NOTO; notochord homeobox (2p13.2)

Gene Summary

Gene:NOTO; notochord homeobox
Databases:HGNC, GeneCard, Gene
Protein:homeobox protein notochord
Updated:12 December, 2014


What does this gene/protein do?
Show (7)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 12 December 2014 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.

  • Lung Cancer
  • Breast Cancer
  • Tumor Markers
  • Bacterial Proteins
  • Chromosomes, Human, Pair None
  • CD Antigens
  • TGFB1
  • Pleural Effusion, Malignant
  • Stomach Cancer
  • Gastric Mucosa
  • Transcription
  • ras Proteins
  • Genetic Predisposition
  • Adolescents
  • Spheroids, Cellular
  • Molecular Sequence Data
  • Cancer DNA
  • Base Sequence
  • Pedigree
  • Helicobacter Infections
  • T-Lymphocytes
  • Immunophenotyping
  • Polymorphism
  • Young Adult
  • Translocation
  • Antigens, Bacterial
  • Childhood Cancer
  • Genomic Islands
  • Colorectal Cancer
  • Single Nucleotide Polymorphism
  • Adenocarcinoma
  • Sensitivity and Specificity
  • Cancer Stem Cells
  • Cancer Gene Expression Regulation
  • Helicobacter pylori and cancer
  • Retinoblastoma-Like Protein p130
  • Polymerase Chain Reaction
  • p53 Protein
  • Age Factors
  • Neoplastic Cell Transformation
Tag cloud generated 12 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (4)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Lung CancerNOTO and Lung Cancer View Publications5
Breast CancerNOTO and Breast Cancer View Publications3
Stomach CancerNOTO and Stomach Cancer View Publications4
Colorectal CancerNOTO and Colorectal Cancer View Publications3

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

Related Links

Latest Publications: NOTO (cancer-related)

Noto A, Raffa S, De Vitis C, et al.
Stearoyl-CoA desaturase-1 is a key factor for lung cancer-initiating cells.
Cell Death Dis. 2013; 4:e947 [PubMed] Free Access to Full Article Related Publications
In recent years, studies of cancer development and recurrence have been influenced by the cancer stem cells (CSCs)/cancer-initiating cells (CICs) hypothesis. According to this, cancer is sustained by highly positioned, chemoresistant cells with extensive capacity of self renewal, which are responsible for disease relapse after chemotherapy. Growth of cancer cells as three-dimensional non-adherent spheroids is regarded as a useful methodology to enrich for cells endowed with CSC-like features. We have recently reported that cell cultures derived from malignant pleural effusions (MPEs) of patients affected by adenocarcinoma of the lung are able to efficiently form spheroids in non-adherent conditions supplemented with growth factors. By expression profiling, we were able to identify a set of genes whose expression is significantly upregulated in lung tumor spheroids versus adherent cultures. One of the most strongly upregulated gene was stearoyl-CoA desaturase (SCD1), the main enzyme responsible for the conversion of saturated into monounsaturated fatty acids. In the present study, we show both by RNA interference and through the use of a small molecule inhibitor that SCD1 is required for lung cancer spheroids propagation both in stable cell lines and in MPE-derived primary tumor cultures. Morphological examination and image analysis of the tumor spheroids formed in the presence of SCD1 inhibitors showed a different pattern of growth characterized by irregular cell aggregates. Electron microscopy revealed that the treated spheroids displayed several features of cellular damage and immunofluorescence analysis on optical serial sections showed apoptotic cells positive for the M30 marker, most of them positive also for the stemness marker ALDH1A1, thus suggesting that the SCD1 inhibitor is selectively killing cells with stem-like properties. Furthermore, SCD1-inhibited lung cancer cells were strongly impaired in their in vivo tumorigenicity and ALDH1A1 expression. These results suggest that SCD1 is a critical target in lung cancer tumor-initiating cells.

Related: Lung Cancer ALDH1A1

Noto JM, Piazuelo MB, Chaturvedi R, et al.
Strain-specific suppression of microRNA-320 by carcinogenic Helicobacter pylori promotes expression of the antiapoptotic protein Mcl-1.
Am J Physiol Gastrointest Liver Physiol. 2013; 305(11):G786-96 [PubMed] Free Access to Full Article Related Publications
Helicobacter pylori is the strongest risk factor for gastric cancer, and strains harboring the cag pathogenicity island, which translocates the oncoprotein CagA into host cells, further augment cancer risk. We previously reported that in vivo adaptation of a noncarcinogenic H. pylori strain (B128) generated a derivative strain (7.13) with the ability to induce adenocarcinoma, providing a unique opportunity to define mechanisms that mediate gastric carcinogenesis. MicroRNAs (miRNAs) are small noncoding RNAs that regulate expression of oncogenes or tumor suppressors and are frequently dysregulated in carcinogenesis. To identify miRNAs and their targets involved in H. pylori-mediated carcinogenesis, miRNA microarrays were performed on RNA isolated from gastric epithelial cells cocultured with H. pylori strains B128, 7.13, or a 7.13 cagA(-) isogenic mutant. Among 61 miRNAs differentially expressed in a cagA-dependent manner, the tumor suppressor miR-320 was significantly downregulated by strain 7.13. Since miR-320 negatively regulates the antiapoptotic protein Mcl-1, we demonstrated that H. pylori significantly induced Mcl-1 expression in a cagA-dependent manner and that suppression of Mcl-1 results in increased apoptosis. To extend these results, mice were challenged with H. pylori strain 7.13 or its cagA(-) mutant; consistent with cell culture data, H. pylori induced Mcl-1 expression in a cagA-dependent manner. In human subjects, cag(+) strains induced significantly higher levels of Mcl-1 than cag(-) strains, and Mcl-1 expression levels paralleled the severity of neoplastic lesions. Collectively, these results indicate that H. pylori suppresses miR-320, upregulates Mcl-1, and decreases apoptosis in a cagA-dependent manner, which likely confers an increased risk for gastric carcinogenesis.

Related: Apoptosis Stomach Cancer Gastric Cancer MCL1

Fattore L, Marra E, Pisanu ME, et al.
Activation of an early feedback survival loop involving phospho-ErbB3 is a general response of melanoma cells to RAF/MEK inhibition and is abrogated by anti-ErbB3 antibodies.
J Transl Med. 2013; 11:180 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Treatment of advanced melanoma has been improved with the advent of the BRAF inhibitors. However, a limitation to such treatment is the occurrence of resistance. Several mechanisms have been identified to be responsible for the development of resistance, either MEK-dependent or MEK-independent. In order to overcome resistance due to reactivation of MEK signaling, MEK inhibitors are being clinically developed with promising results. However, also in this case resistance inevitably occurs. It has been recently reported that ErbB3, a member of the EGFR receptor family, may be involved in the establishment of drug resistance.
METHODS: Three melanoma cell lines were tested: LOX IMVI (BRAF V600E), MST-L (BRAF V600R) and WM266 (BRAF V600D). Phosphorylation of Receptor Tyrosine Kinases (RTKs) was assessed by an RTK array. Western blot analysis was performed on total protein extracts using anti-ErbB3, anti-AKT and anti-ERK 1/2 antibodies. The expression of neuregulin after vemurafenib treatment was assessed by Real Time PCR and Western blotting. The growth inhibitory effects of vemurafenib, GSK1120212b and/or anti-ErbB3 mAbs were evaluated by in vitro colony formation assays.
RESULTS: In the present study we demonstrate that ErbB3 is the main RTK undergoing rapidly hyperphosphorylation upon either treatment with a BRAF inhibitor or with a MEK inhibitor in a panel of melanoma cell lines harboring a variety of V600BRAF mutations and that this results in a strong activation of phospho-AKT. Importantly, ErbB3 activation is fully abrogated by the simultaneous use of anti-ErbB3 monoclonal antibodies, which are also shown to potently synergize with BRAF inhibitors in the inactivation of both AKT and ERK pathways and in the inhibition of melanoma cell growth. We show that upregulation of phospho-ErbB3 is due to an autocrine loop involving increased transcription and production of neuregulin by melanoma cells.
CONCLUSIONS: On the basis of these results, we propose that initial co-treatment with BRAF and/or MEK inhibitors and anti-ErbB3 antibodies should be pursued as a strategy to reduce the ErbB3-dependent feedback survival mechanism and enhance duration of clinical response.

Related: Melanoma ERBB3 Signal Transduction Skin Cancer

Noto Z, Yoshida T, Okabe M, et al.
CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics.
Oral Oncol. 2013; 49(8):787-95 [PubMed] Related Publications
BACKGROUND: Cancer may be derived from cancer stem-like cells (CSCs), which are tumor-initiating cells that have properties similar to those of stem cells. Identification and isolation of CSCs needs to be improved further.
MATERIALS AND METHODS: CSCs markers were examined in human oral cancer cell lines by flow cytometry. The stem cell properties of subpopulations expressing different markers were assessed further by in vitro sphere formation assays, expression of stemness genes, drug resistance assays, and the ability to form tumors in nude mice.
RESULTS: We demonstrated that CSCs could be isolated by the cell surface markers CD44 and stage-specific embryonic antigen-4 (SSEA-4). CD44+SSEA-4+ cells exhibited cancer stem-like properties, including extensive self-renewal into the bulk of cancer cells. In vivo xenograft experiments indicated that CD44+SSEA-4+ cells exhibit the highest tumorigenic capacity compared with the remaining subpopulations and parental cells. Double-positive cells for CD44 and SSEA-4 exhibited preferential expression of some stemness genes and were more resistant to the anticancer drugs, cisplatin and 5-fluorouracil (5-FU). In addition, cells expressing CD44 and SSEA-4 were detected in all tumor specimens analyzed, while coexpression of CD44 and SSEA-4 was not detectable in normal oral mucosa.
CONCLUSION: Our findings suggest that CD44+SSEA-4+ cells exhibit the characteristics of CSCs in oral squamous cell carcinoma and provide a target for the development of more effective therapies.

Related: Oral Cancer

Imperlini E, Colavita I, Caterino M, et al.
The secretome signature of colon cancer cell lines.
J Cell Biochem. 2013; 114(11):2577-87 [PubMed] Related Publications
The definition of the secretome signature of a cancer cell line can be considered a potential tool to investigate tumor aggressiveness and a preclinical exploratory study required to optimize the search of cancer biomarkers. Dealing with a cell-specific secretome limits the contamination by the major components of the human serum and reduces the range of dynamic concentrations among the secreted proteins, thus favouring under-represented tissue-specific species. The aim of the present study is to characterize the secretome of two human colon carcinoma cell lines, CaCo-2 and HCT-GEO, in order to evaluate differences and similarities of two colorectal cancer model systems. In this study, we identified more than 170 protein species, 64 more expressed in the secretome of CaCo-2 cells and 54 more expressed in the secretome of HCT-GEO cells; 58 proteins were shared by the two systems. Among them, more than 50% were deemed to be secretory according to their Gene Ontology annotation and/or to their SignalP or SecretomeP scores. Such a characterization allowed corroborating the potential of a cell culture-based model in order to describe the cell-specific invasive properties and to provide a list of putative cancer biomarkers.

Cefalù AB, Pirruccello JP, Noto D, et al.
A novel APOB mutation identified by exome sequencing cosegregates with steatosis, liver cancer, and hypocholesterolemia.
Arterioscler Thromb Vasc Biol. 2013; 33(8):2021-5 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: In familial hypobetalipoproteinemia, fatty liver is a characteristic feature, and there are several reports of associated cirrhosis and hepatocarcinoma. We investigated a large kindred in which low-density lipoprotein cholesterol, fatty liver, and hepatocarcinoma displayed an autosomal dominant pattern of inheritance.
APPROACH AND RESULTS: The proband was a 25-year-old female with low plasma cholesterol and hepatic steatosis. Low plasma levels of total cholesterol and fatty liver were observed in 10 more family members; 1 member was affected by liver cirrhosis, and 4 more subjects died of either hepatocarcinoma or carcinoma on cirrhosis. To identify the causal mutation in this family, we performed exome sequencing in 2 participants with hypocholesterolemia and fatty liver. Approximately 22 400 single nucleotide variants were identified in each sample. After variant filtering, 300 novel shared variants remained. A nonsense variant, p.K2240X, attributable to an A>T mutation in exon 26 of APOB (c.6718A>T) was identified, and this variant was confirmed by Sanger sequencing. The gentotypic analysis of 16 family members in total showed that this mutation segregated with the low cholesterol trait. In addition, genotyping of the PNPLA3 p.I148M did not show significant frequency differences between carriers and noncarriers of the c.6718A>T APOB gene mutation.
CONCLUSIONS: We used exome sequencing to discover a novel nonsense mutation in exon 26 of APOB (p.K2240X) responsible for low cholesterol and fatty liver in a large kindred. This mutation may also be responsible for cirrhosis and liver cancer in this family.

Related: Liver Cancer

Noto JM, Khizanishvili T, Chaturvedi R, et al.
Helicobacter pylori promotes the expression of Krüppel-like factor 5, a mediator of carcinogenesis, in vitro and in vivo.
PLoS One. 2013; 8(1):e54344 [PubMed] Free Access to Full Article Related Publications
Helicobacter pylori is the strongest known risk factor for the development of gastric adenocarcinoma. H. pylori expresses a repertoire of virulence factors that increase gastric cancer risk, including the cag pathogenicity island and the vacuolating cytotoxin (VacA). One host element that promotes carcinogenesis within the gastrointestinal tract is Krüppel-like factor 5 (KLF5), a transcription factor that mediates key cellular functions. To define the role of KLF5 within the context of H. pylori-induced inflammation and injury, human gastric epithelial cells were co-cultured with the wild-type cag(+) H. pylori strain 60190. KLF5 expression was significantly upregulated following co-culture with H. pylori, but increased expression was independent of the cag island or VacA. To translate these findings into an in vivo model, C57BL/6 mice were challenged with the wild-type rodent-adapted cag(+) H. pylori strain PMSS1 or a PMSS1 cagE(-) isogenic mutant. Similar to findings in vitro, KLF5 staining was significantly enhanced in gastric epithelium of H. pylori-infected compared to uninfected mice and this was independent of the cag island. Flow cytometry revealed that the majority of KLF5(+) cells also stained positively for the stem cell marker, Lrig1, and KLF5(+)/Lrig1(+) cells were significantly increased in H. pylori-infected versus uninfected tissue. To extend these results into the natural niche of this pathogen, levels of KLF5 expression were assessed in human gastric biopsies isolated from patients with or without premalignant lesions. Levels of KLF5 expression increased in parallel with advancing stages of neoplastic progression, being significantly elevated in gastritis, intestinal metaplasia, and dysplasia compared to normal gastric tissue. These results indicate that H. pylori induces expression of KLF5 in gastric epithelial cells in vitro and in vivo, and that the degree of KLF5 expression parallels the severity of premalignant lesions in human gastric carcinogenesis.

Related: Stomach Cancer Gastric Cancer

Gemei M, Mirabelli P, Di Noto R, et al.
CD66c is a novel marker for colorectal cancer stem cell isolation, and its silencing halts tumor growth in vivo.
Cancer. 2013; 119(4):729-38 [PubMed] Related Publications
BACKGROUND: Despite the well recognized expression of the cell surface markers cluster of differentiation 44 (homing cell adhesion molecule) and CD133 (Prominin 1) on human colorectal cancer stem cells (CCSCs), these molecules do not appear to be effective targets for stem cell-directed therapies. Because the surface marker CD66c (also known as carcinoembryonic antigen-related cell adhesion molecule 6) has demonstrated promise as a therapeutic target in pancreatic malignancy, the authors evaluated its potential as a target for stem cell-directed treatment of colorectal cancer.
METHODS: First, the authors characterized CD66c expression by flow cytometry and immunohistochemistry in colon cancer samples and in normal colon tissues. Then, the coexpression of CD66c and CD133 was evaluated on putative CCSCs. CD66c expression also was measured in stem cell-enriched colon spheres. Finally, the effects of small-interfering RNA-mediated CD66c silencing on the in vitro and in vivo growth of Caco2 colon cancer cells were evaluated.
RESULTS: CD66c expression was significantly higher in colon cancers than in contiguous normal colon tissues and paralleled cancer stage. CD66c was absent in CD133-positive cells that were isolated from normal colon, whereas its expression was brightest (CD66c(bright) ) in CD133-positive cells from colon cancer samples. In vitro experiments demonstrated that colon spheres were considerably enriched in a CD66c(bright) population in a fashion comparable to the enrichment observed in fresh liver metastases. In vitro proliferation and clonogenic potential were hampered when CD66c was silenced in Caco2 cells. Finally, in vivo xenograft experiments demonstrated that CD66c silencing almost completely abrogated the tumorigenic potential of Caco2 cells.
CONCLUSIONS: CD66c(bright) expression was associated with colon cancer stem cells and CD66c silencing blocked tumor growth, thereby opening the way to a potential new treatment for colon cancer.

Related: Colorectal (Bowel) Cancer

Corbo C, Orrù S, Gemei M, et al.
Protein cross-talk in CD133+ colon cancer cells indicates activation of the Wnt pathway and upregulation of SRp20 that is potentially involved in tumorigenicity.
Proteomics. 2012; 12(12):2045-59 [PubMed] Related Publications
The cancer stem cell (CSC) theory represents a breakthrough in cancer research. We characterized the protein pattern of CSCs to identify specific intracellular pathways in this subpopulation of tumor cells. We studied colon CSCs using two different colon cancer cell lines: CaCo-2 and HCT-116. Putative CSCs were separated from non-CSCs by flow cytometry using CD133 as stemness marker. Total protein extracts of CD133+ cells were then compared to protein extracts of CD133- cells by 2D DIGE. The protein spots differentially expressed in the two subpopulations of cells were analyzed by mass spectrometry. Bioinformatics analysis of the identified proteins indicated alteration of two main processes: energy metabolism and the Wnt pathway. Interestingly, we observed upregulation of the splicing factor SRp20, a newly identified target gene of the Wnt/β-catenin pathway, and we demonstrated a direct cause-effect relationship between Wnt pathway activation and the increased SRp20 expression. Our results also show that SRp20 influences cell proliferation, which suggests it plays a role in the tumorigenicity of CD133+ cells. In conclusion, activation of the Wnt pathway in CD133+ cells and upregulation of SRp20, which is implicated in tumorigenesis, raises the possibility of a sequential series of molecular events occurring in connection with this process.

Bruno P, Mariotta S, Ricci A, et al.
Reliability of direct sequencing of EGFR: comparison between cytological and histological samples from the same patient.
Anticancer Res. 2011; 31(12):4207-10 [PubMed] Related Publications
The results of a recent study have shown the superiority of treatment with gefitinib or erlotinib in lung tumors positive for epidermal growth factor receptor (EGFR) mutation. As a consequence, the complete diagnosis of lung cancer cannot be limited to histotype classification, but should include a series of molecular biology analyses. In most cases, the diagnosis of lung cancer is performed on cytological specimens; therefore, there is a need to obtain a complete and reliable molecular diagnosis on cytologic specimens. Brushing, transbronchial needle aspiration (TBNA) and broncho alveolar lavage during fibro-bronchoscopy allow the sampling of the lung and the mediastinal lymph node. The aim of this study was to demonstrate that direct sequencing of exons 19 and 21 of EGFR in lung tumors, carried out on the cytological samples obtained through fibro-bronchoscopy, is as reliable as the same analysis carried out on a histological surgical sample obtained from the same individual. We considered 50 patients with a histological diagnosis of lung adenocarcinoma whose cytological samples, obtained by fibro-bronchoscopy and histological samples, obtained by surgical resection were available. A comparison of the sensitivity and reliability of the molecular biology analyses carried out on histological and cytological samples of the same patient was carried out. The combined mutation percentage of exons 19 and 21 of EGFR was 10%. The results of the analyses carried out on cytological samples matched those obtained from the histological samples. The feasibility of EGFR analysis on cytological samples has already been demonstrated in previous studies, however these studies referred to the method of fluorescence in situ hybridization, or did not perform any comparison between histological samples from the same patient; our work, on the other hand, shows that direct sequencing of exons 19 and 21 of the EGFR gene is feasible on fibro-bronchoscopy cytological samples with the same reliability offered by the histological samples obtained from the same patient.

Related: Lung Cancer

Mancini R, Giarnieri E, De Vitis C, et al.
Spheres derived from lung adenocarcinoma pleural effusions: molecular characterization and tumor engraftment.
PLoS One. 2011; 6(7):e21320 [PubMed] Free Access to Full Article Related Publications
Malignant pleural effusions (MPEs) could represent an excellent source to culture a wide variety of cancer cells from different donors. In this study, we set up culture conditions for cancer cells deriving from MPEs of several patients affected by the most frequent form of lung cancer, namely the subset of non small cell lung cancers (NSCLC) classified as Lung Adenocarcinomas (AdenoCa) which account for approximately 40% of lung cancer cases. AdenoCa malignant pleural effusions gave rise to in vitro cultures both in adherent and/or in spheroid conditions in almost all cases analyzed. We characterized in greater detail two samples which showed the most efficient propagation in vitro. In these samples we also compared gene profiles of spheroid vs adherent cultures and identified a set of differentially expressed genes. Finally we achieved efficient tumor engraftment in recipient NOD/SCID mice, also upon inoculation of small number of cells, thus suggesting indirectly the presence of tumor initiating cells.

Related: Lung Cancer

Dalla Via L, Santi S, Di Noto V, et al.
Platinum(II) chloride indenyl complexes: electrochemical and biological evaluation.
J Biol Inorg Chem. 2011; 16(5):695-713 [PubMed] Related Publications
Four platinum(II) complexes of general formula [PtCl(η(1)-C(9)H(7))L(2)] [where L(2) is 1,2-bis(diphenylphosphino)ethane (dppe) 1 or cycloocta-1,5-diene (cod) 3] and [PtCl(2)L(2)] (where L(2) is dppe 2 or cod 4) were studied. Inhibition growth assays on human tumor cell lines evidenced for 1 and 3 an antiproliferative effect and, interestingly, the cytotoxic effect exerted by 1 is similar to that of cisplatin. Electrochemical and NMR measurements allowed us to determine the structural and redox properties. Investigation of the mechanism of action responsible for the cytotoxicity demonstrated a weak capacity of interacting with DNA. Some experiments performed on rat liver mitochondria indicate that 1 acts as an inducer of the mitochondrial permeability transition, thus leading to the release of proapoptotic factors, such as cytochrome c and apoptosis-inducing factor.

Related: Apoptosis Cancer Prevention and Risk Reduction TP53

Kikuchi M, Tanaka J, Kondo T, et al.
Clinical significance of minimal residual disease in adult acute lymphoblastic leukemia.
Int J Hematol. 2010; 92(3):481-9 [PubMed] Related Publications
Monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) is a useful way for assessing treatment response and relapse. We studied the value of MRD and showed a correlation with relapse for 34 adult patients with ALL. MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) with probes derived from fusion chimeric genes (BCR/ABL) (n = 12) or PCR-based detection of clonal immunoglobulin and T cell receptor gene rearrangements (n = 16), or both (n = 6). We analyzed 27 of the 34 patients who could be examined for MRD on day 100 after induction therapy. The overall survival (OS) rate (45.0%) and relapse-free survival (RFS) rate (40.0%) at 2 years in complete remission (CR) patients with MRD level ≥ 10⁻³ (n = 12) were significantly lower than those in CR patients with MRD level <10(-3) (n = 15) (OS rate 79.0%, RFS rate 79.4%) (log-rank test, P = 0.017 and 0.0007). We also applied multicolor flow cytometry for comparison with MRD results analyzed by PCR methods. The comparison of results obtained in 27 follow-up samples showed consistency in 17 samples (63.0%) (P = 0.057). MRD analysis on day 100 is important for treatment decision in adult ALL.

Related: Acute Lymphocytic Leukemia (ALL) Stem Cell and Bone Marrow Transplants

Macaluso M, Montanari M, Noto PB, et al.
Epigenetic modulation of estrogen receptor-alpha by pRb family proteins: a novel mechanism in breast cancer.
Cancer Res. 2007; 67(16):7731-7 [PubMed] Related Publications
Estrogen receptor-alpha (ER-alpha) plays a crucial role in normal breast development and has also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. However, ER-alpha gene expression can change during the course of disease and, consequently, therapy resistance can occur. The molecular mechanism governing ER-alpha transcriptional activity and/or silencing is still unclear. Here, we showed that the presence of a specific pRb2/p130 multimolecular complex on the ER-alpha promoter strongly correlates with the methylation status of this gene. Furthermore, we suggested that pRb2/p130 could cooperate with ICBP90 (inverted CCAAT box binding protein of 90 kDa) and DNA methyltransferases in maintaining a specific methylation pattern of ER-alpha gene. The sequence of epigenetic events for establishing and maintaining the silenced state of ER-alpha gene can be locus- or pathway- specific, and the local remodeling of ER-alpha chromatin structure by pRb2/p130 multimolecular complexes may influence its susceptibility to specific DNA methylation. Our novel hypothesis could provide a basis for understanding how the complex pattern of ER-alpha methylation and transcriptional silencing is generated and for understanding the relationship between this pattern and its function during the neoplastic process.

Related: Azacitidine Breast Cancer EP300 gene RB1 RBL1 retinoblastoma-like 1 (p107)

Scola L, Vaglica M, Crivello A, et al.
Cytokine gene polymorphisms and breast cancer susceptibility.
Ann N Y Acad Sci. 2006; 1089:104-9 [PubMed] Related Publications
Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age- and sex-matched controls. TNF-alpha (-308G/A), TGF-beta1 (+869C/T), IL-10 (-1117G/A; -854C/T; -627C/A), and IFN-gamma (874T/A) single nucleotide polymorphisms (SNPs) were identified by sequence-specific primers (SSP)-PCR or restriction fragment length polymorphism (RFLP)-PCR. Genotype or haplotype distributions for each polymorphisms were consistent with the HWE in these populations. We were unable to demonstrate differences in genotype or allele frequencies between patient and control groups. Data obtained in this study indicate that none of the cytokine SNPs studied is likely to have predisposing or protective effects on BC susceptibility. On the other hand, both positive and negative association with BC have been reported for some of the studied genotypes by different research groups. In conclusion, further studies involving larger numbers of subjects are required.

Related: Breast Cancer Cytokines

Crivello A, Giacalone A, Vaglica M, et al.
Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma.
Ann N Y Acad Sci. 2006; 1089:98-103 [PubMed] Related Publications
It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, developing colorectal cancer similar to human inflammatory bowel disease-associated neoplasia. TGF-beta1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF-beta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting a significant stimulation of tumor growth invasion and metastasis during tumor progression. We assessed association of functional polymorphisms (-1082G/A; -592C/A) and TGF-beta1 (-509C/T; +869C/T) influencing the IL-10 production to colorectal cancer risk in a case-control study of 62 patients and 124 matched controls. No significant differences were observed among cancer patients and controls for IL-10 -1082G/A; -592C/A genotype frequencies. Evaluation of odds ratios (OR) for the TGF-beta1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CT- and +869TT-positive individuals. These results suggest that the +869C allele, responsible for a Leu-->Pro substitution in the signal peptide sequence of the TGF-beta1 protein, may have a predisposing role in the development of colorectal cancer.

Related: Colorectal (Bowel) Cancer IL10 TGFB1

Macaluso M, Montanari M, Noto PB, et al.
Nuclear and cytoplasmic interaction of pRb2/p130 and ER-beta in MCF-7 breast cancer cells.
Ann Oncol. 2006; 17 Suppl 7:vii27-9 [PubMed] Related Publications
Estrogens exhibit important biological functions and influence several pathological processes of hormone-dependent diseases. The biological actions of estrogens require their interaction with two estrogen receptors (ER-alpha and ER-beta), which are ligand-dependent transcription factors. ER-alpha and ER-beta exhibit distinct tissue expression patterns as well as show different patterns of gene regulation. In addition, it has been suggested that ER-beta works as a counter partner of ER-alpha through inhibition of the transactivating functions of ER-alpha. For instance, ER-beta seems to play a different role in breast tumorigenesis than ER-alpha, as ER-beta decreased expression in breast cancer has been correlated with bad prognosis. Biological activities of ER-alpha and ER-beta could be controlled by a number of interacting proteins such as activators/inhibitors, ligand binding and kinases. We have previously reported that pRb2/p130, retinoblastoma related protein, could be involved in the silencing of ER-alpha gene during breast tumorigenesis. Here, we report that ER-beta and pRb2/p130 proteins co-immunoprecipitate in both nucleus and cytoplasm of MCF-7 breast cancer cells. Our hypothesis is that the interaction of pRb2/130 with ER-beta may have a functional significance in regulating ER-beta activity.

Related: Breast Cancer

Fukushima T, Yoshio N, Noto Y, Kida H
MLL gene rearrangement in acute myelogenous leukemia after exposure to tegafur/uracil.
Int J Hematol. 2002; 75(2):178-81 [PubMed] Related Publications
We report a case of acute myelogenous leukemia (AML) with MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia) gene rearrangement after exposure to tegafur/uracil. Cytogenetic and clinical findings in this patient: t(11;17) (q23;q25), AML-M4 morphology, development of AML within a short latent period after first exposure to tegafur/uracil, and good response to remission induction chemotherapy but short remission duration, have been considered typical features of therapy-related acute myelogenous leukemia (t-AML) after exposure to topoisomerase II-targeting agents. This case report suggests that t-AML may develop after exposure to tegafur/uracil and that MLL gene rearrangement may not necessarily be specific to t-AML after exposure to topoisomerase II-targeting agents.

Related: Chromosome 11 Chromosome 17 Acute Myeloid Leukemia (AML) Tegafur-uracil

Di Noto R, Pane F, Camera A, et al.
Characterization of two novel cell lines, DERL-2 (CD56+/CD3+/Tcry5+) and DERL-7 (CD56+/CD3-/TCRgammadelta-), derived from a single patient with CD56+ non-Hodgkin's lymphoma.
Leukemia. 2001; 15(10):1641-9 [PubMed] Related Publications
Two novel IL2-dependent cell lines, DERL-2 and DERL-7, were established from a patient with hepatosplenic gammadelta T cell lymphoma. This patient presented, at diagnosis, two discrete populations of CD56+ cells, one TCRgammadelta+, the second lacking T cell-restricted antigens. The cell lines derived displayed features corresponding to the two cellular components of the disease: DERL-2 was CD56+/CD3+/TcRgammadelta+ while DERL-7 was CD56+/CD3-/TcRgammadelta-. Along with CD56, the two cell lines shared the expression of CD7, CD2, CD158b and CD117. Karyotype analysis showed that both cell lines were near-diploid, with iso-7q and loss of one chromosome 10. In addition, DERL-2 showed 5q+ in all metaphases analyzed, while DERL-7 revealed loss of one chromosome 4. Genotypically, both cell lines shared the same STR pattern at nine loci and demonstrated an identical rearranged pattern of the T cell receptor genes beta, gamma and delta, with respect to the original tumor cells. These data indicated that both cell lines and the original neoplastic populations were T cell-derived and arose from a common ancestor. Among a large panel of cytokines tested, only SCF was able to substitute IL2 in supporting cell proliferation. Moreover, SCF and IL2 acted synergistically, dramatically enhancing cell growth. These cell lines may represent a model to further analyze the overlap area between T and NK cell malignancies, and may provide new information about the synergistic action of IL2 and SCF on normal and neoplastic T/NK cells.

Related: Interleukin 2 (Aldesleukin) Non Hodgkin's Lymphoma

Camera A, Pezzullo L, Villa MR, et al.
Coexistence of two distinct cell populations (CD56(+)TcRgammadelta(+) and CD56(+)TcRgammadelta(-)) in a case of aggressive CD56(+) lymphoma/leukemia.
Haematologica. 2000; 85(5):496-501 [PubMed] Related Publications
BACKGROUND AND OBJECTIVE: Large granular lymphocytes derive from two major lineages: one expressing the CD3 surface antigen (T-lymphocytes), and the other lacking this marker (NK-cells). Although developmental overlaps between natural killer cells and T-cells have been described, malignancies derived from these two cell types are considered as distinct lymphoid disorders.
DESIGN AND METHODS: We report the case of a 30-year old man affected by a lymphoma/leukemia syndrome presenting with hepatosplenic lymphoma which rapidly transformed into aggressive NK-leukemia. Extensive flow cytometry studies and molecular analysis were repeated during the course of the disease, and showed an unexpected changing pattern.
RESULTS: At diagnosis, flow cytometry analysis showed the co-existence of two cell populations, one CD56(+), CD3(+), TcRgd(+), and the other CD56(+), CD3(-) and TcRgd(-). Molecular analysis showed that the TcR genes had the same clonally rearranged pattern involving b, g and d genes in both populations. At disease relapse and during the terminal refractory phase, only CD3(-) cells were present.
INTERPRETATION AND CONCLUSIONS: This is an unusual case of CD56(+) aggressive lymphoma/leukemia characterized by the clonal expansion of two phenotypically different cell populations, variably balanced during the course of the disease. The presence of the same TcR genomic rearrangement suggests the origin from a common progenitor able to differentiate along both T- and NK-pathways.

Related: Leukemia Liver Cancer

Noto S, Maeda T, Hattori S, et al.
A novel human RasGAP-like gene that maps within the prostate cancer susceptibility locus at chromosome 1q25.
FEBS Lett. 1998; 441(1):127-31 [PubMed] Related Publications
We report the molecular cloning of a human cDNA that encodes a molecule having striking homology with Ras-specific GTPase-activating proteins (RasGAPs). Among previously described RasGAPs, the cDNA product is most closely related to Caenorhabditis elegans GAP-2, including a predicted coiled-coil structure near the carboxyl terminus. Expression of the cDNA in Saccharomyces cerevisiae defective in one of two RasGAPs, Ira2, complemented loss of the Ira2 function, indicating that the cDNA product functions as a RasGAP. The RasGAP-like gene is located on the human chromosome 1q25, the locus that appears to contain a hereditary prostate cancer susceptible gene, HPC1.

Related: Chromosome 1 Prostate Cancer

Di Noto R, Luciano L, Lo Pardo C, et al.
JURL-MK1 (c-kit(high)/CD30-/CD40-) and JURL-MK2 (c-kit(low)/CD30+/CD40+) cell lines: 'two-sided' model for investigating leukemic megakaryocytopoiesis.
Leukemia. 1997; 11(9):1554-64 [PubMed] Related Publications
Two novel cell lines (JURL-MK1 and JURL-MK2) have been established from the peripheral blood of a patient in the blastic phase of chronic myelogenous leukemia. The cells grow in a single cell suspension with doubling times of 48 h (JURL-MK1) and 72 h (JURL-MK2). Cytogenetic analysis has shown that JURL-MK1 is hypodiploid whereas JURL-MK2 is near triploid and that both cell lines retain t(9;22). Moreover, JURL-MK1 and JURL-MK2 have a bcr/abl-fused gene with the same junction found in the patient's fresh cells, and both cell lines express the b3/a2 type of hybrid bcr/abl mRNA. The morphology and immunophenotype of these cell lines are reminiscent of megakaryoblasts. In both lines, a limited but consistent percentage of cells expresses gpIIbIIIa (CD41a), gpIIIa (CD61) and CD36, with no expression of gplb (CD42b), glycophorin A, hemoglobin and CD34. Both cell lines are clearly positive for CD33, CD43, CD45RO and CD63, while CD13, CD44, CD54, CD30 and CD40 are specific features of JURL-MK2. Among cytokine receptors, CD117/SCF-R is strongly displayed by a large fraction of JURL-MK1 cells but is hardly detectable on about 20% JURL-MK2 cells. Both cell lines are clearly positive for CD25/IL2R alpha, while a marked expression of CD116/GM-CSF-R and CDw123/IL3R alpha is restricted to JURL-MK2. Induction of cell differentiation in vitro has demonstrated that TPA is able to modulate the JURL-MK1 phenotype, causing an increased expression of platelet-associated antigens. The JURL-MK2 phenotype is easily modulated by both TPA and DMSO, which cause an increased expression of CD41a and CD117 accompanied by a decreased expression of CD30. Proliferation studies demonstrated that JURL-MK1 cell growth is enhanced by stem cell factor, while JURL-MK2 proliferation is unaffected by this cytokine. JURL-MK1 and JURL-MK2 are two novel cell lines with divergent biological features, representing a 'two-sided' model for investigating new aspects of megakaryocytopoiesis.

Related: CD40 (TNFRSF5) Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Tanaka J, Imamura M, Kasai M, et al.
The important balance between cytokines derived from type 1 and type 2 helper T cells in the control of graft-versus-host disease.
Bone Marrow Transplant. 1997; 19(6):571-6 [PubMed] Related Publications
We have investigated cytokine mRNA expression in the peripheral blood mononuclear cells of 20 patients who received allogeneic hematopoietic stem cell transplants to assess the cytokine network after transplantation. IL-4 mRNA expression decreased in five of five (100%) patients with > or = grade III (severe) acute GVHD and increased in 10 of 22 (45%) patients without severe GVHD. In contrast, IL-12 mRNA expression increased in two of two (100%) patients with severe GVHD, but increased in only six of 18 (33%) patients without severe GVHD. Furthermore, IL-10 and/or IL-13 mRNA expression increased in 19 of 22 (86%) patients without severe GVHD, but increased in only one of three (33%) patients with severe GVHD. In patients with allogeneic PBSCT who had severe acute GVHD, the cytokine mRNA expression in patients with allogeneic PBSCT, who had no severe GVHD, showed a similar pattern to that in patients with allogeneic BMT. IL-4 mRNA expression increased in three of five (60%) patients and IL-10 and/or IL-13 mRNA expression increased in five of five (100%) patients. In contrast, IL-12 mRNA expression increased in only one of three (33%) patients. Serum IL-4 concentration in allogeneic PBSCT patients in the early engraftment phase was relatively high, while serum IL-12 concentration was low. These findings suggest that severe GVHD may be related to the cytokine imbalance between type 1 helper T (Th1) cells and type 2 helper T (Th2) cells.

Related: Cytokines Haematological Malignancies & Realted Disorders

Kashii T, Mizushima Y, Lima CE, et al.
Studies on clinicopathological features of lung cancer patients with K-ras/p53 gene alterations: comparison between younger and older groups.
Oncology. 1995 May-Jun; 52(3):219-25 [PubMed] Related Publications
In order to define the roles of the K-ras and p53 genes in the development of lung cancer, especially in young adults, we compared the clinicopathological features of the patients between younger (< or = 45 years, n = 47) and older (< 55 years, n = 50) groups. The gene alterations were examined by the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method. The K-ras gene alterations were detected only in adenocarcinomas, and the p53 gene alterations in all histologic types of lung cancer. There were no significant differences in the frequency of both K-ras and p53 gene alterations between the younger and older groups (9 vs. 11%, 36 vs. 32%). In the younger group, but not in the older one, the percentage for smokers was significantly higher in the p53 gene alteration-positive group than for the negative group (65 vs. 30%). As to the prognosis, there were no significant differences between the p53 gene alteration-positive and -negative cases in both the younger and older groups as well as in all subjects, while a tendency of poorer prognosis was observed in K-ras gene alteration-positive cases than for the -negative ones with adenocarcinomas. These results suggest that (1) the K-ras and p53 gene alterations would have no special roles in terms of the lung carcinogenesis in young adults; (2) a positive relationship between smoking and p53 gene alteration would exist in young adults with lung cancer, and (3) K-ras gene alteration would become a prognostic factor in lung cancer.

Related: Lung Cancer Polymorphisms

Lima CE, Mizushima Y, Kashii T, et al.
Sex differences in clinicopathological features of peripheral T1 adenocarcinoma of the lung.
Anticancer Res. 1994 Mar-Apr; 14(2B):721-3 [PubMed] Related Publications
Clinicopathological features of surgically-treated peripheral T1 adenocarcinoma of the lung were compared between 30 females and 26 males, and the following sex differences were observed; 1) Females were younger than males, 2) There was a higher percentage of smokers among males, 3) The acinar histologic subtype was less frequently found in females, 4) Well differentiated tumors were more frequently found in females, 5) K-ras gene mutations were observed only in males, 6) Prognosis was slightly better in females. As to other factors such as N-factor, tumor ploidy or central fibrosis, there was no statistical difference between the two groups. Although we were not able to explain the causes for the above sex differences, it was speculated that smoking was mainly responsible for them.

Related: Lung Cancer


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Cite this page: Cotterill SJ. NOTO, Cancer Genetics Web: http://www.cancerindex.org/geneweb/NOTO.htm Accessed: date

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