NEUROD1

Gene Summary

Gene:NEUROD1; neuronal differentiation 1
Aliases: BETA2, BHF-1, MODY6, NEUROD, bHLHa3
Location:2q32
Summary:This gene encodes a member of the NeuroD family of basic helix-loop-helix (bHLH) transcription factors. The protein forms heterodimers with other bHLH proteins and activates transcription of genes that contain a specific DNA sequence known as the E-box. It regulates expression of the insulin gene, and mutations in this gene result in type II diabetes mellitus. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:neurogenic differentiation factor 1
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (43)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Immunohistochemistry
  • Cell Differentiation
  • Homeodomain Proteins
  • Transcriptome
  • Chromosome 2
  • Adenoma
  • Adolescents
  • Nerve Tissue Proteins
  • Transcription Factor Pit-1
  • RTPCR
  • Spheroids, Cellular
  • Neoplasm Proteins
  • Intercellular Signaling Peptides and Proteins
  • Base Sequence
  • Cancer RNA
  • T-Box Domain Proteins
  • Gene Knockdown Techniques
  • Promoter Regions
  • Pancreatic Cancer
  • Adenocarcinoma
  • Tumor Markers
  • Basic Helix-Loop-Helix Transcription Factors
  • Trans-Activators
  • Insulinoma
  • Gene Expression
  • DNA-Binding Proteins
  • DNA Methylation
  • Lung Cancer
  • Helix-Loop-Helix Motifs
  • Pituitary Tumors
  • Gene Expression Profiling
  • Messenger RNA
  • Transcription Factors
  • Cancer Gene Expression Regulation
  • Down-Regulation
  • Repressor Proteins
  • Neuroendocrine Tumors
  • Pro-Opiomelanocortin
  • Vascular Endothelial Growth Factor Receptor-2
  • Chromogranin A
Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: NEUROD1 (cancer-related)

Liu S, Jin K, Hui Y, et al.
HOXB7 promotes malignant progression by activating the TGFβ signaling pathway.
Cancer Res. 2015; 75(4):709-19 [PubMed] Free Access to Full Article Related Publications
Overexpression of HOXB7 in breast cancer cells induces an epithelial-mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double-transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFβ/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFβ2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFβ2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFβ2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFβ2 or pharmacologic inhibition of TGFβ signaling. Furthermore, knockdown of TGFβ2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFβ2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFβ2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non-cell-autonomous manner through activation of the TGFβ signaling pathway.

Dhimolea E, Tiniakos DG, Chantzi ΝΙ, et al.
Estrogen receptors β1 and β2 are associated with distinct responses of estrogen receptor α-positive breast carcinoma to adjuvant endocrine therapy.
Cancer Lett. 2015; 358(1):37-42 [PubMed] Related Publications
Our purpose was to assess whether and how ERβ1 and/or ERβ2 expression status could predict response of early stage ERα-positive breast carcinoma to adjuvant endocrine therapy (AET). ERβ1 and ERβ2 expression were determined using immunohistochemistry. ERβ1- and ERβ2-positivity were derived from receiver operating characteristic analysis and the median percentage of immunostained tumor cells, respectively. Patients with recurrent disease were grouped according to whether they relapsed within 4 years or after 4 years from surgery. The predictive significance of ERβ1 and ERβ2 was determined using Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. ERβ1-positivity in the first-4-year relapse patient group was lower and ERβ2-positivity in the post-4-year relapse group was higher compared with no-relapse group. ERβ1-positivity was associated with lower tumor size and longer first-4-year disease-free survival, while ERβ2-positivity was associated with shorter post-4-year disease-free survival. Cox multivariate analysis including ERβ1, ERβ2 and established clinico-pathological variables showed that ERβ1-positivity was an independent predictor of lower first-4-year risk of relapse. Thus, low ERβ1 expression and high ERβ2 expression are markers for identification of AET-treated ERα-positive breast carcinoma patients at risk of early and late relapse, respectively.

Li K, Du H, Lian X, et al.
Characterization of β2-microglobulin expression in different types of breast cancer.
BMC Cancer. 2014; 14:750 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Βeta-2-microglobulin (β2-M) has been demonstrated as a growth factor and signaling molecule in breast cancer and leukemia. The purpose of the study is to characterize β2-M expression in molecular subtypes of breast cancer, thereby investigating the mechanism of β2-M action in breast cancer.
METHODS: β2-M and B-Cell Lymphoma/Leukemia 2 (Bcl-2) transcript expression levels in breast cancer tissue and the corresponding normal tissue were quantified using real-time PCR. The protein expression levels of β2-M, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), tumor protein 53 (p53) and Ki67 were determined by immunohistochemical (IHC) staining. Following silencing of the β2-M by siRNA, the levels of Bcl-2, ER, PR and HER-2 transcripts and the protein expression levels in human breast cancer cells were measured by real-time PCR and western blotting, respectively.
RESULTS: The expression of β2-M transcripts demonstrated no significant differences between the four breast cancer molecular subtypes and no significant correlations with age, clinical stage or lymph node metastasis. β2-M transcript expression demonstrated a positive correlation when compared to Bcl-2 transcript expression (P<0.05). The β2-M protein expression was significantly higher in breast cancer when compared with benign breast tumors (P<0.01), and have no significant correlation with age, clinical stage or lymph node metastasis. There was a significant difference demonstrated in β2-M protein expression in the four breast cancer molecular subtypes (P<0.05), and between the ER+ and ER- groups (P<0.01); however, no significant difference was demonstrated between the HER-2+ and HER-2- groups. β2-M protein expression had a negative correlation with ER protein expression (P<0.01), a positive correlation with p53 protein expression (P<0.01), and no correlation with Ki67 protein expression. β2-M silencing significantly inhibited Bcl-2 mRNA expression, but did not inhibit ER, PR and HER-2 mRNA expression in MCF-7 cells (ER+, PR+ and HER-2-). In addition, Bcl-2 and HER-2 mRNA expression were significantly up-regulated in MDA-MB-231 cells (ER-, PR- and HER-2-), which is consistent with the silencing effect seen at the protein level.
CONCLUSIONS: β2-M expression demonstrated a significant difference in the four breast cancer molecular subtypes, and may be related to apoptosis regulation in breast cancer.

Ishii J, Sato H, Yazawa T, et al.
Class III/IV POU transcription factors expressed in small cell lung cancer cells are involved in proneural/neuroendocrine differentiation.
Pathol Int. 2014; 64(9):415-22 [PubMed] Related Publications
One-third of lung malignancies demonstrate a proneural/neuroendocrine phenotype or type of differentiation. However, it has not been clearly elucidated how proneural/neuroendocrine differentiation is controlled in lung cancers. We recently demonstrated that the POU3F2 gene plays a significant role in proneural/neuroendocrine differentiation of lung cancers. Because class III POU genes (POU3F1, POU3F2, POU3F3, and POU3F4) and class IV POU genes (POU4F1, POU4F2, and POU4F3) share similar properties in neural development, we analyzed the association between class III/IV POU genes and a proneural/neuroendocrine phenotype in lung cancers using seven small cell lung cancer (SCLC) cell lines and twelve non-SCLC (NSCLC) cell lines. Class III/IV POU gene expression was generally restricted to SCLC cells. However, the forced expression of class III/IV POU genes in the NSCLC cell lines induced the expression of neuroendocrine-specific markers (neural call adhesion molecule 1, synaptophysin, and chromogranin A) and proneural transcription factors (achaete-scute homolog-like 1, NeuroD1, and thyroid transcription factor 1) in various degrees. Furthermore, each class III/IV POU gene induced other class III/IV POU genes, suggesting the mutual induction of class III/IV POU genes. These findings suggest that the expression of class III/IV POU genes is important for the proneural/neuroendocrine differentiation of lung cancer cells.

Nie L, Lyros O, Medda R, et al.
Endothelial-mesenchymal transition in normal human esophageal endothelial cells cocultured with esophageal adenocarcinoma cells: role of IL-1β and TGF-β2.
Am J Physiol Cell Physiol. 2014; 307(9):C859-77 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Endothelial-mesenchymal transition (EndoMT) has been recognized as a key determinant of tumor microenvironment in cancer progression and metastasis. Endothelial cells undergoing EndoMT lose their endothelial markers, acquire the mesenchymal phenotype, and become more invasive with increased migratory abilities. Early stages of esophageal adenocarcinoma (EAC) are characterized by strong microvasculature whose impact in tumor progression remains undefined. Our aim was to determine the role of EndoMT in EAC by investigating the impact of tumor cells on normal primary human esophageal microvascular endothelial cells (HEMEC). HEMEC were either cocultured with OE33 adenocarcinoma cells or treated with IL-1β and transforming growth factor-β2 (TGF-β2) for indicated periods and analyzed for EndoMT-associated changes by real-time PCR, Western blotting, immunofluorescence staining, and functional assays. Additionally, human EAC tissues were investigated for detection of EndoMT-like cells. Our results demonstrate an increased expression of mesenchymal markers [fibroblast-specific protein 1 (FSP1), collagen1α2, vimentin, α-smooth muscle actin (α-SMA), and Snail], decreased expression of endothelial markers [CD31, von Willebrand factor VIII (vWF), and VE-cadherin], and elevated migration ability in HEMEC following coculture with OE33 cells. The EndoMT-related changes were inhibited by IL-1β and TGF-β2 gene silencing in OE33 cells. Recombinant IL-1β and TGF-β2 induced EndoMT in HEMEC. Although the level of VEGF expression was elevated in EndoMT cells, the angiogenic property of these cells was diminished. In vivo, by immunostaining EndoMT-like cells were detected at the invasive front of EAC. Our findings underscore a significant role for EndoMT in EAC and provide new insights into the mechanisms and significance of EndoMT in the context of tumor progression.

Bilandzic M, Wang Y, Ahmed N, et al.
Betaglycan blocks metastatic behaviors in human granulosa cell tumors by suppressing NFκB-mediated induction of MMP2.
Cancer Lett. 2014; 354(1):107-14 [PubMed] Related Publications
Metastatic ovarian granulosa cell tumors (GCT) exhibit loss of betaglycan. Here we test the hypothesis that betaglycan blocks GCT metastasis by suppressing NFκB/TGFβ2-induced matrix metalloprotinease-2 (MMP2). Human GCT and a human GCT cell model demonstrated prominent MMP2 expression, which was dependent on NFκB activity and stimulated by TGFβ2 in an NFκB-dependent manner. Betaglycan suppressed both basal and TGFβ2-induced MMP2 expression and countered metastatic behaviors of GCT cells in non-adherent spheroid culture and in vivo xenograft models of metastasis. These data suggest that NFκB/TGFβ2 promotes, and betaglycan impedes, the early stages of GCT metastasis, when tumor cells first invade the peritoneum.

Yu P, Petrus MN, Ju W, et al.
Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model.
Leukemia. 2015; 29(3):556-66 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-α and β2-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL.

Kapitskaya KY, Azhikina TL, Ponomaryova AA, et al.
MIRA analysis of RARβ2 gene methylation in DNA circulating in the blood in lung cancer.
Bull Exp Biol Med. 2014; 157(4):516-9 [PubMed] Related Publications
Analysis of DNA epigenetic mutations in the blood circulating DNA is a prospective trend for creation of noninvasive methods for the diagnosis and treatment efficiency monitoring in cancer. The methylation status of target genes in circulating DNA was evaluated by methods based on preliminary bisulfite conversion of DNA. We used a different approach based on selection of hypermethylated sequences of circulating DNA by means of DNA-methyl-binding protein (methylated CpG island recovery assay, MIRA). Methylation was evaluated for RARβ2 tumor suppression gene in circulating DNA in lung cancer and a trend was detected to higher methylation of this gene in the patients in comparison with healthy donors.

Horie M, Saito A, Noguchi S, et al.
Differential knockdown of TGF-β ligands in a three-dimensional co-culture tumor- stromal interaction model of lung cancer.
BMC Cancer. 2014; 14:580 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Transforming growth factor (TGF)-β plays a pivotal role in cancer progression through regulating cancer cell proliferation, invasion, and remodeling of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the predominant type of stromal cell, in which TGF-β signaling is activated. Among the strategies for TGF-β signaling inhibition, RNA interference (RNAi) targeting of TGF-β ligands is emerging as a promising tool. Although preclinical studies support the efficacy of this therapeutic strategy, its effect on the tumor microenvironment in vivo remains unknown. In addition, differential effects due to knockdown of various TGF-β ligand isoforms have not been examined. Therefore, an experimental model that recapitulates tumor-stromal interaction is required for validation of therapeutic agents.
METHODS: We have previously established a three-dimensional co-culture model of lung cancer, and demonstrated the functional role of co-cultured fibroblasts in enhancing cancer cell invasion and differentiation. Here, we employed this model to examine how knockdown of TGF-β ligands affects the behavior of different cell types. We developed lentivirus vectors carrying artificial microRNAs against human TGF-β1 and TGF-β2, and tested their effects in lung cancer cells and fibroblasts.
RESULTS: Lentiviral vectors potently and selectively suppressed the expression of TGF-β ligands, and showed anti-proliferative effects on these cells. Furthermore, knockdown of TGF-β ligands attenuated fibroblast-mediated collagen gel contraction, and diminished lung cancer cell invasion in three-dimensional co-culture. We also observed differential effects by targeting different TGF-β isoforms in lung cancer cells and fibroblasts.
CONCLUSIONS: Our findings support the notion that RNAi-mediated targeting of TGF-β ligands may be beneficial for lung cancer treatment via its action on both cancer and stromal cells. This study further demonstrates the usefulness of this three-dimensional co-culture model to examine the effect of therapeutic agents on tumor-stromal interaction.

Finalet Ferreiro J, Rouhigharabaei L, Urbankova H, et al.
Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.
PLoS One. 2014; 9(7):e102977 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.

Ataie-Kachoie P, Pourgholami MH, Richardson DR, Morris DL
Gene of the month: Interleukin 6 (IL-6).
J Clin Pathol. 2014; 67(11):932-7 [PubMed] Related Publications
The Interleukin 6 (IL-6) gene encodes the classic proinflammatory cytokine IL-6. It is also known as interferon-β2 (IFN-β2), B cell stimulatory factor-2 and hybridoma/plasmacytoma growth factor. IL-6 is a multifunctional cytokine with a central role in many physiological inflammatory and immunological processes. Due to its major role in initiation as well as resolving inflammation, deregulation of IL-6 is a mainstay of chronic inflammatory and autoimmune diseases. Additionally, IL-6 has been shown to be implicated in pathogenesis of many human malignancies. Thus, a better understanding of IL-6 and its role in various pathological conditions could enable the development of strategies to use it as a therapeutic target. This short review focuses on the structure, regulation and biological activities of IL-6. In addition we discuss the role of IL-6 in diseases with inflammatory background and cancer and also the therapeutic applications of anti-IL-6 agents.

Işeri OD, Sahin FI, Terzi YK, et al.
beta-Adrenoreceptor antagonists reduce cancer cell proliferation, invasion, and migration.
Pharm Biol. 2014; 52(11):1374-81 [PubMed] Related Publications
CONTEXT: Propranolol, atenolol, and ICI118,551 are non-selective β-adrenergic receptor (AR), β1-AR, and β2-AR antagonists, respectively.
OBJECTIVE: We investigated the efficacy of propranolol, atenolol, and ICI118,551 on proliferation, migration, and invasion of non-stimulated breast (MCF7), colon (HT-29), and hepatocellular (HepG2) cancer cells.
MATERIALS AND METHODS: β-AR expression profiling of cells was performed by real time PCR. Cell proliferation was determined by MTT. Boyden chamber and scratch assays were performed to evaluate invasion and migration.
RESULTS AND DISCUSSION: All cell lines expressed β-ARs. ICI118,551 was the most cytotoxic, whereas atenolol was the least effective β-AR antagonist for 24, 48, and 72 h. Cell invasion was inhibited by ICI118,551 (45, 46, and 50% for MCF7, HT29, and HepG2, respectively) and propranolol (72, 65, and 90% for MCF7, HT29, and HepG2, respectively). Propranolol, atenolol, and ICI118,551 reduced migration of MCF7, HT-29, and HepG2 cells to varying extents depending on the application concentration and duration. Propranolol and atenolol reduced migration of MCF7 and HT-29 in a concentration-dependent manner, whereas migration of these cells decreased after 48 and 72 h of ICI118,551 applications.
CONCLUSION: Beta2-AR antagonist seemed to be the most cytotoxic β-blocker on non-stimulated cancer cells. Propranolol and ICI118,551 were more effective than atenolol in inhibiting invasion and migration of non-stimulated MCF7 and HT-29 cells; ICI118,551 being the most potent. Concordantly, β2-selective blockage seemed to be more effective for non-stimulated cells. Effect of the selective β-AR antagonists showed variation depending on the concentration, incubation time, and histological origin of cells.

Kidd M, Modlin IM, Drozdov I
Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors.
BMC Genomics. 2014; 15:595 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
BACKGROUND: Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors.
RESULTS: We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis-associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15).
CONCLUSIONS: An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors.

Maldonado L, Brait M, Michailidi C, et al.
An epigenetic marker panel for recurrence risk prediction of low grade papillary urothelial cell carcinoma (LGPUCC) and its potential use for surveillance after transurethral resection using urine.
Oncotarget. 2014; 5(14):5218-33 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
By a candidate gene approach, we analyzed the promoter methylation (PM) of 8 genes genes (ARF, TIMP3, RAR-β2, NID2, CCNA1, AIM1, CALCA and CCND2) by quantitative methylation specific PCR (QMSP) in DNA of 17 non-recurrent and 19 recurrent noninvasive low grade papillary urothelial cell carcinoma (LGPUCC) archival tissues. Among the genes tested, by establishing an empiric cutoff value, CCND2, CCNA1, NID2, and CALCA showed higher frequency of methylation in recurrent than in non-recurrent LGPUCC: CCND2 10/19 (53%) vs. 2/17 (12%) (p=0.014); CCNA1 11/19 (58%) vs. 4/17 (23.5%) (p=0.048); NID2 13/19 (68%) vs. 3/17 (18%) (p=0.003) and CALCA 10/19 (53%) vs. 4/17 (23.5%) (p=0.097), respectively. We further analyzed PM of CCND2, CCNA1, and CALCA in urine DNA from UCC patients including LGPUCC and controls. The frequency of CCND2, CCNA1 and CALCA was significantly higher (p<0.0001) in urine of UCC cases [ 38/148 (26%), 50/73 (68%) and 94/148 (63.5%) respectively] than controls [0/56 (0%), 10/60 (17%) and 16/56 (28.5%), respectively)]. Most importantly we found any one of the 3 markers methylation positive in 25 out of 30 (83%) cytology negative LGPUCC cases. We also explored the biological function of CCNA1 in UCC. Prospective confirmatory studies are needed to develop a reliable tool for prediction of recurrence using primary LGPUCC tissues and/or urine.

Stella F, Pedrazzini E, Baialardo E, et al.
Quantitative analysis of CKS1B mRNA expression and copy number gain in patients with plasma cell disorders.
Blood Cells Mol Dis. 2014; 53(3):110-7 [PubMed] Related Publications
In this study, we have examined CKS1B gene expression and copy number in a total of 114- patients at diagnosis: 83 with multiple myeloma (MM) and 31 with monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with cytogenetics, FISH and clinical characteristic. Significant CKS1B mRNA levels in MM compared to MGUS cases (p<0.048) were detected. In MM, the frequency of 1q21 (CKS1B) copy gain was significantly higher in cases with abnormal karyotype compared to patients with normal karyotype (p=0.021). Global analysis showed a positive correlation between CKS1B expression and 1q21 copy number (p<0.0001). No association between CKS1B mRNA expression and clinical parameters was found. However, a significantly higher level of β2 microglobulin in cases with 1q21 gains than those without (p=0.0094) was observed. Overall survival was shorter in cases with 1q21 gain compared to those with normal 1q21 region (p=0.0082). Our results suggest a role for CKS1B in the multiple step process of progression of MGUS to MM and show that CKS1B copy gain has a more significant prognostic value than its overexpression. This adverse impact on survival probably reflects the genetic instability associated to chromosome 1q alterations resulting in a more aggressive behavior of the disease.

Del Campo AB, Carretero J, Muñoz JA, et al.
Adenovirus expressing β2-microglobulin recovers HLA class I expression and antitumor immunity by increasing T-cell recognition.
Cancer Gene Ther. 2014; 21(8):317-32 [PubMed] Related Publications
Optimal tumor cell surface expression of human leukocyte antigen (HLA) class I molecules is essential for the presentation of tumor-associated peptides to T-lymphocytes. However, a hallmark of many types of tumor is the loss or downregulation of HLA class I expression associated with ineffective tumor antigen presentation to T cells. Frequently, HLA loss can be caused by structural alterations in genes coding for HLA class I complex, including the light chain of the complex, β2-microglobulin (β2m). Its best-characterized function is to interact with HLA heavy chain and stabilize the complex leading to a formation of antigen-binding cleft recognized by T-cell receptor on CD8+ T cells. Our previous study demonstrated that alterations in the β2m gene are frequently associated with cancer immune escape leading to metastatic progression and resistance to immunotherapy. These types of defects require genetic transfer strategies to recover normal expression of HLA genes. Here we characterize a replication-deficient adenoviral vector carrying human β2m gene, which is efficient in recovering proper tumor cell surface HLA class I expression in β2m-negative tumor cells without compromising the antigen presentation machinery. Tumor cells transduced with β2m induced strong activation of T cells in a peptide-specific HLA-restricted manner. Gene therapy using recombinant adenoviral vectors encoding HLA genes increases tumor antigen presentation and represents a powerful tool for modulation of tumor cell immunogenicity by restoration of missing or altered HLA genes. It should be considered as part of cancer treatment in combination with immunotherapy.

Nemunaitis J, Barve M, Orr D, et al.
Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG™) in advanced cancer of the liver.
Oncology. 2014; 87(1):21-9 [PubMed] Related Publications
Therapies for advanced hepatocellular carcinoma (HCC) are limited. We carried out a phase I trial of a novel autologous whole-cell tumor cell immunotherapy (FANG™), which incorporates a dual granulocyte macrophage colony-stimulating factor (GM-CSF) expressive/bifunctional small hairpin RNA interference (bi-shRNAi) vector. The bi-shRNAi DNA targets furin, which is a proconvertase of transforming growth factors beta (TGFβ) 1 and 2. Safety, mechanism, immunoeffectiveness, and suggested benefit were previously shown [Senzer et al.: Mol Ther 2012;20:679-689; Senzer et al.: J Vaccines Vaccin 2013;4:209]. We now provide further follow-up of a subset of 8 HCC patients. FANG manufacturing was successful in 7 of 8 attempts (one failure due to insufficient cell yield). Median GM-CSF expression was 144 pg/10(6) cells, TGFβ1 knockdown was 100%, and TGFβ2 knockdown was 93% of the vector-transported cells. Five patients were vaccinated (1 or 2.5×10(7) cells/intradermal injection, 6-11 vaccinations). No FANG toxicity was observed. Three of these patients demonstrated evidence of an immune response to the autologous tumor cell sample. Long-term follow-up demonstrated survival of 319, 729, 784, 931+, and 1,043+ days of the FANG-treated patients. In conclusion, evidence supports further assessment of the FANG immunotherapy in HCC.

Yamazaki S, Miyoshi N, Kawabata K, et al.
Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking β₂-adrenergic signaling.
Arch Biochem Biophys. 2014; 557:18-27 [PubMed] Related Publications
Endogenous catecholamines such as adrenaline (A) and noradrenaline (NA) are released from the adrenal gland and sympathetic nervous system during exposure to stress. The adrenergic system plays a central role in stress signaling, and excessive stress was found to be associated with increased production of reactive oxygen species (ROS). Overproduction of ROS induces oxidative damage in tissues and causes the development of diseases such as cancer. In this study, we investigated the effects of quercetin-3-O-glucuronide (Q3G), a circulating metabolite of quercetin, which is a type of natural flavonoid, on the catecholamine-induced β2-adrenergic receptor (β2-AR)-mediated response in MDA-MB-231 human breast cancer cells expressing β2-AR. Treatment with A or NA at concentrations above 1μM generated significant levels of ROS, and NA treatment induced the gene expression of heme oxygenase-1 (HMOX1), and matrix metalloproteinase-2 (MMP-2) and -9 (MMP9). Inhibitors of p38 MAP kinase (SB203580), cAMP-dependent protein kinase (PKA) (H-89), activator protein-1 (AP-1) transcription factor (SR11302), and NF-κB and AP-1 (Tanshinone IIA) decreased MMP2 and MMP9 gene expression. NA also enhanced cAMP induction, RAS activation and phosphorylation of ERK1/2. These results suggested that the cAMP-PKA, MAPK, and ROS-NF-κB pathways are involved in β2-AR signaling. Treatment with 0.1μM Q3G suppressed ROS generation, cAMP and RAS activation, phosphorylation of ERK1/2 and the expression of HMOX1, MMP2, and MMP9 genes. Furthermore, Q3G (0.1μM) suppressed invasion of MDA-MB-231 breast cancer cells and MMP-9 induction, and inhibited the binding of [(3)H]-NA to β2-AR. These results suggest that Q3G may function to suppress invasion of breast cancer cells by controlling β2-adrenergic signaling, and may be a dietary chemopreventive factor for stress-related breast cancer.

Kondoh T, Kuribayashi K, Tanaka M, et al.
CD7 promotes extramedullary involvement of the B-cell acute lymphoblastic leukemia line Tanoue by enhancing integrin β2-dependent cell adhesiveness.
Int J Oncol. 2014; 45(3):1073-81 [PubMed] Related Publications
Extramedullary involvement (EMI) is a factor that defines prognosis of acute lymphoblastic leukemia; however, the molecular mechanism(s) remain elusive. Here, we show that CD7 promotes EMI of the human B-cell acute lymphoblastic leukemia cell line Tanoue. The Tanoue cell line expressing firefly luciferase, Luc-Tanoue, was transplanted into non-obese diabetic/severe combined immunodeficient mice, and cells infiltrated into the brain were cultured ex vivo. This process was repeated 4 times to obtain the highly invasive line Luc-Tanoue-F4. Comparison of the global gene expression signatures of Luc-Tanoue-F4 and Luc-Tanoue indicated that the CD7 gene showed the largest increase in expression among EMI-related genes in Luc-Tanoue-F4 cells. Overexpression of CD7 in Tanoue enhanced cell invasiveness. Among cell migration, proliferation, adhesion and protease activity, only cell adhesiveness showed enhancement in Luc-Tanoue-F4. Expression of the intracellular domain, but not the extracellular domain, of CD7 enhanced cell adhesiveness. Luc-Tanoue-F4 showed a higher level of integrin β2 expression; overexpression of CD7 induced the expression of integrin β2 in Luc-Tanoue. These results show that CD7 induces integrin β2 and enhances cell adhesiveness and invasiveness in Tanoue cells. This study highlights the role of the CD7/integrin β2 axis as a critical pathway in the process of EMI of human B-cell acute lymphoblastic leukemia.

Riches JC, O'Donovan CJ, Kingdon SJ, et al.
Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations.
Blood. 2014; 123(26):4101-10 [PubMed] Article available free on PMC after 26/06/2015 Related Publications
The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with β2-integrin expression being modulated by NOTCH1 mutation status.

Shan T, Cui X, Li W, et al.
Novel regulatory program for norepinephrine-induced epithelial-mesenchymal transition in gastric adenocarcinoma cell lines.
Cancer Sci. 2014; 105(7):847-56 [PubMed] Related Publications
Norepinephrine and epinephrine, catecholamine hormones that are major mediators for chronic stress-induced cancers, are implicated in the progression of a number of cancer cells, including gastric adenocarcinoma. However, the underlying mechanisms of these hormones have not been well elucidated. Epithelial-mesenchymal transition (EMT) is a crucial event responsible for cancer cell invasion and metastasis. The hypothesis regarding whether the promotive effects of norepinephrine (NE) on cancer are in part due to its ability to induce an EMT program has not been proven. In this study, we show that NE does not only obviously induce EMT alterations in the morphological characteristics of gastric adenocarcinoma cells, but also increases the markers of EMT, including vimentin expression, and decreases E-cadherin expression, further resulting in cell motility and invasiveness. We also reveal that these actions are mainly mediated through the activation of β2 -AR-HIF-1α-Snail signaling pathways. In summary, this study implies that NE induces EMT in gastric adenocarcinoma through the regulation of β2 -AR-HIF-1α-Snail activity. The data provide a new perspective on chronic stress in a negative social and psychological state, which may be a risk factor for cancer development and progression.

Yang H, Mi R, Wang Q, et al.
Expression of neuron-specific enolase in multiple myeloma and implications for clinical diagnosis and treatment.
PLoS One. 2014; 9(5):e94304 [PubMed] Article available free on PMC after 26/06/2015 Related Publications
OBJECTIVE: To determine the expression of neuron-specific enolase (NSE) in patients with multiple myeloma (MM) and to evaluate its clinical value as a tumor marker and, an indicator of disease progression and treatment efficacy.
METHODS: Using electrochemiluminescence immunoassay (ECLIA), we measured the serum levels of NSE in 47 healthy subjects (control group), 25 patients with small cell lung cancer (lung cancer group), and 52 patients with MM (MM group). For the MM group, serum NSE levels were measured and other disease indicators and related symptoms were monitored before and after chemotherapy. The relationship between NSE expression and other MM-related factors was analyzed. In addition, immunohistochemical staining was performed on bone marrow biopsy specimens from patients with MM.
RESULTS: In the control group, serum NSE levels were within the normal range as previously reported, while the lung cancer group and the untreated MM group exhibited NSE levels that were significantly higher relative to the control group (P<0.05). The difference in NSE expression between the lung cancer group and untreated MM group was statistically significant (P<0.05). NSE levels were significantly decreased in MM patients after chemotherapy and were positively correlated with an MM disease index [beta-2 microglobulin (β2-MG)]. Changes in NSE were not related to the response rate to chemotherapy but rather were correlated with progression-free survival.
CONCLUSIONS: Patients with MM may have increased serum NSE levels, and changes in NSE may provide insight into treatment efficacy of chemotherapy and disease progression. Perhaps NSE expression is a viable biomarker for MM and can be a useful reference for the design and adjustment of clinical MM treatment programs.

Kim JH, Kang GH
Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer.
World J Gastroenterol. 2014; 20(15):4230-43 [PubMed] Article available free on PMC after 26/06/2015 Related Publications
Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn's-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.

Mostafavi H, Khaksarian M, Joghataei MT, et al.
Selective β2 adrenergic agonist increases Cx43 and miR-451 expression via cAMP-Epac.
Mol Med Rep. 2014; 9(6):2405-10 [PubMed] Related Publications
It has been demonstrated that connexin 43 (Cx43) and microRNAs have significant roles in glioma. Cyclic adenosine monophosphate (cAMP) is suggested to be a regulator of connexins and microRNAs. However, it remains elusive whether cAMP and exchange protein directly activated by cAMP (Epac2), have a regulatory effect on Cx43 and microRNA-451 (miR-451) in astrocytoma cells. We treated 1321N1 astrocytoma cells with a selective β2 adrenergic agonist and a selective Epac activator with and without adenyl cyclase and protein kinase A inhibition. Cx43 and miR-451 expression were measured. Next, we evaluated the effect of miR-451 overexpression on Cx43 expression. Cell proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The results demonstrated that cAMP-Epac2 increased Cx43 and miR-451 expression. However, the alteration of miR-451 expression required a higher dose of drugs. Overexpression of miR-451 had no significant effect on Cx43 expression. The MTT assay showed that cAMP-Epac stimulation and miR-451 overexpression had a synergic inhibitory effect on cell proliferation. These findings may expand our understanding of the molecular biology of glioma and provide new potential therapeutic targets.

Zhu M, Yin F, Fan X, et al.
Decreased TIP30 promotes Snail-mediated epithelial-mesenchymal transition and tumor-initiating properties in hepatocellular carcinoma.
Oncogene. 2015; 34(11):1420-31 [PubMed] Related Publications
The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to tumor recurrence and metastases. Recently, epithelial-mesenchymal transition (EMT) has been implicated in tumor invasion and metastasis. However, the underlying molecular mechanisms are yet to be elucidated. Here, we show that 30-kDa Tat-interacting protein (TIP30), also called CC3, is significantly downregulated during transforming growth factor-β-induced EMT. In our in vitro and in vivo studies, we show that decreased TIP30 expression leads to EMT, as well as enhanced motility and invasion of HCC cells. Also, increased self-renewal ability and chemotherapeutic resistance are observed with TIP30 depletion. Moreover, Snail is one of the key transcription factors promoting EMT, and overexpression of TIP30 greatly decreased nucleic accumulation in Snail through the regulation of intracellular localization. Small interfering RNAs targeting Snail attenuated EMT and tumor-initiating properties induced by TIP30 deficiency. We further confirmed that TIP30 competitively interrupted the interaction of Snail with importin-β2 to block the nuclear import of Snail. Consistently, TIP30 expression significantly correlates with E-cadherin expression in HCC patients. TIP30 or combination of E-cadherin is a powerful marker in predicting the prognosis of HCC. Taken together, our results suggest a novel and critical role of TIP30 involved in HCC progression and aggressiveness.

Virijevic M, Perunicic-Jovanovic M, Djunic I, et al.
Pretreatment risk factors for overall survival in patients with gastrointestinal and non-gastrointestinal mucosa associated lymphoid tissue lymphomas.
J BUON. 2014 Jan-Mar; 19(1):178-82 [PubMed] Related Publications
PURPOSE: The aim of this 10-year retrospective study was to investigate prognostic clinical and laboratory factors significant for the outcome of patients with mucosa associated lymphoid tissue (MALT) lymphoma.
METHODS: The study involved 87 patients diagnosed with MALT lymphoma: 37 (42.5%) with gastrointestinal (GI) and 50 (57.5%) with non-GI localization. The following pretreatment laboratory parameters were analyzed: hemoglobin, serum albumin and lactate dehydrogenase (LDH) level, beta2-microglobulin (bgr;2-M) and bacteriological (H.pylori) status. Estimated clinical features were: stage of disease, ECOG performance status (PS), tumor mass, number of extranodal localizations, presence of B symptomatology, splenomegaly and enlarged lymph nodes. Diagnosis of MALT lymphoma was based on histopathological analysis of tissue samples, obtained by endoscopy or surgery.
RESULTS: The median disease-free survival (DFS) was 36 months and the 5-year overall survival (OS) was 64%. OS rate of patients with non-GI localization was higher compared with patients with GI localization (p=0.001). Multivariate analysis showed hypoalbuminemia to be the most significant parameter associated with poor OS (p<0.001) for both patient groups. The most significant prognostic factor for poor OS in patients with GI localization was LDH level (p=0.031), while hypoalbuminemia was the most significant prognostic factor for poor OS in the group with non-GI disease localization (p=0.001).
CONCLUSION: Proper therapeutic approach for MALT lymphoma patients could be planned taking into consideration poor prognostic parameters, i.e. hypoalbuminemia and elevated LDH for GI patients and hypoalbuminemia for non- GI lymphoma patients.

Stilgenbauer S, Schnaiter A, Paschka P, et al.
Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.
Blood. 2014; 123(21):3247-54 [PubMed] Related Publications
Mutations in TP53, NOTCH1, and SF3B1 were analyzed in the CLL8 study evaluating first-line therapy with fludarabine and cyclophosphamide (FC) or FC with rituximab (FCR) among patients with untreated chronic lymphocytic leukemia (CLL). TP53, NOTCH1, and SF3B1 were mutated in 11.5%, 10.0%, and 18.4% of patients, respectively. NOTCH1(mut) and SF3B1(mut) virtually showed mutual exclusivity (0.6% concurrence), but TP53(mut) was frequently found in NOTCH1(mut) (16.1%) and in SF3B1(mut) (14.0%) patients. There were few significant associations with clinical and laboratory characteristics, but genetic markers had a strong influence on response and survival. In multivariable analyses, an independent prognostic impact was found for FCR, thymidine kinase (TK) ≥10 U/L, unmutated IGHV, 11q deletion, 17p deletion, TP53(mut), and SF3B1(mut) on progression-free survival; and for FCR, age ≥65 years, Eastern Cooperative Oncology Group performance status ≥1, β2-microglobulin ≥3.5 mg/L, TK ≥10 U/L, unmutated IGHV, 17p deletion, and TP53(mut) on overall survival. Notably, predictive marker analysis identified an interaction of NOTCH1 mutational status and treatment in that rituximab failed to improve response and survival in patients with NOTCH1(mut). In conclusion, TP53 and SF3B1 mutations appear among the strongest prognostic markers in CLL patients receiving current-standard first-line therapy. NOTCH1(mut) was identified as a predictive marker for decreased benefit from the addition of rituximab to FC. This study is registered at www.clinicaltrials.gov as #NCT00281918.

Olkhov-Mitsel E, Zdravic D, Kron K, et al.
Novel multiplex MethyLight protocol for detection of DNA methylation in patient tissues and bodily fluids.
Sci Rep. 2014; 4:4432 [PubMed] Article available free on PMC after 26/06/2015 Related Publications
Aberrant DNA methylation is a hallmark of cancer and is an important potential biomarker. Particularly, combined analysis of a panel of hypermethylated genes shows the most promising clinical performance. Herein, we developed, optimized and standardized a multiplex MethyLight assay to simultaneously detect hypermethylation of APC, HOXD3 and TGFB2 in DNA extracted from prostate cancer (PCa) cell lines, archival tissue specimens, and urine samples. We established that the assay is capable of discriminating between fully methylated and unmethylated alleles with 100% specificity and demonstrated the assay as highly accurate and reproducible as the singleplex approach. For proof of principle, we analyzed the methylation status of these genes in tissue and urine samples of PCa patients as well as PCa-free controls. These data show that the multiplex MethyLight assay offers a significant advantage when working with limited quantities of DNA and has potential applications in research and clinical settings.

Masunaga A, Inoue K, Mizukami H, et al.
Neuroendocrine carcinoma arising in a hepatitis C virus-infected liver: mechanism of the tumor development may be similar to that of development of pancreatic neuroendocrine cells.
Pathol Int. 2014; 64(2):81-5 [PubMed] Related Publications
We experienced a case of neuroendocrine carcinoma (NC). The tumor developed in the cirrhotic liver of a 62-year-old Japanese man who had been infected with hepatitis C virus. The tumor cells showed high N/C ratio, formed many rosettes, and expressed CD56, synaptophysin, HepPar1 and pancreatic and duodenal homeobox 1. MIB1 expression was 65%. Because both liver and pancreas are derived from a common endodermal layer during fetal development, we speculated that the tumor may have formed via the interaction of neurogenin 3, insulinoma-associated 1 gene and NeuroD/beta2, which are involved in the stage at which some pancreatic cells commit to becoming endocrine cells. Molecular analysis revealed that the NC had higher relative expression levels of mRNA of the three molecules than did the nontumorous liver. The results indicate that the NC in this patient may have formed via the same mechanism that acts in the development of pancreatic neuroendocrine cells.

Ma H, Cai H, Zhang Y, et al.
Membrane palmitoylated protein 3 promotes hepatocellular carcinoma cell migration and invasion via up-regulating matrix metalloproteinase 1.
Cancer Lett. 2014; 344(1):74-81 [PubMed] Related Publications
Membrane associated guanylate kinase (MAGUK) family, has been extensively studied in cellular adhesion and signal transduction at sites of cell–cell contact. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, its role in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that membrane palmitoylated protein 3 (MPP3), a member of MAGUK family, was significantly up-regulated in both high metastatic potential cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Higher level of MPP3 correlated with poorer survival of patients with HCC. Forced expression of MPP3 significantly enhanced HCC cell migration and invasion, whereas knockdown of this gene inhibited this oncogenic effect. Mechanismly, we found that MPP3 promoted HCC cell migration and invasion via up-regulating matrix metalloproteinase 1 (MMP1). These findings indicate that MPP3 play an important role in HCC metastasis by promoting cell migration and invasion, suggesting that it may serve as a novel prognostic marker and molecular target for therapy of HCC.

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