ASAH1

Gene Summary

Gene:ASAH1; N-acylsphingosine amidohydrolase (acid ceramidase) 1
Aliases: AC, PHP, ASAH, PHP32, ACDase, SMAPME
Location:8p22
Summary:This gene encodes a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit that is cleaved to the mature enzyme posttranslationally. The encoded protein catalyzes the synthesis and degradation of ceramide into sphingosine and fatty acid. Mutations in this gene have been associated with a lysosomal storage disorder known as Farber disease. Multiple transcript variants encoding several distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:acid ceramidase
HPRD
Source:NCBIAccessed: 08 August, 2015

Ontology:

What does this gene/protein do?
Show (14)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 08 August 2015 using data from PubMed using criteria.

Literature Analysis

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

  • Melanoma
  • Messenger RNA
  • Enzyme Inhibitors
  • Simian virus 40
  • Neoplasm Metastasis
  • Dose-Response Relationship, Drug
  • Tumor Markers
  • Transcription
  • Non-Small Cell Lung Cancer
  • src-Family Kinases
  • Chromosome 8
  • Drug Resistance
  • Sensitivity and Specificity
  • Acid Ceramidase
  • Cell Proliferation
  • Sphingolipids
  • Ceramidases
  • Amidohydrolases
  • Sphingosine
  • Genetic Therapy
  • Genes, Reporter
  • Propanolamines
  • Cell Survival
  • Apoptosis
  • Principal Component Analysis
  • Fas Ligand Protein
  • siRNA
  • Galactosylgalactosylglucosylceramidase
  • Cancer Gene Expression Regulation
  • Up-Regulation
  • Lung Cancer
  • T-Lymphocytes, Cytotoxic
  • Prostate Cancer
  • Tumor Suppressor Proteins
  • Signal Transduction
  • Lysophospholipids
  • Myristates
  • Ceramides
  • Oleic Acids
  • Thyroid Cancer
Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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

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

Latest Publications: ASAH1 (cancer-related)

Shida A, Futawatari N, Fukuyama T, et al.
Frequent High Expression of Kita-Kyushu Lung Cancer Antigen-1 (KK-LC-1) in Gastric Cancer.
Anticancer Res. 2015; 35(6):3575-9 [PubMed] Related Publications
BACKGROUND: The tumor-associated antigen Kita-Kyushu lung cancer antigen-1 (KK-LC-1) has been reported as not being expressed in normal tissues, except for the testis, and in the setting of non-small cell lung cancer. The present study demonstrated that KK-LC-1 is expressed in gastric cancer.
MATERIALS AND METHODS: We analyzed the expression of KK-LC-1 and cancer/testis antigens (CTAs) in surgical specimens of 49 gastric carcinomas. The expression of KK-LC-1 and CTAs was assessed using reverse transcription-polymerase chain reaction.
RESULTS: KK-LC-1 expression was observed in gastric carcinomas. The number of lesions with expression of KK-LC-1, Melanoma antigen gene encoding-A1 (MAGE-A1), MAGE-A3 and New York Esophageal squamous cell carcinoma-1 (NY-ESO-1) was 40 (81.6%), 17 (34.7%), 22 (44.9%) and 8 (16.3%) out of the 49 specimens, respectively.
CONCLUSION: KK-LC-1 should be categorized as a CTA. The frequency of KK-LC-1 expression was higher than that of the other CTAs. KK-LC-1 might be a useful target for immunotherapy and in diagnosis of gastric cancer.

Kim HS, Lee HS, Nam KH, et al.
Telomere length abnormalities and telomerase RNA component expression in gastroenteropancreatic neuroendocrine tumors.
Anticancer Res. 2015; 35(6):3501-10 [PubMed] Related Publications
Telomere lengths in normal human cells are tightly regulated within a narrow range. Telomere length abnormalities are prevalent genetic alterations in malignant transformation. We studied telomere length abnormalities, telomerase RNA component (TERC) expression, alpha-thalassemia X-linked mental retardation (ATRX) expression, and death domain-associated protein (DAXX) expression in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We used tissue microarrays to perform telomere fluorescent in situ hybridization (FISH) and TERC in situ hybridization in 327 formalin-fixed paraffin-embedded tissues of GEP-NETs. Telomere length abnormalities were detected in 35% of 253 informative cases by using telomere FISH. Ten cases had altered lengthening of telomeres (ALT), an ALT-positive phenotype (4%), and 79 cases had telomere shortening (31%). The ALT-positive phenotype was significantly associated with tumors of pancreatic origin (7/10) and loss of ATRX or DAXX protein (8/10). Telomere shortening was significantly associated with low TERC expression. In the survival analysis, loss of ATRX or DAXX protein was associated with a decreased overall survival. Multivariate regression analysis showed that lymph node metastasis and high TERC expression were independent prognostic factors of reduced overall survival (OS) for patients with GEP-NETs. Our results showed that telomere lengthening (the ALT-positive phenotype) and telomere shortening accompanied by low TERC levels are two types of clinically significant telomere abnormalities in GEP-NETs.

Tanji N, Kikugawa T, Ochi T, et al.
Circulating Cytokine Levels in Patients with Prostate Cancer: Effects of Neoadjuvant Hormonal Therapy and External-beam Radiotherapy.
Anticancer Res. 2015; 35(6):3379-83 [PubMed] Related Publications
AIM: The aim of the study was to better characterize the temporal induction of inflammatory cytokines in the serum of patients with prostate cancer (PCa) treated with radiotherapy and to ascertain the influence of hormonal therapy upon those expressions.
PATIENTS AND METHODS: Between May 2007 and December 2009, 30 patients with localized PCa were treated with 3-dimensional conformal external-beam radiotherapy. Fifteen patients had received neoadjuvant hormonal therapy using a leuteinizing hormone-releasing hormone (LH-RH) analog for six months prior to radiotherapy. The cytokine levels were collectively measured using a multiplex assay system.
RESULTS: Seventeen cytokines were at detectable levels throughout the blood sampling times before and during radiotherapy. Hormonal therapy for six months significantly decreased the serum levels of fibroblast growth factor-2 (FGF2) and vascular endothelial growth factor (VEGF). The levels of epidermal growth factor (EGF), granulocyte-colony stimulating factor (G-CSF), and interferon-gamma (IFNγ) significantly increased during radiotherapy. Most cytokine levels, except for eotaxin, G-CSF, growth-related oncogene (GRO), transforming growth factor-beta (TGFβ)-1 and TGFβ2, significantly increased during radiotherapy compared to the levels observed before radiotherapy.
CONCLUSION: The present study revealed the influence of hormonal, and of radiation therapy on the proinflammatory cytokine levels in the sera of patients with PCa. In addition, neoadjuvant hormonal therapy amplified the radiation-induced alteration of serum cytokines. Further studies to characterize the mechanism underlying a radiation- or hormone-induced inflammatory state are, therefore, necessary.

Hara R, Kikuchi H, Setoguchi T, et al.
Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors.
Anticancer Res. 2015; 35(6):3289-98 [PubMed] Related Publications
AIM: We sought to address the mechanisms by which intestinal gastrointestinal stromal tumors (GIST) have a markedly higher risk of recurrence than gastric GISTs.
MATERIALS AND METHODS: Gene expression levels were compared among six primary gastric, three intestinal and six metastatic liver GISTs using cDNA microarray. Protein levels of Slit homolog 2 (SLIT2) were analyzed by immunohistochemistry in 25 primary gastric and 10 intestinal GIST.
RESULTS: Intestinal GIST had gene expression profiles similar to clinically malignant and metastatic GIST. In gene set-enrichment analysis, the gene sets MITOTIC_CELL CYCLE and NEURON_DIFFERENTIATION were up-regulated and down-regulated, respectively, in intestinal GIST compared to gastric GIST. High-risk gastric GISTs and intestinal GIST, expressed similar levels of SLIT2 protein, which were lower than those of low-risk gastric GISTs.
CONCLUSION: The gene-expression profile of intestinal GISTs was similar to that of metastatic liver GISTs. Besides higher proliferative activity, down-regulation of SLIT2 might be involved in clinically malignant phenotypes of intestinal GIST.

Kuramitsu Y, Tanaka I, Wang Y, et al.
Inflammation-Related Tumor Progression in Murine Fibrosarcoma Exhibited Over-expression of Sex-determining Region Y-box 2 (Sox2) Compared to Parental Regressor Cells.
Anticancer Res. 2015; 35(6):3217-21 [PubMed] Related Publications
BACKGROUND/AIM: Tumor progression is one of the most serious issues to overcome cancer disease. As a model of inflammation-induced tumor progression, we used the regressive murine fibrosarcoma cell clone QR-32 and the progressive malignant clone QRsP-11, that was derived from QR-32. Heat shock protein beta-1 (Hspb1) is a molecular chaperone. Hspb1 plays roles in not only cell protection but also chemo-resistance, tumorigenicity and protection from apoptosis. In a recent study, we showed that Hspb1 was up-regulated in QRsP-11 compared to QR-32.
MATERIALS AND METHODS: We compared the expression levels of Hspb1, Hsf1 and Sox2 in QR-32 and QRsP-11 cells by means of western blotting.
RESULTS: Hsf1, a transcription factor for Hspb1 was not increased in QRsP-11. Sex determining region Y-box 2 (Sox2) is a transcription factor, reported to interact with Hspb1. Sox2 was up-regulated in QRsP-11 compared to QR-32.
CONCLUSION: These results suggest that Sox2-Hspb1 signaling is a possible pathway responsible to tumor progression of QRsP-11.

Ito T, Hamasaki M, Matsumoto S, et al.
p16/CDKN2A FISH in Differentiation of Diffuse Malignant Peritoneal Mesothelioma From Mesothelial Hyperplasia and Epithelial Ovarian Cancer.
Am J Clin Pathol. 2015; 143(6):830-8 [PubMed] Related Publications
OBJECTIVES: It can be difficult to differentiate diffuse malignant peritoneal mesothelioma (DMPM) from reactive mesothelial hyperplasia (RMH) or peritoneal dissemination of gynecologic malignancies, such as epithelial ovarian cancer (EOC), which cause a large amount of ascites. Detection of the homozygous deletion of p16/CDKN2A (p16) by fluorescence in situ hybridization (FISH) is an effective adjunct in the diagnosis of malignant pleural mesothelioma. The aim of this study was to investigate the ability of the p16 FISH assay to differentiate DMPM from RMH and EOC.
METHODS: p16 FISH was performed in 28 DMPMs (successful in 19), 30 RMHs, and 40 EOC cases. The cutoff values of p16 FISH were more than 10% for homozygous deletion and more than 40% for heterozygous deletion.
RESULTS: According to the above criteria, nine (47.4%) of 19 successful DMPM cases were homozygous deletion positive, and three (15.8%) of 19 were heterozygous deletion positive, whereas all RMH cases were negative for the p16 deletion. In all four major histologic subtypes of EOC, neither p16 homozygous nor heterozygous deletions were detected. To differentiate DMPM from RMH or EOC, the sensitivity of the p16 homozygous deletion was 32% (9/28), and the specificity was 100%.
CONCLUSIONS: Our study suggests that p16 FISH analysis is useful in differentiating DMPM from RMH and EOC when homozygous deletion is detected.

Kazama S, Kitayama J, Hiyoshi M, et al.
Phospholipase A2 Group III and Group X Have Opposing Associations with Prognosis in Colorectal Cancer.
Anticancer Res. 2015; 35(5):2983-90 [PubMed] Related Publications
BACKGROUND: Although secretory phospholipase A2 (sPLA2) has been shown to be involved in various biological processes, its specific roles in sub-types of cancer development remain to be elucidated.
MATERIALS AND METHODS: We examined the expression of sPLA2 group III (GIII) in 142 patients with colorectal cancer using immunohistochemistry, and its correlation with clinicopathological features and outcomes. In addition, we examined the co-expression of sPLA2GIII and sPLA2GX using serial tissue sections to clarify the roles of both proteins in colorectal carcinogenesis.
RESULTS: In 66 cases, diffuse staining of sPLA2GIII was seen; this was defined as the group with high expression. High expression was associated with a significantly higher rate of lymph node metastasis (p=0.02) and poorer survival (p=0.03) compared with low expression. Patients with low sPLA2GIII and high sPLA2GX expression had a significantly higher survival rate than those with high sPLA2GIII and low sPLA2GX expression (p=0.038).
CONCLUSION: sPLA2GIII expression may be used as a risk factor for lymph node metastasis and a prognostic marker in colorectal cancer. In addition, sPLA2GIII and sPLA2GX may play opposing roles in colorectal carcinogenesis.

Nabeki B, Ishigami S, Uchikado Y, et al.
Interleukin-32 expression and Treg infiltration in esophageal squamous cell carcinoma.
Anticancer Res. 2015; 35(5):2941-7 [PubMed] Related Publications
BACKGROUND/AIM: Interleukin-32 (IL32) has been newly-identified as a proinflammatory cytokine. In the present study, we aimed to clarify the clinical role of IL32-positive cells in esophageal squamous cell cancer (ESCC) and regulatory T-cell (Treg) infiltration in the stroma. A total of 179 patients with ESCC who underwent surgical resection from 1990 to 2004 were eligible for this study. The expression of IL32 and the degree of stromal infiltration by Tregs were examined simultaneously. The association between each factor and the clinicopathological features was analyzed. Sixty and 74 out of 179 patients with ESCC were regarded as having IL32-positive tumors and many Tregs (high-Treg group), respectively. The IL32-positive and high-Treg groups had significantly deeper tumor invasion than did the IL32-negative and low-Treg groups (p<0.05, for both groups). The multivariate analysis indicated that a combination of IL32 expression and presence of Tregs was one of the poor independent factors (p<0.05). IL32 expression and Treg infiltration in ESCC play an important synergistic role in tumor growth and invasion. The combination of IL32 positivity and degree of infiltration of Treg is a useful prognostic marker in ESCC.

Ausawasamrit A, Itthiwarapornkul N, Chaotham C, et al.
Lupalbigenin from Derris scandens Sensitizes Detachment-induced Cell Death in Human Lung Cancer Cells.
Anticancer Res. 2015; 35(5):2827-34 [PubMed] Related Publications
BACKGROUND/AIM: The ability of cancer cells to resist to anoikis has been shown to augment cancer cell metastasis in many cancers. In search for potential substances for anti-metastatic approaches, this study aimed to investigate anoikis-sensitizing activity of lupalbigenin, extracted from Derris scandens.
MATERIALS AND METHODS: Human lung cancer cells were treated with non-cytotoxic concentrations of lupalbigenin in a detachment condition. Anoikis was evaluated at various time points using MTT viability assays. The effect of lupalbigenin on anchorage-independent growth was performed by soft-agar assay. The survival signaling proteins, as well as regulatory proteins of apoptosis and metastasis, were examined by western blot analysis.
RESULTS: Lupalbigenin treatment significantly down-regulated survival proteins, including protein kinase B (pAKT/AKT) and extracellular signal-regulated kinase (pERK/ERK), as well as anti-apoptotic protein B-cell lymphoma 2 (BCL-2), resulting in the enhancement of the cellular response to anoikis and the decrease of growth and survival in an anchorage-independent condition.
CONCLUSION: Lupalbigenin sensitizes detachment-induced cell death in human lung cancer cell through down-regulation of pro-survival proteins.

Kang YH, Kim D, Jin EJ
Down-regulation of Phospholipase D Stimulates Death of Lung Cancer Cells Involving Up-regulation of the Long ncRNA ANRIL.
Anticancer Res. 2015; 35(5):2795-803 [PubMed] Related Publications
Dysregulation of phospholipase D (PLD) has been found in several types of human cancer, but the underlying regulatory mechanism remains poorly-understood. Herein we found PLD inhibition in human H460 lung cancer cells has anti-tumorigenic effects such as stimulation of apoptosis and autophagy. In the present study, in order to identify the responsible key regulator of these anti-tumorigenic effects of PLD inhibition, we analyzed the expression levels of 90 long non-coding RNAs (lncRNAs). Among them, the expression level of antisense noncoding RNA in the INK4 locus (ANRIL) was increased up to 13.6-fold by PLD inhibition in H460 human lung cancer cells. Moreover, knockdown of ANRIL using its specific small-interfering RNA significantly suppressed PLD inhibition-induced apoptosis. Collectively, our findings showed that ANRIL is an lncRNA responsible in anti-tumorigenesis caused by PLD inhibition and combined incorporation of ANRIL into PLD inhibition-induced anti-tumorigenic signaling network could be a new effective therapeutic approach for controlling lung cancer.

Kang S, Chae YS, Lee SJ, et al.
Aquaporin 3 Expression Predicts Survival in Patients with HER2-positive Early Breast Cancer.
Anticancer Res. 2015; 35(5):2775-82 [PubMed] Related Publications
BACKGROUND/AIM: Recent studies have revealed aquaporins (AQPs) as targets for novel anti-tumor therapy since they are likely to play a role in carcinogenesis, tumor progression and invasion. Accordingly, we analyzed the prognostic impact of AQP3 expression and polymorphisms in a number of patients with early breast cancer (EBC).
MATERIALS AND METHODS: AQP3 expression was investigated on the basis of the immunohistochemistry of tissue microarray specimens from 447 EBC patients who underwent surgery between 2003 and 2008. We scored the staining intensity (0 through 3) and percentage of positive tumor cells (0 through 4); the staining score was defined as sum of these scores used to categorize the AQP3 expression as negative (0 through 2), weak (3 through 5) or strong (6 or more). For AQP3 polymorphisms, seven single nucleotide polymorphisms (SNPs) (rs10813981, rs34391490, rs2228332, rs2227285, rs591810, rs17553719 and rs3860987) were selected using in silico analysis and genotyped using the Sequenom MassARRAY.
RESULTS: A total of 180 (40.3%) patients were identified as AQP3-positive (staining score >2), including 86 (19.2%) cases of strong expression (stating score >5). In a univariate analysis, AQP3 expression was significantly associated with survival for the patients with HER2-over-expressing EBC. Moreover, a multivariate survival analysis revealed that AQP3 expression was an independent prognostic marker of disease-free survival (DFS): hazard ratio (HR)=3.137, 95% confidence interval (CI)=1.079-9.125, p=0.036; distant DFS (DDFS): HR=2.784, 95%CI=0.921-8.414, p=0.070, for the HER2-over-expressing EBC patients. Meanwhile, none of selected AQP3 polymorphisms were related to AQP3 expression in tumor tissue or survival in the current study.
CONCLUSION: AQP3 expression in tumor tissue may be considered as a potential prognostic marker in patients with HER2-over-expressing EBC after curative surgery.

Park GB, Hur DY, Kim D
Combining CAL-101 with Celecoxib Enhances Apoptosis of EBV-transformed B-Cells Through MAPK-induced ER Stress.
Anticancer Res. 2015; 35(5):2699-708 [PubMed] Related Publications
BACKGROUND: Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells.
MATERIALS AND METHODS: The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting.
RESULTS: Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib.
CONCLUSION: The apoptosis of EBV-transformed B-cells and NHL cells caused by CAL-101 and celecoxib might be related to inhibiting the RHOA/ROCK pathway and might also be associated with mitogen-activated protein kinase (MAPK)-mediated ER stress.

Ohashi T, Yoshimasu T, Oura S, et al.
Class III Beta-tubulin Expression in Non-small Cell Lung Cancer: A Predictive Factor for Paclitaxel Response.
Anticancer Res. 2015; 35(5):2669-74 [PubMed] Related Publications
AIM: In order to clarify whether class III beta-tubulin (TUBB3) is a predictive marker for paclitaxel (PTX) chemotherapy, chemosensitivity was examined using an in vitro drug sensitivity assay.
PATIENTS AND METHODS: Twelve specimens from non-small cell lung cancer (NSCLC) patients were obtained for dose-response curve analysis and measurement of the half-maximal effective dose (ED50) of PTX using the histoculture drug response assay (HDRA). Forty-one specimens were evaluated using the HDRA and the inhibition ratio (IR) at a concentration of 25 μg/ml PTX (IR25) was measured. TUBB3 expression was evaluated by H-score in immunohistochemical staining.
RESULTS: The ED50 of PTX was 24.5 ± 8.06 μg/ml. The median H-score was significantly higher (p=0.0076) in the high effective dose (HE)-group (ED50 >25 μg/ml) than in the low effective (LE)-group (ED50 ≤ 25 μg/ml). The mean IR25 was 53.8 ± 26.6%. The median H-score for the high-inhibition ratio (HI)-group (IR25 >50%) was significantly higher (p=0.0337) than the low-inhibition ratio (LI)-group (IR25 ≤ 50%).
CONCLUSION: High TUBB3 expression in NSCLC appeared to correlate with lower PTX sensitivity.

Jia W, Zhu J, Martin TA, et al.
Epithelial-mesenchymal Transition (EMT) Markers in Human Pituitary Adenomas Indicate a Clinical Course.
Anticancer Res. 2015; 35(5):2635-43 [PubMed] Related Publications
BACKGROUND/AIM: Pituitary adenomas are brain tumors with invasive properties. Epithelial-mesenchymal-transition (EMT) is a cellular process linked to the transformation to an aggressive cancer phenotype. In the present study, we investigated the expression of a panel of EMT markers, namely E-cadherin, N-cadherin, SLUG, SNA1 and TWIST in a cohort of human pituitary adenomas.
MATERIALS AND METHODS: Fresh-frozen human pituitary tumors (n=95) were collected immediately after surgery for histology. Gene transcripts of the EMT markers were quantified using quantitative-polymerase chain reaction (PCR) analysis. Levels of expression were analyzed against clinical, pathological, invasion and endocrine functions.
RESULTS: Levels of E-cadherin and N-cadherin had a negative and positive correlation with the appearance of intratumoral cystic lesions of pituitary tumors. E-cadherin and TWIST were associated with tumor size and staging. There was a significant link between SLUG/TWIST and the destruction of the sella fosa bones (p<0.030). EMT markers also showed links with the endocrine functions of pituitary tumors. In pituitary tumors, SLUG and SNA1 had significant correlation with N-cadherin.
CONCLUSION: EMT markers are significant indicators of the appearance of cystic lesions, tumor progression, bone destruction and endocrine functions. These markers are valuable biomarkers in assessing the clinical course of pituitary adenomas.

Chong GO, Jeon HS, Han HS, et al.
Differential MicroRNA Expression Profiles in Primary and Recurrent Epithelial Ovarian Cancer.
Anticancer Res. 2015; 35(5):2611-7 [PubMed] Related Publications
BACKGROUND/AIM: Although it has been shown that microRNAs influence messenger RNA post-transcriptional control and can attribute to human tumorigenesis, little is known regarading the differences in microRNA expression between primary and recurrent epithelial ovarian cancer (EOC). The purpose of the present study was to assess the differential expression of microRNA between primary and recurrent EOC.
MATERIALS AND METHODS: Between September 2013 and May 2014, the expression of microRNAs in tumor tissues from 5 primary and 5 recurrent EOC cases were analyzed. The tumor histotype was serous cystadenocarcinoma in all patients. Total RNA was extracted from tumor samples and microRNA expression levels were measured by performing microarray analysis. Expression levels were compared between the two groups and analyzed statistically.
RESULTS: Several microRNAs were differentially expressed in recurrent EOC compared to primary EOC, including 18 under-expressed microRNAs and 33 over-expressed microRNAs among 6,658 human microRNAs. Four specific microRNAs were the most significantly over-expressed in recurrent EOC: miR-551b, miR-19b, miR-196b and miR-3198. Moreover, 4 specific microRNAs were the most significantly down-expressed in recurrent EOC: miR-8084, miR-3201, miR-3613 and miR-7515.
CONCLUSION: Based on our data, dysregulation of microRNA expression was associated with the recurrence of EOC. Moreover, significantly over- and down-regulated microRNAs can be useful biomarkers for the prediction of recurrence in EOC.

Oh S, Ju JH, Yang W, et al.
EGFR negates the proliferative effect of oncogenic HER2 in MDA-MB-231 cells.
Arch Biochem Biophys. 2015; 575:69-76 [PubMed] Related Publications
Members of the EGFR family are potent mediators of normal cell growth and development. HER2 possesses an active tyrosine kinase domain, but no direct ligand has been identified. To investigate the differential effect of HER2 in breast cell lines, HER2 was overexpressed in MCF-10A, MCF7 and MDA-MB-231 cells. HER2 overexpression promoted proliferation, survival and migration in MCF-10A and MCF-7 cells. No significant differences were seen in proliferation, survival or migration between MDA-MB-231 vec and HER2 cells. The activity of downstream HER2 proteins increased in MCF-10A HER2 and MCF-7 HER2 cells but not in MDA-MB-231 HER2 cells. Exogenously expressed HER2 failed to associate with EGFR or HER3 in MDA-MB-231 cells, while overexpression of HER2 enhanced HER family dimerization in MCF-10A and MCF-7 cells.

Kwan ML, Bernard PS, Kroenke CH, et al.
Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
BACKGROUND: Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown.
METHODS: We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided.
RESULTS: Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes.
CONCLUSIONS: History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.

Yuhas Y, Ashkenazi S, Berent E, Weizman A
Immunomodulatory activity of ketamine in human astroglial A172 cells: Possible relevance to its rapid antidepressant activity.
J Neuroimmunol. 2015; 282:33-8 [PubMed] Related Publications
To determine if the immunomodulatory effect of ketamine is relevant to its rapid antidepressant activity, cultured human astroglial cells were incubated with ketamine, cytokine mix, or both. At 24h, ketamine dose-dependently (100-500 μM) decreased IL-6 and TNFα production and gene expression and, at clinically relevant concentration (100 μM), augmented IL-β release and gene expression in both unstimulated and cytokine-stimulated cells. In unstimulated cells, ketamine also increased IL-8 production and mRNA expression. The reduction in IL-6 mRNA was significant within 1h in unstimulated cells and at 4h after stimulation. Ketamine suppressed the production of the only established depression-relevant proinflammatory cytokines, IL-6 and TNFα.

Wang Y, Fan X, Li H, et al.
Tumor border sharpness correlates with HLA-G expression in low-grade gliomas.
J Neuroimmunol. 2015; 282:1-6 [PubMed] Related Publications
Human leukocyte antigen-G (HLA-G) is a tumor microenvironment molecule that is involved in the escape of cancerous tumors from host immune recognition and destruction. This study investigated the potential relationship between HLA-G expression levels and the sharpness of low-grade glioma tumor borders in magnetic resonance images. Preoperative T2-weighted images from 72 patients were retrospectively examined by manually segmenting the hyperintensive tumor areas and subsequently registering them to a standard brain template. Then, the intensity of the voxels inside the tumor border (tumor voxels) was compared with that of the voxels outside the tumor border (paratumor voxels). The radiologic sharpness of a tumor was defined as the mean ratio of the intensity of the tumor voxels to the intensity of the paratumor voxels. Tumors with high HLA-G expression were associated with larger tumors and lower mean hyperintensive contrast. These findings suggest that tumors with blurred boundaries may be those prone to diffuse invasion. Additionally, patients with tumors having high HLA-G expression were less likely to have undergone complete resections. Thus, this study is the first to identify an association between HLA-G expression and the radiologic morphology of the tumor border, and may further our understanding of the role of the HLA gene in immune escape in patients with low-grade gliomas.

Zhou F, Huang X, Zhang Z, et al.
Functional polymorphisms of ITGB1 are associated with clinical outcome of Chinese patients with resected colorectal cancer.
Cancer Chemother Pharmacol. 2015; 75(6):1207-15 [PubMed] Related Publications
PURPOSE: Integrin β1 (ITGB1) has been recognized to play a major role in tumor growth, invasion and metastasis. However, effects of single-nucleotide polymorphisms (SNPs) in ITGB1 gene on the prognosis of patients with colorectal cancer (CRC) have not been reported.
METHODS: A total of 372 patients with resected colorectal adenocarcinoma were enrolled in our study. Three functional SNPs (rs2230395, rs1187075 and rs1187076) in ITGB1 were selected and genotyped using the Sequenom iPLEX genotyping system.
RESULTS: We identified two SNPs (rs2230395 and rs1187075) in ITGB1 gene to be significantly associated with CRC overall survival (OS). Compared with the homozygous wild-type (AA) and heterozygous variant (AC), rs2230395 homozygous variant (CC) conferred a 1.55-fold (95 % CI 1.00-2.41, P = 0.049) increased risk of death. Similar result was obtained for homozygous variant (AA) in rs1187075 with a 1.62-fold (95 % CI 1.08-2.42, P = 0.020). In stratified analysis, this association in rs2230395 remained to be significant in patients receiving chemotherapy, but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival in subgroups stratified by rs2230395 and rs1187075 genotypes. We found that chemotherapy resulted in a significantly better OS in patients with the homozygous wild-type (WW) or heterozygous variant (WV) genotype in both rs2230395 and rs1187075 when compared with patients with homozygous variant (VV) genotype.
CONCLUSIONS: Our data suggest that ITGB1 SNPs might be a prognostic biomarker for CRC patients, especially in those receiving chemotherapy. Our findings warrant validation in larger independent populations.

Kato M, Muromoto R, Togi S, et al.
PML suppresses IL-6-induced STAT3 activation by interfering with STAT3 and HDAC3 interaction.
Biochem Biophys Res Commun. 2015; 461(2):366-71 [PubMed] Related Publications
The promyelocytic leukemia protein PML acts as a tumor suppressor by forming transcription-regulatory complexes with a variety of repressor proteins. In the present study, we found that endogenous PML suppresses interleukin (IL)-6-induced gene expression as well as phosphorylation and transcriptional activation of STAT3 in hepatoma cells. We also found that PML-mediated suppression of IL-6-induced STAT3 activation by disrupting interactions between STAT3 and HDAC3. These results indicate that PML modulates IL-6-induced STAT3 activation and hepatoma cell growth by interacting with HDAC3.

Shibasaki Y, Seki Y, Tanaka T, et al.
The association of level of reduction of Wilms' tumor gene 1 mRNA transcript in bone marrow and outcome in acute myeloid leukemia patients.
Leuk Res. 2015; 39(6):667-71 [PubMed] Related Publications
We focused on the level of reduction of Wilms' tumor gene 1 (WT1) mRNA in bone marrow as minimal residual disease during chemotherapies in adult acute myeloid leukemia (AML) patients. Forty-eight patients were enrolled in this study. Log levels of reduction of WT1 mRNA transcript after induction therapy compared with those at diagnosis were associated with disease-free survival (DFS) (P=0.0066) and overall survival (OS) (P=0.0074) in patients who achieved complete remission. Also log levels of reduction of WT1 mRNA transcript after final consolidation therapy compared with those at diagnosis were associated with DFS (P=0.015) and OS (P=0.012). By multivariate analysis, log levels of reduction of WT1 mRNA transcript after induction therapy and after final consolidation therapy compared with those at diagnosis were extracted as risk factors for outcome. Our results suggest that early and deep reduction of tumor burden may be important for the outcome of AML patients. In addition, it may be useful for the decision to proceed with allogeneic SCT as post-remission therapy.

Pilli VS, Gupta K, Kotha BP, Aradhyam GK
Snail-mediated Cripto-1 repression regulates the cell cycle and epithelial-mesenchymal transition-related gene expression.
FEBS Lett. 2015; 589(11):1249-56 [PubMed] Related Publications
Transcription factor Snail mediates epithelial to mesenchymal transitions (EMT) by coordinate repression of epithelial markers, facilitating mass cell movement during germ layer formation. Aberrant reprogramming in its signaling pathways causes metastatic cancer. Snail's involvement in "fate-changing" decisions is however not understood. Cripto-1 shares a common temporal expression pattern with Snail during development. While Cripto-1 is required for mammary morphogenesis and hematopoietic stem cell renewal, its unregulated expression causes metastatic cancers. Therefore, we suspected that Snail regulates the expression of Cripto-1 controlling decisions such as motility, transformation and differentiation. We demonstrate that Snail represses Cripto-1 gene by direct transcriptional interaction and propose a novel mechanism by which it co-ordinately regulates cell fate decisions during development and could be causal of cancers.

Wang GZ, Cheng X, Li XC, et al.
Tobacco smoke induces production of chemokine CCL20 to promote lung cancer.
Cancer Lett. 2015; 363(1):60-70 [PubMed] Related Publications
Tobacco kills nearly 6 million people each year, and 90% of the annual 1.59 million lung cancer deaths worldwide are caused by cigarette smoke. Clinically, a long latency is required for individuals to develop lung cancer since they were first exposed to smoking. In this study, we aimed to identify clinical relevant inflammatory factors that are critical for carcinogenesis by treating normal human lung epithelial cells with tobacco carcinogen nicotine-derived nitrosaminoketone (NNK) for a long period (60 days) and systematic screening in 84 cytokines/chemokines. We found that a chemokine CCL20 was significantly up-regulated by NNK, and in 78/173 (45.1%) patients the expression of CCL20 was higher in tumor samples than their adjacent normal lung tissues. Interestingly, CCL20 was up-regulated in 48/92 (52.2%) smoker and 29/78 (37.2%) nonsmoker patients (p = 0.05), and high CCL20 was associated with poor prognosis. NNK induced the production of CCL20, which promoted lung cancer cell proliferation and migration. In addition, an anti-inflammation drug, dexamethasone, inhibited NNK-induced CCL20 production and suppressed lung cancer in vitro and in vivo. These results indicate that CCL20 is crucial for tobacco smoke-caused lung cancer, and anti-CCL20 could be a rational approach to fight against this deadly disease.

Kreuzinger C, Gamperl M, Wolf A, et al.
Molecular characterization of 7 new established cell lines from high grade serous ovarian cancer.
Cancer Lett. 2015; 362(2):218-28 [PubMed] Related Publications
Cancer cell lines are good in vitro models to study molecular mechanisms underlying chemoresistance and cancer recurrence. Recent works have demonstrated that most of the available ovarian cancer cell lines are most unlikely high grade serous (HGSOC), the major type of epithelial ovarian cancer. We aimed at establishing well characterized HGSOC cell lines, which can be used as optimal models for ovarian cancer research. We successfully established seven cell lines from HGSOC and provided the major genomic alterations and the transcriptomic landscapes of them. They exhibited different gene expression patterns in the key pathways involved in cancer resistance. Each cell line harbored a unique TP53 mutation as their corresponding tumors and expressed cytokeratins 8/18/19 and EpCAM. Two matched lines were established from the same patient, one at diagnosis and being sensitive to carboplatin and the other during chemotherapy and being resistant. Two cell lines presented respective BRCA1 and BRCA2 mutations. To conclude, we have established seven cell lines and well characterized them at genomic and transcriptomic levels. They are optimal models to investigate the molecular mechanisms underlying the progression, chemo resistance and recurrence of HGSOC.

Kato H, Sekine Y, Furuya Y, et al.
Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor.
Biochem Biophys Res Commun. 2015; 461(1):115-21 [PubMed] Related Publications
Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment.

Kravtsova-Ivantsiv Y, Shomer I, Cohen-Kaplan V, et al.
KPC1-mediated ubiquitination and proteasomal processing of NF-κB1 p105 to p50 restricts tumor growth.
Cell. 2015; 161(2):333-47 [PubMed] Related Publications
NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.

Sakai Y, Yamamori T, Yasui H, Inanami O
Downregulation of the DNA repair enzyme apurinic/apyrimidinic endonuclease 1 stimulates transforming growth factor-β1 production and promotes actin rearrangement.
Biochem Biophys Res Commun. 2015; 461(1):35-41 [PubMed] Related Publications
The DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) plays a central role in base excision repair and functions as a reductive activator of various transcription factors. Multiple other functionalities have been ascribed to APE1 in addition to these major functions. A recent study showed that APE1 knockdown upregulated the expression of a set of genes related to extracellular matrix (ECM) production, indicating an additional novel biological role for this enzyme. Based on this finding, we have investigated the effect of APE1 downregulation on ECM-related gene expression and its biological consequences. Endogenous APE1 expression was downregulated in human cervical carcinoma HeLa cells and human lung carcinoma A549 cells using siRNA. When the expression of six ECM-related genes (TGFB1, LAMC1, FN1, COL1A1, COL3A1, and COL4A1) was evaluated, we found that APE1 knockdown upregulated the expression of TGFB1 in both cell lines. APE1 downregulation promoted actin rearrangement, inducing F-actin accumulation in HeLa cells and the dissipation of stress fibers in A549 cells. We also discovered that APE1 knockdown enhanced cellular motility in A549 cells, which was suppressed by the inhibition of transforming growth factor (TGF)-β1 signaling. These results suggested that APE1 controls the organization of actin cytoskeleton through the regulation of TGF-β1 expression, providing novel insights into the biological significance of APE1.

Sugita S, Ito K, Yamashiro Y, et al.
EGFR-independent autophagy induction with gefitinib and enhancement of its cytotoxic effect by targeting autophagy with clarithromycin in non-small cell lung cancer cells.
Biochem Biophys Res Commun. 2015; 461(1):28-34 [PubMed] Related Publications
Gefitinib (GEF), an inhibitor for EGFR tyrosine kinase, potently induces autophagy in non-small cell lung cancer (NSCLC) cell lines such as PC-9 cells expressing constitutively activated EGFR kinase by EGFR gene mutation as well as A549 and H226 cells with wild-type EGFR. Unexpectedly, GEF-induced autophagy was also observed in non-NSCLC cells such as murine embryonic fibroblasts (MEF) and leukemia cell lines K562 and HL-60 without EGFR expression. Knockout of EGFR gene in A549 cells by CRISPR/Cas9 system still exhibited autophagy induction after treatment with GEF, indicating that the autophagy induction by GEF is not mediated through inhibiting EGFR kinase activity. Combined treatment with GEF and clarithromycin (CAM), a macrolide antibiotic having the effect of inhibiting autophagy flux, enhances the cytotoxic effect in NSCLC cell lines, although treatment with CAM alone exhibits no cytotoxicity. GEF treatment induced up-regulation of endoplasmic reticulum (ER)-stress related genes such as CHOP/GADD153 and GRP78. Knockdown of CHOP in PC-9 cells and Chop-knockout MEF both exhibited less sensitivity to GEF than controls. Addition of CAM in culture medium resulted in further pronounced GEF-induced ER stress loading, while CAM alone exhibited no effect. These data suggest that GEF-induced autophagy functions as cytoprotective and indicates the potential therapeutic possibility of using CAM for GEF therapy. Furthermore, it is suggested that the intracellular signaling for autophagy initiation in response to GEF can be completely dissociated from EGFR, but unknown target molecule(s) of GEF for autophagy induction might exist.

Smith MJ
Germline and somatic mutations in meningiomas.
Cancer Genet. 2015; 208(4):107-14 [PubMed] Related Publications
Meningiomas arise from the arachnoid layer of the meninges that surround the brain and spine. They account for over one third of all primary central nervous system tumors in adults and confer a significant risk of location-dependent morbidity due to compression or displacement. A significant increase in risk of meningiomas is associated with neurofibromatosis type 2 (NF2) disease through mutation of the NF2 gene. In addition, approximately 5% of individuals with schwannomatosis disease develop meningiomas, through mutation of the SWI/SNF chromatin remodeling complex subunit, SMARCB1. Recently, a second SWI/SNF complex subunit, SMARCE1, was identified as a cause of clear cell meningiomas, indicating a wider role for this complex in meningioma disease. The sonic hedgehog (SHH)-GLI1 signaling pathway gene, SUFU, has also been identified as the cause of hereditary multiple meningiomas in a large Finnish family. The recent identification of somatic mutations in components of the SHH-GLI1 and AKT1-MTOR signaling pathways indicates the potential for cross talk of these pathways in the development of meningiomas. This review describes the known meningioma predisposition genes and their links to the recently identified somatic mutations.

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