplasia, other types of mucosal lesions may be associated with long lasting IBD and CRC e.g. villous hypermucinous change and serrated change/dysplasia, NOS. Since these lesions share certain genetic or immunohistochemical changes with the related CRC, a suspicion is raised that these lesions may also have preneoplastic potential. Awareness of these changes is necessary to prevent their missing and under-reporting, and further studies of these lesions should be carried out.

Jiang N, Hu Y, Wei W, et al.
Detection of microRNA using a polydopamine mediated bimetallic SERS substrate and a re-circulated enzymatic amplification system.
Mikrochim Acta. 2019; 186(2):65 [PubMed] Related Publications
A surface-enhanced Raman scattering (SERS) method is described for the determination of microRNA that is associated with various forms of cancer. The substrate consists of functionalized gold-silver bimetallic structure, and the sensitivity is strongly enhanced by making use of a re-circulated enzymatic amplification system (REAS). Poly-dopamine acts as both a reductant and a protective of the substrates. It was employed to link the gold core and silver satellite. The unique "hot spots" consisting of a Au@PDA@Ag nanocomposite improve the Raman signal and sensitivity. The reductive feature of PDA can prevent the susceptible oxidation of metallic silver to maintain the high Raman activity. To improve the sensitivity of the assays, a re-circulated enzymatic amplification system was developed in which the nicking endonuclease triggers the nucleic acid reaction system to enter an amplified cycle. By integrating the bimetallic nanosubstrate and magnetic separation into the REAS, microRNA can be detected by SERS (best at the Raman band of 1586 cm

Oluwasanjo A, Kartan S, Johnson W, et al.
Peripheral T-Cell Lymphoma, not Otherwise Specified (PTCL-NOS).
Cancer Treat Res. 2019; 176:83-98 [PubMed] Related Publications
Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a World Health Organization (WHO)-defined diagnostic category within the highly heterogeneous group of mature post-thymic T-cell neoplasms. It is the most common subtype of mature post-thymic T-cell neoplasms globally, accounting for up to 35% of PTCL cases in Europe and North America. PTCL-NOS is a diagnosis of exclusion, comprising several disease entities that differ in biology, clinical presentation, and outcome. The diagnosis of PTCL-NOS is made based on the presence of typical histopathological features of lymphoma, an aberrant T-cell immunophenotype, often with a loss of CD5 and CD7, and a clonal T-cell receptor (TCR) gene rearrangement, in the appropriate clinical context. Unlike other types of T-cell lymphoma, recurrent mutations to assist with the diagnosis have not been identified. Patients often present with advanced stage. Prognosis is poor, with a 5-year overall survival (OS) of 20-30%. Anthracycline-based combination chemotherapy remains the most frequently used frontline strategy, with overall response rates (ORR) of 50-60%, and complete response rates (CRR) of 20-30%. Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) results in progression-free survivals (PFS) that compare favorably with historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking. Over the past decade, therapeutic agents approved in the relapsed and refractory setting have produced response rates of up to 33% and median PFS up to 18 months. Overall, outcomes remain poor and there is a dire need for more effective treatments. This review discusses the latest information on the diagnosis and treatment of PTCL-NOS.

Iqbal J, Amador C, McKeithan TW, Chan WC
Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma.
Cancer Treat Res. 2019; 176:31-68 [PubMed] Related Publications
Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

Gerashchenko GV, Grygoruk OV, Kononenko OA, et al.
Expression pattern of genes associated with tumor microenvironment in prostate cancer.
Exp Oncol. 2018; 40(4):315-322 [PubMed] Related Publications
AIM: To assess relative expression (RE) levels of CAF-, TAM-specific, immune defense-associated genes in prostate tumors and to show correlation of RE with clinical, pathological and molecular characteristics, with the aim to define clinically significant specific alterations in a gene expression pattern.
METHODS: RE of 23 genes was analyzed by a quantitative polymerase chain reaction in 37 freshly frozen samples of prostate cancer tissues of a different Gleason score (GS) and at various tumor stages, compared with RE in 37 paired conventionally normal prostate tissue (CNT) samples and 20 samples of prostate adenomas.
RESULTS: Differences in RE were shown for 11 genes out of 23 studied, when tumor samples were compared with corresponding CNTs. 7 genes, namely ACTA2, CXCL14, CTGF, THY1, FAP, CD163, CCL17 were upregulated in tumors. 4 genes, namely CCR4, NOS2A, MSMB, IL1R1 were downregulated in tumors. 14 genes demonstrated different RE in TNA at different stages: CXCL12, CXCL14, CTGF, FAP, HIF1A, THY1, CCL17, CCL22, CCR4, CD68, CD163, NOS2A, CTLA4, IL1R1. RE changes of 9 genes - CXCL12, CXCL14, HIF1A, CCR4, CCL17, NOS2A, CTLA4, IL1R1, IL2RA - were found in tumors with different GS. Moreover, 9 genes showed differences in RE in TNA, dependently on the presence or absence of the TMPRSS2/ERG fusion and 7 genes showed differences in RE of groups with differential PTEN expression. Significant correlations were calculated between RE of 9 genes in adenocarcinomas and the stage, and GS; also, between RE of 2 genes and the fusion presence; and between RE of 4 genes and PTEN expression.
CONCLUSIONS: Several gene expression patterns were identified that correlated with the GS, stage and molecular characteristics of tumors, i.e. presence of the TMPRSS2/ERG fusion and alterations in PTEN expression. These expression patterns can be used for molecular profiling of prostate tumors, with the aim to develop personalized medicine approaches. However, the proposed profiling requires a more detailed analysis and a larger cohort of patients with prostate tumor.

Gao Y, Zhou S, Xu Y, et al.
Nitric oxide synthase inhibitors 1400W and L-NIO inhibit angiogenesis pathway of colorectal cancer.
Nitric Oxide. 2019; 83:33-39 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: It has been widely accepted that angiogenesis plays fundamental roles in colorectal cancer development, and therapeutic targeting of this pathway has achieved promising outcome. Recent reports have highlighted the involvement of nitric oxide synthases (NOS) in the development of angiogenesis in cancer; however, the mechanism and therapeutic value of NOS inhibitors in colon cancer are largely unknown.
OBJECTIVE: In this study, we investigated the effects and mechanism of the NOS inhibitors 1400W and L-NIO on the angiogenesis pathway in colorectal cancer cells.
METHODS: Two colorectal cancer cell lines, HT 29 and HCT 116, were used for in vitro study. The expression of iNOS and eNOS in cells was knocked down via shRNA transfection. MTS assays and wound healing assays were performed to assess cell proliferation and migration after shRNA transfection or treatment with 1400W, L-NIO, and 5-fluorouracil. Human angiogenesis PCR arrays and proteome profiler human angiogenesis arrays were used to detect changes in key genes/proteins involved in modulating angiogenesis after 1400W and L-NIO treatment.
RESULTS: Knockdown of iNOS and eNOS significantly inhibited colorectal cancer cell growth. Treatment with NOS inhibitors inhibited colorectal cancer cell growth and migration, and was associated with suppression of the expression of key genes/proteins involved in the angiogenesis pathway. In addition, the combined use of NOS inhibitors with 5-fluorouracil showed enhanced inhibition of cell proliferation and migration.
CONCLUSION: NOS inhibitors could suppress colorectal cancer cell growth and migration, likely via suppressing the angiogenesis pathway.

Cicek T, Ozturk A, Yılmaz A, et al.
Adequacy of EBUS-TBNA specimen for mutation analysis of lung cancer.
Clin Respir J. 2019; 13(2):92-97 [PubMed] Related Publications
OBJECTIVE: Convex probe endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a minimally invasive technique with high sensitivity in the mediastinal staging of non-small cell carcinoma (NSCLC). In recent years, molecular testing has been developed to study genetic mutations in NSCLC. There are studies revealing improved survival in advanced NSCLC using targeted therapy as the first-line treatment in these patients. The aim of this study was to evaluate the adequacy of EBUS-TBNA in providing adequate size specimens for EGFR, ALK and ROS1 genetic mutation analysis in patients with adenocarcinoma or not otherwise specified (NOS) lung cancer.
MATERIALS AND METHODS: Charts of patients diagnosed with lung adenocarcinoma or NOS via EBUS-TBNA were retrospectively reviewed. Information on patient demographics, number of lymph nodes sampled, their size and location, targeted gene mutations and the adequacy of the material sampled for the molecular testing was recorded.
RESULTS: A total of 114 patients were included in the study, adenocarcinoma 86 (75%) and NOS 28 (25%). EGFR gene mutation was studied in all of the patients included in the study while ALK in 113 and ROS1 in 98. The material adequacy ratios for EGFR gene mutation, ALK and ROS1 rearrangements were found to be 88.6%, 93.8% and 91.8%, respectively. EGFR gene mutation, ALK and ROS1 rearrangements were found positive in 13 (11.4%), 9 (8%) and 1 (1%) patients, respectively.
CONCLUSION: The study demonstrated that EBUS-TBNA provides adequate material for mutation analysis in patients with newly diagnosed adenocarcinoma or NOS lung cancer.

Jung YY, Hwang ST, Sethi G, et al.
Potential Anti-Inflammatory and Anti-Cancer Properties of Farnesol.
Molecules. 2018; 23(11) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Farnesol, an acyclic sesquiterpene alcohol, is predominantly found in essential oils of various plants in nature. It has been reported to exhibit anti-cancer and anti-inflammatory effects, and also alleviate allergic asthma, gliosis, and edema. In numerous tumor cell lines, farnesol can modulate various tumorigenic proteins and/or modulates diverse signal transduction cascades. It can also induce apoptosis and downregulate cell proliferation, angiogenesis, and cell survival. To exert its anti-inflammatory/anti-oncogenic effects, farnesol can modulate Ras protein and nuclear factor kappa-light-chain-enhancer of activated B cells activation to downregulate the expression of various inflammatory mediators such as cyclooxygenase-2, inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin-6. In this review, we describe the potential mechanisms of action underlying the therapeutic effects of farnesol against cancers and inflammatory disorders. Furthermore, these findings support the clinical development of farnesol as a potential pharmacological agent in clinical studies.

Liu S, Xu C, Zhang Y, et al.
Feature selection of gene expression data for Cancer classification using double RBF-kernels.
BMC Bioinformatics. 2018; 19(1):396 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Using knowledge-based interpretation to analyze omics data can not only obtain essential information regarding various biological processes, but also reflect the current physiological status of cells and tissue. The major challenge to analyze gene expression data, with a large number of genes and small samples, is to extract disease-related information from a massive amount of redundant data and noise. Gene selection, eliminating redundant and irrelevant genes, has been a key step to address this problem.
RESULTS: The modified method was tested on four benchmark datasets with either two-class phenotypes or multiclass phenotypes, outperforming previous methods, with relatively higher accuracy, true positive rate, false positive rate and reduced runtime.
CONCLUSIONS: This paper proposes an effective feature selection method, combining double RBF-kernels with weighted analysis, to extract feature genes from gene expression data, by exploring its nonlinear mapping ability.

Tang XF, Yang L, Duan S, et al.
Intestinal T-cell and NK/T-cell lymphomas: A clinicopathological study of 27 Chinese patients.
Ann Diagn Pathol. 2018; 37:107-117 [PubMed] Related Publications
BACKGROUND: Intestinal T-cell and NK/T- cell lymphomas are rare and aggressive. The diagnosis is quite difficult, especial in biopsy specimens. This study investigates the clinicopathological features of intestinal T-cell and NK/T-cell lymphomas to aid their differential diagnosis.
METHODS: Clinical data of 27 cases were collected. Including extranodal NK/T-cell lymphoma, nasal type (ENKTCL-N), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS), anaplastic large-cell lymphoma, ALK+ (ALCL, ALK+) and angioimmunoblastic T-cell lymphoma (AITL). The histologic features, immunohistochemical findings, T-cell receptor gene rearrangement results, and follow-up data were analyzed, with review of literature.
RESULTS: The age of the patients (N = 27) was 15-85 years (mean, 47.5 years), and male:female ratio, 3.5:1. Abdominal pain and B symptoms were the most common symptoms. Although 85.2% of the patients were in clinical stage I-II, 59.3% died within 1 year. MEITL showed certain distinctive clinic opathological features from ENKTCL-N. Compared to lesions at other sites, there were no differences in the morphological features, immunophenotype and TCR gene rearrangement of intestinal ENKTCL-N, PTCL, NOS, ALCL, ALK+ and AITL.
CONCLUSION: Intestinal T-cell and NK/T-cell lymphomas are a heterogeneous group of lymphomas. They could be classified to 5 histological subtypes in our study. ENKTCL-N and MEITL formed the majority of the tumor types. Each subtype has distinctive pathological features, but most of them have diamal prognosis.

Nosrati A, Monabati A, Sadeghipour A, et al.
MYC, BCL2, and BCL6 rearrangements in primary central nervous system lymphoma of large B cell type.
Ann Hematol. 2019; 98(1):169-173 [PubMed] Related Publications
Primary central nervous system lymphoma (PCNSL) is a rare specific subtype of non-Hodgkin lymphoma limited to the brain, leptomeninges, spinal cord, or eyes without any systemic presentation and relapse which mostly takes place in CNS. In more than 95% of patients, it is of diffuse large B cell lymphoma (DLBCL) type. Categorizing PCNSL to germinal center cell like or activated B cell like, as we usually do for DLBCL NOS, may not be applicable for predicting outcome. Possible prognostic significance of MYC, BCL2, and/or BCL6 rearrangements may be important given what we know about their impact in systemic DLBCL, but we have limited knowledge about the status of double or triple hit molecular changes in PCNSL. Here, we have investigated prevalence of these molecular alterations in PCNSL. Two independent tissue microarrays constructed from 78 formalin-fixed paraffin-embedded blocks of confirmed PCNSL were tested for rearrangement of MYC, BCL2, and BCL6 by interphase fluorescent in situ hybridization (FISH) using break apart dual color probes. BCL6 translocation was detected in 15 (12%) cases. Translocation involving MYC and BCL2 was identified in 3 cases (3.8%) and 1 case (1.3%) respectively. One double hit lymphoma was discovered with both MYC/BCL2 translocation (1.3%). To the best of our knowledge, few organized studies have been conducted for MYC, BCL2, and/or BCL6 rearrangement in PCNSL. This study is evaluating large number of PCNSL. Double or triple hit events which are rarely seen in PCNSL.

Geeviman K, Babu D, Prakash Babu P
Pantoprazole Induces Mitochondrial Apoptosis and Attenuates NF-κB Signaling in Glioma Cells.
Cell Mol Neurobiol. 2018; 38(8):1491-1504 [PubMed] Related Publications
Gastric H

Yokoyama K, Shimizu E, Yokoyama N, et al.
Cell-lineage level-targeted sequencing to identify acute myeloid leukemia with myelodysplasia-related changes.
Blood Adv. 2018; 2(19):2513-2521 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Acute myeloid leukemia (AML) is a clonal myeloid neoplasm that typically arises de novo; however, some cases evolve from a preleukemic state, such as myelodysplastic syndrome (MDS). Such secondary AMLs and those with typical MDS-related clinical features are known as AMLs with myelodysplasia-related changes (AML-MRC). Because patients with AML-MRC have poor prognosis, more accurate diagnostic approaches are required. In this study, we performed targeted sequencing of 54 genes in 3 cell populations (granulocyte, blast, and T-cell fractions) using samples from 13 patients with MDS, 16 patients with clinically diagnosed AML-MRC, 4 patients with suspected AML-MRC but clinically diagnosed as AML not otherwise specified (AML-NOS), and 11 patients with de novo AML. We found that overlapping mutations, defined as those shared at least by the blast and granulocyte fractions, were significantly enriched in patients with MDS and AML-MRC, including those with suspected AML-MRC, indicating a substantial history of clonal hematopoiesis. In contrast, blast-specific nonoverlapping mutations were significantly enriched in patients with de novo AML. Furthermore, the presence of overlapping mutations, excluding

Svrcek M, Borralho Nunes P, Villanacci V, et al.
Clinicopathological and Molecular Specificities of Inflammatory Bowel Disease-Related Colorectal Neoplastic Lesions: The Role of Inflammation.
J Crohns Colitis. 2018; 12(12):1486-1498 [PubMed] Related Publications
Compared with the general population, patients with inflammatory bowel disease [IBD] have an increased risk of developing colorectal cancer. Molecular mechanisms underlying colorectal carcinogenesis in the setting of IBD are not well understood. However, modern molecular investigative tools have facilitated the identification of features that help distinguish IBD-related carcinoma from sporadic carcinoma. Moreover, with advances in endoscopic technology and improved understanding of the natural history, the management of colorectal neoplastic lesions in IBD patients has evolved. This review discusses the clinicopathological and molecular features of colorectal neoplastic lesions complicating IBD. Chronic inflammation is believed to promote the development of neoplasia, partly by producing reactive oxygen and nitrogen species [ROS and NOS], which may interact with genes involved in carcinogenetic pathways. Furthermore, alterations in microbiota and in the innate and adaptive immune responses might contribute to this process, particularly by initiating, regulating, and sustaining chronic inflammation. Earlier detection and better characterization of neoplastic colorectal lesions complicating IBD and a better knowledge of the molecular mechanisms underlying carcinogenesis in this setting should facilitate improvements in the risk stratification of patients with longstanding IBD and in the management of dysplastic and malignant colorectal lesions that arise in this setting.

Sugio T, Miyawaki K, Kato K, et al.
Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS.
Blood Adv. 2018; 2(17):2242-2252 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

Kuai Y, Gong X, Ding L, et al.
Wilms' tumor 1-associating protein plays an aggressive role in diffuse large B-cell lymphoma and forms a complex with BCL6 via Hsp90.
Cell Commun Signal. 2018; 16(1):50 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Wilms' tumor 1-associating protein (WTAP) is a nuclear protein, which is ubiquitously expressed in many tissues. Furthermore, in various types of malignancies WTAP is overexpressed and plays a role as an oncogene. The function of WTAP in diffuse large B-cell lymphoma (DLBCL), however, remains unclear.
METHODS: Immunohistochemistry was applied to evaluate the levels of WTAP expression in DLBCL tissues and normal lymphoid tissues. Overexpression and knock-down of WTAP in DLBCL cell lines, verified on mRNA and protein level served to analyze cell proliferation and apoptosis in DLBCL cell lines by flow cytometry. Finally, co-immunoprecipitation (Co-IP), IP, and GST-pull down assessed the interaction of WTAP with Heat shock protein 90 (Hsp90) and B-cell lymphoma 6 (BCL6) as well as determined the extend of its ubiquitinylation.
RESULTS: WTAP protein levels were consistently upregulated in DLBCL tissues. WTAP promoted DLBCL cell proliferation and improved the ability to confront apoptosis, while knockdown of WTAP in DLBCL cell lines allowed a significant higher apoptosis rate after treatment with Etoposide, an anti-tumor drug. The stable expression of WTAP was depended on Hsp90. In line, we demonstrated that WTAP could form a complex with BCL6 via Hsp90 in vivo and in vitro.
CONCLUSION: WTAP is highly expressed in DLBCL, promoting growth and anti-apoptosis in DLBCL cell lines. WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL. Down-regulation of WTAP could improve the chemotherapeutic treatments in DLBCL.

Machan S, Córdoba R, Carvajal N, et al.
Atypical Histiocytic Lesion Preceding a Peripheral T-Cell Lymphoma Involving the Skin Exhibiting the Same Molecular Alterations.
Am J Dermatopathol. 2019; 41(2):148-154 [PubMed] Related Publications
Peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS) is a diagnosis of exclusion, showing extreme cytological and phenotypic heterogeneity. Skin involvement of PTCL may be primary or secondary. Diagnosis of histiocytosis may be difficult, requiring clinical-pathological correlation. We describe a laryngeal atypical histiocytic lesion (AHL) and a nasal PTCL, NOS with cutaneous involvement in the same patient presenting with peculiar histopathologic and immunophenotypic features. The laryngeal neoplasm showed morphological and immunophenotypic evidence of histiocytic differentiation and does not fit any other category of the WHO classification nor the revised classification of histiocytosis. The nasal and cutaneous lesions presented features close to natural killer/T-cell lymphoma and gamma-delta T-cell lymphoma but did not meet accurately the WHO criteria. A somatic activating Q61K mutation was found on exon 3 of the NRAS gene in both AHL and PTCL, NOS. The mutation on NRAS gene in both AHL and PTCL, NOS may suggest a common origin from a precursor cell.

Xiao B, Huang Z, Zhou R, et al.
The Prognostic Value of Expression of the Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) in Patients with Solid Malignant Tumors: A Systematic Review and Meta-Analysis.
Med Sci Monit. 2018; 24:5462-5472 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND The long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) is expressed in solid malignant tumors. The aim of this systematic review and meta-analysis was to determine whether expression of the lncRNA SNHG1 was associated with prognosis in patients with malignancy. MATERIAL AND METHODS A literature review from Jan 1970 to July 2018 identified publications in the English language. Databases searched included: PubMed, OVID, Web of Science, the Cochrane Database, Embase, EBSCO, Google Scholar. Systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Newcastle-Ottawa Scale (NOS) assessment tool for risk of bias was used. RESULTS Eight publications (570 patients) and eight solid tumors were identified, including osteosarcoma, colorectal cancer, hepatocellular carcinoma, non-small cell lung cancer, esophageal cancer, ovarian cancer, glioma, and gastric cancer. Meta-analysis showed that expression of the lncRNA SNHG1 was significantly correlated with reduced overall survival (OS) (HR=1.917; 95% CI, 1.58-2.31) (P<0.001). Subgroup analysis showed that lncRNA SNHG1 expression was significantly correlated with TNM stage (OR=3.99; 95% CI, 2.48-6.43) and lymph node metastasis (OR=3.12; 95% CI, 1.95-4.98). There were no significant correlations between lncRNA SNHG1 expression and patient gender, tumor subtype, or tumor size. CONCLUSIONS Systematic literature review and meta-analysis identified eight publications that included 570 patients with eight types of solid malignant tumor, and showed that the expression of the lncRNA SNHG1 was significantly associated with worse clinical outcome.

Siddharth S, Nayak A, Das S, et al.
The soluble nectin-4 ecto-domain promotes breast cancer induced angiogenesis via endothelial Integrin-β4.
Int J Biochem Cell Biol. 2018; 102:151-160 [PubMed] Related Publications
Cancer stem cells secrete diffusible factors into the microenvironment that bind to specific endothelial cell receptors and initiate an angiogenesis cascade. Tumor-induced angiogenesis is an important parameter of tumorigenesis and is critical for tumor growth and metastasis. A pvrl-4 encoded gene, NECTIN-4, has potential roles in cancer cell growth and aggressiveness, and it is only expressed in cancer cells. There is evidence that nectin-4 plays a role in tumorigenesis, but the function of nectin-4 in tumor angiogenesis has lacked thorough evidence of mechanism. Using highly metastatic breast cancer cells and human umbilical vein endothelial cells (HUVECs), we have developed an excellent angiogenesis model and systematically studied the contribution of nectin-4 to angiogenesis. We also provide in-depth in ovo, in vivo and in vivo evidence that nectin-4 causes angiogenesis. Following hypoxia, metastatic breast cancer stem cells (mBCSCs) driven ADAM-17 expression causes the shedding of the ecto-domain of nectin-4 into the microenvironment, which physically interacts with integrin-β4 specifically on endothelial cells. This interaction promotes angiogenesis via the Src, PI3K, AKT, iNOS pathway and not by Phospho-Erk or NF-κβ pathways. In vitro, in ovo and in vivo induction and abrogation of an angiogenesis cascade in the presence and absence of the nectin-4 ecto-domain, respectively, confirms its role in angiogenesis. Thus, disrupting the interaction between nectin-4 ecto-domain and integrin-β4 may provide a means of targeting mBCSC-induced angiogenesis.

Zhang F, Li K, Pan M, et al.
miR-589 promotes gastric cancer aggressiveness by a LIFR-PI3K/AKT-c-Jun regulatory feedback loop.
J Exp Clin Cancer Res. 2018; 37(1):152 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: As novel biomarkers for various cancers, microRNAs negatively regulate genes expression via promoting mRNA degradation and suppressing mRNA translation. miR-589 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in gastric cancer. Here, we aim to investigate the biological effect of miR-589 on gastric cancer and to reveal the possible mechanism.
METHODS: Real-time PCR was performed to evaluate the expression of miR-589 in 34 paired normal and stomach tumor specimens, as well as gastric cell lines. Functional assays, such as wound healing, transwell assays and in vivo assays, were used to detect the biological effect of miR-589 and LIFR. We determined the role of miR-589 in gastric cancer tumorigenesis in vivo using xenograft nude models. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were performed for target evaluation, and the relationships were confirmed by western blot assay.
RESULT: MiR-589 expression was significantly higher in tumor tissues and gastric cancer cells than those in matched normal tissues and gastric epithelial cells, respectively. Clinically, overexpression of miR-589 is associated with tumor metastasis, invasion and poor prognosis of GC patients. Gain- and loss-of function experiments showed that miR-589 promoted cell migration, metastasis and invasion in vitro and lung metastasis in vivo. Mechanistically, we found that miR-589 directly targeted LIFR to activate PI3K/AKT/c-Jun signaling. Meanwhile, c-Jun bound to the promoter region of miR-589 and activated its transcription. Thus miR-589 regulated its expression in a feedback loop that promoted cell migration, metastasis and invasion.
CONCLUSION: Our study identified miR-589, as an oncogene, markedly induced cell metastasis and invasion via an atypical miR-589-LIFR-PI3K/AKT-c-Jun feedback loop, which suggested miR-589 as a potential biomarker and/or therapeutic target for the gastric cancer management.

Suh SS, Hong JM, Kim EJ, et al.
Anti-inflammation and Anti-Cancer Activity of Ethanol Extract of Antarctic Freshwater Microalga,
Int J Med Sci. 2018; 15(9):929-936 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Inflammation mediated by the innate immune system is an organism's protective mechanism against infectious environmental risk factors. It is also a driver of the pathogeneses of various human diseases, including cancer development and progression. Microalgae are increasingly being focused on as sources of bioactive molecules with therapeutic potential against various diseases. Furthermore, the antioxidant, anti-inflammatory, and anticancer potentials of microalgae and their secondary metabolites have been widely reported. However, the underlying mechanisms remain to be elucidated. Therefore, in this study, we investigated the molecular mechanisms underlying the anti-inflammatory and anticancer activities of the ethanol extract of the Antarctic freshwater microalga

Li S, Lin P, Medeiros LJ
Advances in pathological understanding of high-grade B cell lymphomas.
Expert Rev Hematol. 2018; 11(8):637-648 [PubMed] Related Publications
INTRODUCTION: The designation high-grade B-cell lymphoma (HGBL) has been incorporated into the 2016 Revision of the WHO classification of lymphoid neoplasms and includes two types: (1) HGBL, not otherwise specified; and (2) HGBL with MYC and BCL2 and/or BCL6 rearrangements, also known as double or triple hit lymphoma (DHL/THL). These categories of lymphomas represent 1-2% of non-Hodgkin lymphomas and a considerable portion of DLBCL patients who are primary refractory to R-CHOP therapy. It corresponds to the designation 'B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma' in the 2008 WHO classification. Areas covered: This paper provides an update of HGBL, focusing on their pathologic features, prognosis, and diagnostic workup. It highlights advances in our understanding of DHL/THL. Expert commentary: The diagnosis relies on FISH testing and the major controversial question is when to perform it to diagnose virtually all DHL/THL cases, but also being cost effective. Currently there is no consensus. Considering the high refractory rate of these patients to standard R-CHOP induction, the authors recommend FISH testing in all newly diagnosed large B-cell lymphoma by using our stepwise test strategy. With the progress of molecular genetics, the prognosis will be further stratified and HGBL-NOS maybe further evolve too.

Badawy AA, El-Magd MA, AlSadrah SA
Therapeutic Effect of Camel Milk and Its Exosomes on MCF7 Cells In Vitro and In Vivo.
Integr Cancer Ther. 2018; 17(4):1235-1246 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND/OBJECTIVES: In the Middle East, people consume camel milk regularly as it is believed to improve immunity against diseases and decrease the risk for cancer. Recently, it was noted that most of the beneficial effects of milk come from their nanoparticles, especially exosomes. Herein, we evaluated the anticancer potential of camel milk and its exosomes on MCF7 breast cancer cells (in vitro and in vivo) and investigated the possible underlying molecular mechanism of action.
METHODS/RESULTS: Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFκB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD
CONCLUSIONS: Overall, administration of camel milk-derived exosomes showed better anticancer effect, but less immune response, than treatment by camel milk. Moreover, local injection of exosomes led to better improvement than oral administration. These findings suggest that camel milk and its exosomes have anticancer effect possibly through induction of apoptosis and inhibition of oxidative stress, inflammation, angiogenesis and metastasis in the tumor microenvironment. Thus, camel milk and its exosomes could be used as an anticancer agent for cancer treatment.

Lone W, Alkhiniji A, Manikkam Umakanthan J, Iqbal J
Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review.
Curr Hematol Malig Rep. 2018; 13(4):318-328 [PubMed] Related Publications
PURPOSE OF REVIEW: Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative neoplasms, with at least 29 distinct entities described in current WHO classification. Using present diagnostic approaches, more than a third of PTCL cases cannot be classified, hence designated as PTCL-not otherwise specified (PTCL-NOS). Herein, we summarize the current genomic findings and their role in the molecular pathogenesis in different PTCL entities.
RECENT FINDINGS: Gene expression profiling (GEP) studies have identified distinct molecular signatures for accurate diagnosis and elucidated oncogenic pathways enriched in major PTCL entities. Furthermore, genomic characterization has identified recurrent somatic mutations and potential therapeutic targets. Further efforts are underway to develop genetically faithful murine models. GEP studies have identified molecular subgroups of PTCL, characterized by distinct genetic and epigenetic alterations. Understanding the molecular mechanisms of T cell lymphomagenesis using in vivo model will help to reveal novel therapeutic targets.

El-Bakoush A, Olajide OA
Formononetin inhibits neuroinflammation and increases estrogen receptor beta (ERβ) protein expression in BV2 microglia.
Int Immunopharmacol. 2018; 61:325-337 [PubMed] Related Publications
Formononetin is a bioactive non-steroidal polyphenol found in a variety of plants. In this study we evaluated the effects of formononetin on neuroinflammation in LPS-stimulated BV2 microglia. Results showed that formononetin significantly reduced the production of TNF-α, IL-6 and IL-1β, nitrite and PGE

Li YF, Zhang HT, Xin L
Hyaluronic acid-modified polyamidoamine dendrimer G5-entrapped gold nanoparticles delivering METase gene inhibits gastric tumor growth via targeting CD44+ gastric cancer cells.
J Cancer Res Clin Oncol. 2018; 144(8):1463-1473 [PubMed] Related Publications
BACKGROUND: Gastric cancer (GC) is the second most common leading cause of cancer-related death. Cancer stem cell (CSC) with the mark of CD44 played an important role in GC. rMETase was wildly exploited as chemotherapeutic option for GC. Polymers synthetic nanoparticle drug delivery systems have been commonly used for cancer therapy. With the decorating of Hyaluronic acid (HA), a receptor of CD44, nanoparticles exhibit with good biocompatibility and aqueous solubility.
METHODS: The characteristic of nanoparticles (NPs) was analyzed by TEM and DLS. The viability and proliferation of GC cells were examined by MTT assays. The levels of CD44, Cyt C, and c-caspase 3 were examined by Western blot. The level of ROS was measured by DCFH-DA assays. The morphology of tissues was detected using hematoxylin-eosin (H&E) stain. Nude mice xenograft models were used to evaluate the effect of HA-PAMAM-Au-METase on GC.
RESULTS: The transfection of rMETase carried by HA-G5 PAMAM-Au visibly inhibited the proliferation and tumorsphere formation of GC cells through obviously enhancing METase activity. Elevation of METase activity suppressed the proliferation of CD44(+) GC cells through down-regulating MET in cellular supernatant that resulted in the increase of Cyc C and ROS levels. The number of CD44(+) GC cells in nude mice injected with G5 PAMAM-Au-METase decorated by HA was markly declined resulting in the inhibition of tumor growth.
CONCLUSION: HA-G5 PAMAM-Au-METase significantly suppressed tumor growth of GC by targeted damaging the mitochondrial function of CD44(+) gastric CSCs.

Qian Y, Song JL, Sun P, et al.
Molecules. 2018; 23(5) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
This study investigated the enhanced antiproliferative effect of

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