ADRM1

Gene Summary

Gene:ADRM1; adhesion regulating molecule 1
Aliases: ARM1, ARM-1, GP110
Location:20q13.33
Summary:This gene encodes a member of the adhesion regulating molecule 1 protein family. The encoded protein is a component of the proteasome where it acts as a ubiquitin receptor and recruits the deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L5. Increased levels of the encoded protein are associated with increased cell adhesion, which is likely an indirect effect of this intracellular protein. Dysregulation of this gene has been implicated in carcinogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:proteasomal ubiquitin receptor ADRM1
HPRD
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 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.

  • Membrane Glycoproteins
  • Cell Movement
  • Gene Amplification
  • Up-Regulation
  • Transfection
  • Neoplasm Metastasis
  • Tioguanine
  • Antineoplastic Agents
  • Colorectal Cancer
  • Cell Adhesion
  • Lymphatic Metastasis
  • Gemcitabine
  • Cancer DNA
  • Cystadenocarcinoma, Serous
  • Transcription Factors
  • Gene Knockdown Techniques
  • Trans-Activators
  • RTPCR
  • Cell Cycle Proteins
  • VEGFA
  • Reproducibility of Results
  • Cancer Gene Expression Regulation
  • Ovarian Cancer
  • RECK
  • Chromosome 20
  • Staging
  • Messenger RNA
  • Base Sequence
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins
  • Neoplasm Proteins
  • Proteasome Endopeptidase Complex
  • Integrins
  • ADRM1
  • RNA Interference
  • Oligonucleotide Array Sequence Analysis
  • Gene Expression Profiling
  • Molecular Sequence Data
  • Deoxycytidine
  • Gene Expression
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

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: ADRM1 (cancer-related)

Zhang F, Li C, Liu H, et al.
The functional proteomics analysis of VEGF-treated human epithelial ovarian cancer cells.
Tumour Biol. 2014; 35(12):12379-87 [PubMed] Related Publications
Vascular endothelial growth factor (VEGF), one of the most important angiogenic factor, can impact the tumor cell proliferation and invasion, but the mechanism remains unclear. This study is to investigate the key proteins which may play an important role in the VEGF-induced progress of ovarian cancer cells. The total protein from HO-8910 cells was separated by two-dimensional electrophoresis (2-DE), and differentially expressed proteins were identified by matrix-assisted laser desorption and ionization time-of-flight tandem mass spectrometry (MALDI-TOF MS) and PDQuest image analysis software. Furthermore, real-time PCR, Western blot, and immunocytochemistry were also used to confirm different expression levels of differential proteins. Morphological changes and invasion capability were evaluated by electron microscope and Matrigel invasion assay, respectively. The highly reproducible and well-resolved 2-DE patterns of both HO-8910/VEGF and HO-8910 cells were acquired. A total of 17 expressed differential proteins were identified, 8 proteins were upregulated (ACTB, TIM, PDIA3, PDIA1, DCTN2, KIC17, SIAS, and KIC10) and 9 downregulated (KIC18, GRP78, CAPG, PPIA, ROA2, LMNA, EZRI, ADRM1, and ENOA). Ultrastructure of VEGF-treated group showed more malignant characteristic compared with control group, an obvious increase in the number of cells penetrating the Matrigel membrane in VEGF-treated group (P < 0.05). These results suggested that VEGF could impact ovarian cancer's malignant progression by regulating expression of associated proteins.

Ulrich CM, Rankin C, Toriola AT, et al.
Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among patients with stage II or III rectal cancer (INT-0144; SWOG 9304).
Cancer. 2014; 120(21):3329-37 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recurrence and toxicity occur commonly among patients with rectal cancer who are treated with 5-fluorouracil (5-FU). The authors hypothesized that genetic variation in folate-metabolizing genes could play a role in interindividual variability. The objective of the current study was to evaluate the associations between genetic variants in folate-metabolizing genes and clinical outcomes among patients with rectal cancer treated with 5-FU.
METHODS: The authors investigated 8 functionally significant polymorphisms in 6 genes (methylenetetrahydrofolate reductase [MTHFR] [C677T, A1298C], SLC19A1 [G80A], SHMT1 [C1420T], dihydrofolate reductase [DHFR] [Del19bp], TS 1494del,and TSER) involved in folate metabolism in 745 patients with TNM stage II or III rectal cancer enrolled in a phase 3 adjuvant clinical trial of 3 regimens of 5-FU and radiotherapy (INT-0144 and SWOG 9304).
RESULTS: There were no statistically significant associations noted between polymorphisms in any of the genes and overall survival, disease-free survival (DFS), and toxicity in the overall analyses. Nevertheless, there was a trend toward worse DFS among patients with the variant allele of MTHFR C677T compared with wild-type, particularly in treatment arm 2, in which patients with the MTHFR C677T TT genotype had worse overall survival (hazards ratio, 1.76; 95% confidence interval, 1.06-2.93 [P = .03]) and DFS (hazards ratio, 1.84; 95% confidence interval, 1.12-3.03 [P = .02]) compared with those with homozygous wild-type. In addition, there was a trend toward reduced hematological toxicity among patients with variants of SLC19A1 G80A in treatment arm 1 (P for trend, .06) and reduced esophagitis/stomatitis noted among patients with variants of TSER in treatment arm 3 (P for trend, .06).
CONCLUSIONS: Genetic variability in folate-metabolizing enzymes was found to be associated only to a limited degree with clinical outcomes among patients with rectal cancer treated with 5-FU.

Jang SH, Park JW, Kim HR, et al.
ADRM1 gene amplification is a candidate driver for metastatic gastric cancers.
Clin Exp Metastasis. 2014; 31(6):727-33 [PubMed] Related Publications
We searched for candidate target genes in metastatic gastric cancer, using comparative genomic hybridization (CGH) and mRNA expression array analysis of endoscopic biopsy samples collected from 32 patients. Recurrent amplicons included 17q21.2 (36,569,293-37,307,055), 8q24.13-q24.21 (126,357,475-130,159,285), and 20q13.33 (60,211,249-61,382,787). In this paper, we focused on the 1.1-Mb genomic region containing 24 genes in chromosome 20q13.33 (from 60,211,249 to 61,382,787), the third most frequent amplicon that was amplified in three of 32 patients (9.4 %), with log2 tumor/reference ratios ranging from 0.6 to 1.5. Of three genes in the 20q13.33 amplicon, ADRM1 was chosen for functional analyses. ADRM1 knockdown suppressed the proliferation of two human gastric cancer cells, SNU-601 and SNU-216. Overexpression of Adrm1 promoted cell proliferation of conditionally-immortalized, mouse ImSt gastric epithelial cells, with increased S1 phase fraction and decreased expression of p21(Cip1). These results collectively indicate that ADRM1 promoted gastric epithelial cell proliferation by cell cycle progression. Therefore, ADRM1 is a candidate target gene in the chromosome 20q13.33 amplicon that may possibly be linked to development of gastric cancer.

Freytag SO, Stricker H, Lu M, et al.
Prospective randomized phase 2 trial of intensity modulated radiation therapy with or without oncolytic adenovirus-mediated cytotoxic gene therapy in intermediate-risk prostate cancer.
Int J Radiat Oncol Biol Phys. 2014; 89(2):268-76 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer.
METHODS AND MATERIALS: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival.
RESULTS: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer.
CONCLUSIONS: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Karlan BY, Thorpe J, Watabayashi K, et al.
Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women.
Cancer Epidemiol Biomarkers Prev. 2014; 23(7):1383-93 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies.
METHODS: We conducted a randomized controlled pilot trial to estimate surgical PPV of a "2 of 3 tests positive" screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, in women at high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm.
RESULTS: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1 and 11 in Arm 2). On the basis of 12 women with at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2.
CONCLUSIONS: Positive screens were more frequent when HE4 was included in the primary screen.
IMPACT: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.

Anchoori RK, Karanam B, Peng S, et al.
A bis-benzylidine piperidone targeting proteasome ubiquitin receptor RPN13/ADRM1 as a therapy for cancer.
Cancer Cell. 2013; 24(6):791-805 [PubMed] Free Access to Full Article Related Publications
The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of ubiquitin receptor RPN13 in the 19S regulatory particle and inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins. Multiple myeloma (MM) lines, even those resistant to bortezomib, were sensitive to RA190 via endoplasmic reticulum stress-related apoptosis. RA190 stabilized targets of human papillomavirus (HPV) E6 oncoprotein, and preferentially killed HPV-transformed cells. After oral or intraperitoneal dosing of mice, RA190 distributed to plasma and major organs except the brain and inhibited proteasome function in skin and muscle. RA190 administration profoundly reduced growth of MM and ovarian cancer xenografts, and oral RA190 treatment retarded HPV16(+) syngeneic mouse tumor growth, without affecting spontaneous HPV-specific CD8(+) T cell responses, suggesting its therapeutic potential.

Le DT, Lutz E, Uram JN, et al.
Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer.
J Immunother. 2013; 36(7):382-9 [PubMed] Free Access to Full Article Related Publications
Preclinical reports support the concept of synergy between cancer vaccines and immune checkpoint blockade in nonimmunogenic tumors. In particular, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies have been successfully combined with GM-CSF cell-based vaccines (GVAX). Ipilimumab (anti-CTLA-4) has been tested as a single agent in patients with pancreatic ductal adenocarcinoma (PDA) resulting in a delayed response at a dose of 3 mg/kg. Our study evaluated ipilimumab 10 mg/kg (arm 1) and ipilimumab 10 mg/kg + GVAX (arm 2). A total of 30 patients with previously treated advanced PDA were randomized (1:1). Induction doses were administered every 3 weeks for a total of 4 doses followed by maintenance dosing every 12 weeks. Two patients in arm 1 showed evidence of stable disease (7 and 22 wk) but none demonstrated CA19-9 biochemical responses. In contrast, 3 patients in arm 2 had evidence of prolonged disease stabilization (31, 71, and 81 wk) and 7 patients experienced CA19-9 declines. In 2 of these patients, disease stabilization occurred after an initial period of progression. The median overall survival (OS) (3.6 vs. 5.7 mo, hazards ratio: 0.51, P = 0.072) and 1 year OS (7 vs. 27%) favored arm 2. Similar to prior ipilimumab studies, 20% of patients in each arm had grade 3/4 immune-related adverse events. Among patients with OS > 4.3 months, there was an increase in the peak mesothelin-specific T cells (P = 0.014) and enhancement of the T-cell repertoire (P = 0.031). In conclusion, checkpoint blockade in combination with GVAX has the potential for clinical benefit and should be evaluated in a larger study.

Long J, Luo G, Liu C, et al.
Development of a unique mouse model for pancreatic cancer lymphatic metastasis.
Int J Oncol. 2012; 41(5):1662-8 [PubMed] Related Publications
Lymphatic metastasis of pancreatic cancer is a predictor of poor prognosis. However, the molecular mechanisms are largely unknown, thus, making the development of appropriate cell lines and experimental models critically important for future investigations. The purpose of the present study was to establish a 'pancreatic cancer cell and mouse model with high lymphatic metastasis potential' for in-depth study of the underlying mechanisms. The BxPC-3-LN subline, derived from the BxPC-3 human pancreatic cancer cell line, was established through serial passages in nude mice via footpad injections. The subline was able to develop notable lymphatic metastases in 100% of the recipient mice 8 weeks after tumor cell implantation. Compared with the parental BxPC-3 cells, BxPC-3-LN cells were more aggressive, displaying invasive ultrastructure, increased migration and invasion ability, and chemoresistance. Metastasis-related gene alteration including upregulation of MMP14, MMP24, MIF and ADRM1, and downregulation of TGFB2 and ROBO1 were also observed in BxPC-3-LN cells by cDNA microarrays. Thus, the newly selected BxPC-3-LN subline can serve as a unique model for further study of lymphatic metastasis of pancreatic cancer.

Yang X, Miao X, Wen Y, et al.
A possible connection between adhesion regulating molecule 1 overexpression and nuclear factor kappa B activity in hepatocarcinogenesis.
Oncol Rep. 2012; 28(1):283-90 [PubMed] Related Publications
Adhesion regulating molecule 1 (ADRM1), a 19S proteasome cap-associated protein, and nuclear factor kappa B (NF-κB), a protein transcription factor controlling DNA transcription, may play an important role in tumorigenesis. Overexpression of ADRM1 and activation of NF-κB are well-observed in hepatocellular carcinoma (HCC). However, little is known about whether both are functionally connected during hepatocarcinogenesis, and the mechanisms involved. In this study, using laboratory techniques including short hairpin RNA (shRNA)-mediated knockdown, immunohistochemistry (IHC), both semi-quantitative and real-time RT-PCR, western blotting, MTT assay, transwell assay, flow cytometry and electrophoretic mobility shift assay (EMSA), the expression of ADRM1, the effects of ADRM1 knockdown on NF-κB activity, as well as the biological behavior of HCC cells including proliferation, migration, invasion and apoptosis were investigated in the samples from HCC patients and HCC cell lines. We found that both mRNA and protein levels of ADRM1 were increased in HCC tissues and that this increase in ADRM1 expression was parallel to the metastatic potential of HCC cell lines. After ADRM1 knockdown in MHCC97-H cells, the expression of IκB-α was increased and the NF-κB activity was reduced. Furthermore, ADRM1 knockdown inhibited MHCC97-H cell proliferation and induced cell apoptosis, and the migration and invasion of MHCC97-H cells were significantly repressed. These results indicate that there is a clear functional connection between ADRM1 and NF-κB in hepatocarcinogenesis, despite the precise mechanisms through which the two work together still being unknown.

Fridley BL, Batzler A, Li L, et al.
Gene set analysis of purine and pyrimidine antimetabolites cancer therapies.
Pharmacogenet Genomics. 2011; 21(11):701-12 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Responses to therapies, either with regard to toxicities or efficacy, are expected to involve complex relationships of gene products within the same molecular pathway or functional gene set. Therefore, pathways or gene sets, as opposed to single genes, may better reflect the true underlying biology and may be more appropriate units for analysis of pharmacogenomic studies. Application of such methods to pharmacogenomic studies may enable the detection of more subtle effects of multiple genes in the same pathway that may be missed by assessing each gene individually.
METHODS: A gene set analysis of 3821 gene sets is presented assessing the association between basal messenger RNA expression and drug cytotoxicity using ethnically defined human lymphoblastoid cell lines for two classes of drugs: pyrimidines [gemcitabine (dFdC) and arabinoside] and purines [6-thioguanine and 6-mercaptopurine].
RESULTS: The gene set nucleoside-diphosphatase activity was found to be significantly associated with both dFdC and arabinoside, whereas gene set γ-aminobutyric acid catabolic process was associated with dFdC and 6-thioguanine. These gene sets were significantly associated with the phenotype even after adjusting for multiple testing. In addition, five associated gene sets were found in common between the pyrimidines and two gene sets for the purines (3',5'-cyclic-AMP phosphodiesterase activity and γ-aminobutyric acid catabolic process) with a P value of less than 0.0001. Functional validation was attempted with four genes each in gene sets for thiopurine and pyrimidine antimetabolites. All four genes selected from the pyrimidine gene sets (PSME3, CANT1, ENTPD6, ADRM1) were validated, but only one (PDE4D) was validated for the thiopurine gene sets.
CONCLUSION: In summary, results from the gene set analysis of pyrimidine and purine therapies, used often in the treatment of various cancers, provide novel insight into the relationship between genomic variation and drug response.

Fejzo MS, Ginther C, Dering J, et al.
Knockdown of ovarian cancer amplification target ADRM1 leads to downregulation of GIPC1 and upregulation of RECK.
Genes Chromosomes Cancer. 2011; 50(6):434-41 [PubMed] Related Publications
Approximately 25,000 ovarian cancers are diagnosed in the United States annually, and 75% of cases are in the advanced stage when they are largely incurable. There is a critical need for improved early detection tools and development of novel treatments. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. In addition, overexpression of ADRM1 correlated significantly with shorter time to recurrence and overall survival. Herein, array-CGH and microarray expression of ovarian cancer cell lines provides evidence consistent with the primary tumor data that ADRM1 is a 20q13 amplification target. Knockdown of ADRM1 in amplified ovarian cell-line OAW42 results in downregulation of growth factor GIPC1 and upregulation of tumor-suppressor RECK RNA and protein. In our dataset of 141 ovarian primary tumors, ADRM1 overexpression significantly correlates with GIPC1 overexpression. In addition, there is a significant anticorrelation between ADRM1 overexpression and RECK expression. Further research is necessary to determine whether targeting knockdown of ADRM1 in 20q13-amplified ovarian cancers results in growth inhibition and tumor suppression via downstream targets GIPC1 and RECK.

Avvisati G, Lo-Coco F, Paoloni FP, et al.
AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance.
Blood. 2011; 117(18):4716-25 [PubMed] Related Publications
All-trans-retinoic acid (ATRA) has greatly modified the prognosis of acute promyelocytic leukemia; however, the role of maintenance in patients in molecular complete remission after consolidation treatment is still debated. From July 1993 to May 2000, 807 genetically proven newly diagnosed acute promyelocytic leukemia patients received ATRA plus idarubicin as induction, followed by 3 intensive consolidation courses. Thereafter, patients reverse-transcribed polymerase chain reaction-negative for the PML-RARA fusion gene were randomized into 4 arms: oral 6-mercaptopurine and intramuscular methotrexate (arm 1); ATRA alone (arm 2); 3 months of arm1 alternating to 15 days of arm 2 (arm 3); and no further therapy (arm 4). Starting from February 1997, randomization was limited to ATRA-containing arms only (arms 2 and 3). Complete remission was achieved in 761 of 807 (94.3%) patients, and 681 completed the consolidation program. Of these, 664 (97.5%) were evaluated for the PML-RARA fusion gene, and 586 of 646 (90.7%) who tested reverse-transcribed polymerase chain reaction-negative were randomized to maintenance. The event-free survival estimate at 12 years was 68.9% (95% confidence interval, 66.4%-71.4%), and no differences in disease-free survival at 12 years were observed among the maintenance arms.

Lu M, Freytag SO, Stricker H, et al.
Adaptive seamless design for an efficacy trial of replication-competent adenovirus-mediated suicide gene therapy and radiation in newly-diagnosed prostate cancer (ReCAP Trial).
Contemp Clin Trials. 2011; 32(3):453-60 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Cumulative evidence has suggested investigation of the efficacy of Replication-Competent Adenovirus-mediated Suicide Gene Therapy in newly-diagnosed Prostate Cancer (ReCAP). There is a challenge in designing an efficacy trial for newly-diagnosed prostate cancer given its long natural history. The regulatory agency recommended a Phase II trial for safety before conducting the efficacy trial.
EXPERIMENTAL DESIGN: The ReCAP trial is an adaptive seamless, multi-site open-label, randomized Phase II/III trial. Two hundred eighty men will be randomized to receive either replication-competent adenovirus-mediated suicide gene therapy followed by radiation (Arm 1) or radiation alone (Arm 2). Phase II trial component will include the first 21 patients in Arm 1 with complete toxicity through day 90 for safety evaluation. The primary efficacy endpoint is the time free from biochemical and/or clinical failure (FFF). The secondary efficacy endpoints are 2-year prostate biopsies and overall survival. Unequal spaced interim looks are proposed with the adaptive sample-size re-estimation.
RESULTS: This trial has been approved by the FDA for the study therapy investigation and is currently recruiting patients.
CONCLUSIONS: Challenges remain in designing newly-diagnosed prostate cancer trials. Adaptive seamless design is time-saving and a cost-effective design in the development of novel medical therapies, but requires a specified statistical plan in the decision process involved.

Huang Y, Ratovitski EA
Phospho-ΔNp63α/Rpn13-dependent regulation of LKB1 degradation modulates autophagy in cancer cells.
Aging (Albany NY). 2010; 2(12):959-68 [PubMed] Free Access to Full Article Related Publications
Oxidative stress was shown to promote the translocation of Ataxia-telangiectasia mutated (ATM) to cytoplasm and trigger the LKB1-AMPK-tuberin pathway leading to a down-regulation of mTOR and subsequently inducing the programmed cell death II (autophagy). Cisplatin was previously found to induce the ATM-dependent phosphorylation of ΔNp63α in squamous cell carcinoma (SCC) cells. In this study, phosphorylated (p)-ΔNp63α was shown to bind the ATM promoter, to increase the ATM promoter activity and to enhance the ATM cytoplasmic accumulation. P-ΔNp63α protein was further shown to interact with the Rpn13 protein leading to a proteasome-dependent degradation of p-ΔNp63α and thereby protecting LKB1 from the degradation. In SCC cells (with an altered ability to support the ATM-dependent ΔNp63α phosphorylation), the non-phosphorylated ΔNp63α protein failed to form protein complexes with the Rpn13 protein and thereby allowing the latter to bind and target LKB1 into a proteasome-dependent degradation pathway thereby modulating a cisplatin-induced autophagy. We thus suggest that SCC cells sensitive to cisplatin-induced cell death are likely to display a greater ratio of p-ΔNp63α/non-phosphorylated ΔNp63α than cells with the innate resistant/impaired response to a cisplatin-induced cell death. Our data also suggest that the choice made by Rpn13 between p-ΔNp63α or LKB1 to be targeted for degradation is critical for cell death decision made by cancer cells in response to chemotherapy.

Chen W, Hu XT, Shi QL, et al.
Knockdown of the novel proteasome subunit Adrm1 located on the 20q13 amplicon inhibits colorectal cancer cell migration, survival and tumorigenicity.
Oncol Rep. 2009; 21(2):531-7 [PubMed] Related Publications
The novel proteasome subunit Adrm1 located on the 20q13 amplicon was differentially expressed in colorectal cancer by semiquantitative RT-PCR. Adrm1 mRNA was overexpressed in 46.2% (18/39) colorectal cancer tissues compared to their matched normal mucosa and significantly correlated with lymph node metastasis of colorectal cancer (P=0.037). Knockdown of Adrm1 by shRNA in human colon carcinoma RKO cells inhibited their anchorage-independent growth, cell migration as well as cell proliferation through inducing apoptosis and cell cycle arrest at the G1 phase. In addition, stable RNA interference of Adrm1 gene synergistic with 5-Fu treatment suppressed RKO cell growth in vitro. Collectively, these data suggested that Adrm1 is potentially oncogenic and may play an important role in colon tumorigenesis. Regiment with combined application of Adrm1 RNA interference and chemotherapy may emerge as a novel therapeutic strategy for Adrm1 overexpressed colorectal cancer.

Carvalho B, Postma C, Mongera S, et al.
Multiple putative oncogenes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression.
Gut. 2009; 58(1):79-89 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify the oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on mRNA expression of genes in this amplicon.
METHODS: Segmentation of DNA copy number changes on 20q was performed by array CGH (comparative genomic hybridisation) in 34 non-progressed colorectal adenomas, 41 progressed adenomas (ie, adenomas that present a focus of cancer) and 33 adenocarcinomas. Moreover, a robust analysis of altered expression of genes in these segments was performed by microarray analysis in 37 adenomas and 31 adenocarcinomas. Protein expression was evaluated by immunohistochemistry on tissue microarrays.
RESULTS: The genes C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5, mapping at 20q, were significantly overexpressed in carcinomas compared with adenomas as a consequence of copy number gain of 20q.
CONCLUSION: This approach revealed C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCFL5 genes to be important in chromosomal instability-related adenoma to carcinoma progression. These genes therefore may serve as highly specific biomarkers for colorectal cancer with potential clinical applications.

Fejzo MS, Dering J, Ginther C, et al.
Comprehensive analysis of 20q13 genes in ovarian cancer identifies ADRM1 as amplification target.
Genes Chromosomes Cancer. 2008; 47(10):873-83 [PubMed] Related Publications
Approximately 25,000 ovarian cancers are diagnosed in the US annually, and 75% of cases are in the advanced stage when they are largely incurable. There is a critical need for improved early detection tools and development of novel treatments. Because chromosome band 20q13 is a commonly DNA amplified region in ovarian cancer and increase in 20q13 copy number may be an early event, we examined the DNA amplification and RNA expression pattern of 239 microarray probes mapping to this region with the goal of identifying gene(s) associated with ovarian cancer. Using Agilent expression microarray analysis and FISH to tumor tissue arrays, we narrowed the candidates to 19 genes that were consistently overexpressed in a subset of tumors amplified for both ZNF217 and TPD54, although, interestingly the candidates do not include these two amplified genes. Unsupervised clustering of 225 ovarian samples with respect to RNA expression of these 19 genes allowed identification of a 20q-amplified subset of 51 (23%) tumors and this subset was significantly correlated with poor outcome. Of the 19 candidate genes in this subset, ADRM1 overexpression was the most highly correlated with amplification, was amplified in a higher percentage of tumors than ZNF217 and TPD54, and was significantly upregulated with respect to stage, recurrence and metastasis. In addition, overexpression of ADRM1 correlates significantly with shorter time to recurrence and overall survival. Functional analysis is now warranted to determine whether ADRM1 is a target for early screening and/or therapy for ovarian cancer.

Lockey TD, Zhan X, Surman S, et al.
Epstein-Barr virus vaccine development: a lytic and latent protein cocktail.
Front Biosci. 2008; 13:5916-27 [PubMed] Related Publications
Epstein-Barr Virus (EBV) is the causative agent of acute infectious mononucleosis and associates with malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma, and non-Hodgkin's lymphoma. Additionally, EBV is responsible for B-lymphoproliferative disease in the context of HIV-infection, genetic immunodeficiencies and organ/stem-cell transplantation. Here we discuss past and current efforts to design an EBV vaccine. We further describe preliminary studies of a novel cocktail vaccine expressing both lytic and latent EBV proteins. Specifically, a tetrameric vaccinia virus (VV) -based vaccine was formulated to express the EBV lytic proteins gp350 and gp110, and the latent proteins EBNA-2 and EBNA-3C. In a proof-of-concept study, mice were vaccinated with the individual or mixed VV. Each of the passenger genes was expressed in vivo at levels sufficient to elicit binding antibody responses. Neutralizing gp350-specific antibodies were also elicited, as were EBV-specific T-cell responses, following inoculation of mice with the single or mixed VV. Results encourage further development of the cocktail vaccine strategy as a potentially powerful weapon against EBV infection and disease in humans.

Pilarsky C, Wenzig M, Specht T, et al.
Identification and validation of commonly overexpressed genes in solid tumors by comparison of microarray data.
Neoplasia. 2004 Nov-Dec; 6(6):744-50 [PubMed] Free Access to Full Article Related Publications
Cancers originating from epithelial cells are the most common malignancies. No common expression profile of solid tumors compared to normal tissues has been described so far. Therefore we were interested if genes differentially expressed in the majority of carcinomas could be identified using bioinformatic methods. Complete data sets were downloaded for carcinomas of the prostate, breast, lung, ovary, colon, pancreas, stomach, bladder, liver, and kidney, and were subjected to an expression analysis using SAM. In each experiment, a gene was scored as differentially expressed if the q value was below 25%. Probe identifiers were unified by comparing the respective probe sequences to the Unigene build 155 using BlastN. To obtain differentially expressed genes within the set of analyzed carcinomas, the number of experiments in which differential expression was observed was counted. Differential expression was assigned to genes if they were differentially expressed in at least eight experiments of tumors from different origin. The identified candidate genes ADRM1, EBNA1BP2, FDPS, FOXM1, H2AFX, HDAC3, IRAK1, and YY1 were subjected to further validation. Using this comparative approach, 100 genes were identified as upregulated and 21 genes as downregulated in the carcinomas.

Katoh M, Katoh M
Identification and characterization of TPARM gene in silico.
Int J Oncol. 2003; 23(4):1213-7 [PubMed] Related Publications
Several tumor suppressor genes are located within human chromosome 11q23 region. We have cloned and characterized MFRP and RNF26 genes at 11q23.3. We also identified and characterized KIAA1735/MTHDIX gene at 11q23.1 and CLDN24 gene at 11q23.2 by using bioinformatics. Here, a novel human gene corresponding to a 5'-truncated FLJ20535 cDNA was identified. FLJ20535 corresponded to nucleotide position 55-2255 of FLJ13859, and nucleotide position 52-2169 of FLJ13859 was the coding region. Because of tetratricopeptide repeat (TPR) and armadillo repeat (ARM) domains within its gene product, the novel human gene was designated TPARM. Mouse E330017O07Rik cDNA was derived from mouse Tparm gene. Human TPARM (705 aa) and mouse Tparm (704 aa), showing 75.4% total-amino-acid identity, consist of TPR domain and three ARM domains. TPR domain of TPARM was most homologous to that of SMAP1, while ARM1-ARM3 domains of TPARM were most homologous to ARM7-ARM9 domains of CTNNB1 (also known as beta-catenin). TPARM might be implicated in the WNT-beta-catenin signaling pathway. TPARM mRNA was expressed in testis, prostate, lung, germinal center B-cells, and also in neuroblastoma, teratocarcinoma, colon cancer, and gastric cancer. Human TPARM gene was found to consist of 22 exons. TPARM gene, located between NCAM1 and DRD2 genes, was mapped to human chromosome 11q23.2. TPARM as well as NCAM1 and DRD2 were predicted to be candidate tumor suppressor genes within the commonly deleted region of malignant melanoma on 11q23.1-q23.2 (between microsatellite markers D11S1347 and D11S4122).

Neuhierl B, Feederle R, Hammerschmidt W, Delecluse HJ
Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency of infection.
Proc Natl Acad Sci U S A. 2002; 99(23):15036-41 [PubMed] Free Access to Full Article Related Publications
The Epstein-Barr virus (EBV) genome has been detected in lymphomas and in tumors of epithelial or mesenchymal origin such as nasopharyngeal carcinoma or leiomyosarcoma. Thus, there is little doubt that EBV can infect cells of numerous lineages in vivo, in contrast to its in vitro infectious spectrum, which appears restricted predominantly to B lymphocytes. We show here that the EBV BALF4 gene product, the glycoprotein gp110, dramatically enhances the ability of EBV to infect human cells. gp110(high) viruses were up to 100 times more efficient than their gp110(low) counterparts in infecting lymphoid or epithelial cells. In addition, gp110(high) viruses infected the carcinoma cell line HeLa and the T cell lymphoma cell line Molt-4, both previously thought to be refractory to EBV infection. Analysis of several virus isolates showed that the amount of BALF4 present within mature virions markedly differed among these strains. In some strains, gp110 was found expressed during lytic replication not only at the nuclear but also at the cellular membrane. Heterologous expression of gp110 during the virus lytic phase neither altered virus concentration nor affected virus binding to cells. It appears that gp110 plays a crucial role after the virus has adhered to its cellular target. gp110 constitutes an important virulence factor that determines infection of non-B cells by EBV. Therefore, the use of gp110(high) viruses will help to determine the range of the target cells of EBV beyond B lymphocytes and provide a useful in vitro model to assess the oncogenic potential of EBV in these cells.

Bown N, Lastowska M, Cotterill S, et al.
17q gain in neuroblastoma predicts adverse clinical outcome. U.K. Cancer Cytogenetics Group and the U.K. Children's Cancer Study Group.
Med Pediatr Oncol. 2001; 36(1):14-9 [PubMed] Related Publications
BACKGROUND: It is now recognized that gain of chromosome 17 material is the most frequent genetic abnormality of neuroblastoma cells. Several studies have linked 17q gain with known adverse prognostic factors: patient age >1 year, advanced stage disease, deletion of chromosome arm 1 p, and amplification of the MYCN oncogene. We sought to further investigate the clinical and prognostic associations of chromosome 17 status in relation to other well-established predictive factors.
PROCEDURE: In a collaborative study by UK cytogenetics centres, we compiled a series of 104 neuroblastoma tumours for which the status of chromosome 17 was confidently defined by cytogenetics, metaphase or interphase FISH, or CGH analysis. The results were correlated with data on 1p and MYCN, and with centrally collated clinical and survival information.
RESULTS: Gain of 17q (i.e., unbalanced gain of segment 17q21-qter) was found in 66.3% of tumours, while 33.7% showed a '17q normal' status (i.e., no gain at all, or gain of whole chromosome 17 relative to ploidy). Gain of 17q was strongly associated with advanced stage disease, patient age >1 year, 1p deletion, and MYCN amplification (all P< 0.01). In univariate analysis, 17q gain was a significant predictor of adverse outcome (projected 5 year relapse-free survival 15.6% compared to 75.2% in cases lacking this feature in tumour cells; (P < 0.0001). In multivariate analysis, 17q gain was more strongly associated with adverse outcome than was either stage (Stage 4 vs other combined) or 1p status.
CONCLUSION: We conclude that gain of chromosome segment 17q21-qter is of great biological and clinical importance in neuroblastoma, and that its detection at diagnosis should be a priority.

Herrold RE, Marchini A, Fruehling S, Longnecker R
Glycoprotein 110, the Epstein-Barr virus homolog of herpes simplex virus glycoprotein B, is essential for Epstein-Barr virus replication in vivo.
J Virol. 1996; 70(3):2049-54 [PubMed] Free Access to Full Article Related Publications
The Epstein-Barr virus (EBV) glycoprotein gp110 has substantial amino acid homology to gB of herpes simplex virus but localizes differently within infected cells and is essentially undetectable in virions. To investigate whether gp110, like gB, is essential for EBV infection, a selectable marker was inserted within the gp110 reading frame, BALF4, and the resulting null mutant EBV stain, B95-110HYG, was recovered in lymphoblastoid cell lines (LCLs). While LCLs infected with the parental virus B95-8 expressed the gp110 protein product following productive cycle induction, neither full-length gp110 nor the predicted gp110 truncation product was detectable in B95-110HYG LCLs. Infectious virus could not be recovered from B95-110HYG LCLs unless gp110 was provided in trans. Rescued B95-110HYG virus latently infected and growth transformed primary B lymphocytes. Thus, gp110 is required for the production of transforming virus but not for the maintenance of transformation of primary B lymphocytes by EBV.

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