Gene Summary

Gene:UCHL1; ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)
Aliases: NDGOA, PARK5, PGP95, PGP9.5, Uch-L1, HEL-117, PGP 9.5
Summary:The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.[provided by RefSeq, Sep 2009]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin carboxyl-terminal hydrolase isozyme L1
Source:NCBIAccessed: 28 February, 2015


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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 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.

Tag cloud generated 28 February, 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: UCHL1 (cancer-related)

Sun Y, Zhu L, Huang X, et al.
Immunohistochemical localization of nerve fibers in the pseudocapsule of fibroids.
Eur J Histochem. 2014; 58(2):2249 [PubMed] Free Access to Full Article Related Publications
The pseudocapsule surrounding fibroids consists of compressed myometrium containing nerves and blood vessels that continue into adjacent myometrium. Oxytocin (OXT) is thought to affect wound healing after myomectomy. We determined the presence of OXT and protein gene product 9.5 (PGP9.5) immunoreactive nerve fibers in pseudocapsule compared to adjacent myometrium. Samples (N=106) of pseudocapsule and adjacent myometrium were collected from 57 women with uterine fibroids undergoing myomectomy, and stained with anti-OXT and PGP 9.5 antibodies to demonstrate the presence of nerve fibers. Nerve fibers in the pseudocapsule stained positively with OXT (89/106, 84.0%) and PGP 9.5 (94/106, 88.7%). The densities of nerve fibers staining with PGP 9.5 and OXT in the pseudocapsule were highest in the isthmus (23.68±22.45/mm2 and 43.35±40.74/mm2, respectively). There were no significant differences in the density of nerve fibers, stained with either OXT or PGP 9.5, between the pseudocapsule, and adjacent normal myometrium regardless of the fibroid location in the uterus (P>0.05). These results suggest that the pseudocapsule should avoid to be damaged during the myomectomy procedure.

Olar A, He D, Florentin D, et al.
Biologic correlates and significance of axonogenesis in prostate cancer.
Hum Pathol. 2014; 45(7):1358-64 [PubMed] Related Publications
Cancer-related axonogenesis and neurogenesis are recently described biologic phenomena. Our previously published data showed that nerve density and the number of neurons in the parasympathetic ganglia are increased in prostate cancer (PCa) and associated with aggressive disease. Tissue microarrays were constructed from 640 radical prostatectomy specimens with PCa. Anti-protein gene product 9.5 (PGP 9.5) antibodies were used to identify and quantify nerve density. Protein expression was objectively analyzed using deconvolution imaging, image segmentation, and image analysis. Data were correlated with clinicopathological variables and tissue biomarkers available in our database. Nerve density, as measured by PGP 9.5 expression, had a weak but significant positive correlation with the lymph node status (ρ = 0.106; P = .0275). By Cox univariate analysis, PGP 9.5 was a predictor of time to biochemical recurrence, but not on multivariate analysis. Increased nerve density correlated with increased proliferation of PCa cells. It also correlated with expression of proteins involved in survival pathways (Phosphorylated alpha serine/threonine-protein kinase, NFκB, GSK-2, PIM-2, c-Myc, SKP-2, SRF, P27n, PTEN), with increased levels of hormonal regulation elements (androgen receptor, estrogen receptor α), and coregulators and repressors (SRC-1, SRC-2, AIB-1, DAX). Axonogenesis is a recently described phenomenon of paramount importance in the biology of PCa. Although the degree of axonogenesis is predictive of aggressive behavior in PCa, it does not add to the information present in current models on multivariate analysis. We present data that corroborate that axonogenesis is involved in biologic processes such as proliferation of PCa, through activation of survival pathways and interaction with hormonal regulation.

Heitzer E, Artl M, Filipits M, et al.
Differential survival trends of stage II colorectal cancer patients relate to promoter methylation status of PCDH10, SPARC, and UCHL1.
Mod Pathol. 2014; 27(6):906-15 [PubMed] Related Publications
Surgical excision of colorectal cancer at early clinical stages is highly effective, but 20-30% of patients relapse. Therefore, it is of clinical relevance to identify patients at high risk for recurrence, who would benefit from adjuvant chemotherapy. The objective of this study was to identify prognostic and/or predictive methylation markers in stage II colorectal cancer patients. Therefore, we selected six gene promoters (FZD9, PCDH10 (protocadherin 10), SFRP2, SPARC (secreted protein acidic and rich in cysteine), UCHL1 (ubiquitin carboxyl-terminal hydrolase 1), and WIF1) for methylation analysis in formalin-fixed, paraffin-embedded primary tumor samples of colorectal cancer patients (n=143) who were enrolled in a prospective randomized phase III trial of the Austrian Breast and Colorectal cancer Study Group. Patients were randomized to adjuvant chemotherapy with 5-fluorouracil and leucovorin or surveillance only. Survival analyses revealed that combined evaluation of three promoters (PCDH10, SPARC, and UCHL1) showed differential effects with regard to disease-free survival and overall survival in the two treatment groups (significance level 0.007). In the chemotherapy arm, a statistically insignificant trend for patients without methylation toward longer survival was observed (P=0.069 for disease-free survival and P=0.139 for overall survival). Contrary, patients in the surveillance arm without methylation in their gene promoters had shorter disease-free survival and overall survival (P=0.031 for disease-free survival and P=0.003 for overall survival), indicating a prognostic effect of methylation in this group (test for interaction, P=0.006 for disease-free survival and P=0.018 for overall survival). These results indicate that promoter methylation status of PCDH10, SPARC, and UCHL1 may be used both as prognostic and predictive molecular marker for colorectal cancer patients and, therefore, may facilitate treatment decisions for stage II colorectal cancer.

Brait M, Maldonado L, Noordhuis MG, et al.
Association of promoter methylation of VGF and PGP9.5 with ovarian cancer progression.
PLoS One. 2013; 8(9):e70878 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To elucidate the role of biological and clinical impact of aberrant promoter hypermethylation (PH) in ovarian cancer (OC).
EXPERIMENTAL DESIGN: PH of PGP9.5, HIC1, AIM1, APC, PAK3, MGMT, KIF1A, CCNA1, ESR1, SSBP2, GSTP1, FKBP4 and VGF were assessed by quantitative methylation specific PCR (QMSP) in a training set. We selected two genes (VGF and PGP9.5) for further QMSP analysis in a larger independent validation (IV) set with available clinical data. Biologic relevance of VGF gene was also evaluated.
RESULTS: PH frequency for PGP9.5 and VGF were 85% (316/372) and 43% (158/366) respectively in the IV set of samples while no PH was observed in controls. In 372 OC cases with available follow up, PGP9.5 and VGF PH were correlated with better patient survival [Hazard Ratios (HR) for overall survival (OS) were 0.59 (95% Confidence Intervals (CI)  = 0.42-0.84, p = 0.004), and 0.73 (95%CI = 0.55-0.97, p = 0.028) respectively, and for disease specific survival (DSS) were 0.57 (95%CI 0.39-0.82, p = 0.003) and 0.72 (95%CI 0.54-0.96, p = 0.027). In multivariate analysis, VGF PH remained an independent prognostic factor for OS (HR 0.61, 95%CI 0.43-0.86, p<0.005) and DSS (HR 0.58, 95%CI 0.41-0.83, p<0.003). Furthermore, PGP9.5 PH was significantly correlated with lower grade, early stage tumors, and with absence of residual disease. Forced expression of VGF in OC cell lines inhibited cell growth.
CONCLUSIONS: Our results indicate that VGF and PGP9.5 PH are potential biomarkers for ovarian carcinoma. Confirmatory cohorts with longitudinal follow-up are required in future studies to define the clinical impact of VGF and PGP9.5 PH before clinical application.

Kruijff S, Sidhu SB, Sywak MS, et al.
Negative parafibromin staining predicts malignant behavior in atypical parathyroid adenomas.
Ann Surg Oncol. 2014; 21(2):426-33 [PubMed] Related Publications
BACKGROUND: The histopathological criteria for carcinoma proposed by the World Health Organization (WHO) are imperfect predictors of the malignant potential of parathyroid tumors. Negative parafibromin (PF) and positive protein gene product 9.5 (PGP9.5) staining are markers of CDC73 mutation and occur commonly in carcinoma but rarely in adenomas. We investigated whether PF and PGP9.5 staining could be used to predict the behavior of atypical parathyroid adenomas--tumors with atypical features that do not fulfill WHO criteria for malignancy.
METHODS: Long-term outcomes were compared across four groups: group A, WHO-positive criteria/PF-negative staining; group B, WHO(+)/PF(+), group C; WHO(-)/PF(-); and group D, WHO(-)/PF(+).
RESULTS: Eighty-one patients were included in the period 1999-2012: group A (n = 13), group B (n = 14), group C (n = 21), and group D (n = 33). Mortality and recurrence rates, respectively, for group A were 15 and 38%, for group B 7 and 36%, for group C 0 and 10%, and for group D 0 and 0%. The PGP9.5(+) ratios for groups A to D were 85, 78, 71, and 12%, further informing prognosis. Five-year disease-free survival for groups A to D were 55, 80, 78, and 100%, respectively. Tumor recurrence was significantly associated with PF (p = 0.048) and PGP9.5 (p = 0.003) staining.
CONCLUSIONS: Although WHO criteria are essential to differentiate parathyroid carcinoma from benign tumors, the presence of negative PF staining in an atypical adenoma predicts outcome better, whereas PF-positive atypical adenomas do not recur and can be considered benign. PF-negative atypical adenomas have a low but real recurrence risk and should be considered tumors of low malignant potential.

Schröder C, Milde-Langosch K, Gebauer F, et al.
Prognostic relevance of ubiquitin C-terminal hydrolase L1 (UCH-L1) mRNA and protein expression in breast cancer patients.
J Cancer Res Clin Oncol. 2013; 139(10):1745-55 [PubMed] Related Publications
PURPOSE: The ubiquitin C-terminal hydrolase L1 (UCH-L1) belongs to the family of deubiquitinating enzymes. It is overexpressed in various tumour entities and associated with metastases formation in some solid tumours. However, only limited information about its role in breast cancer is available. The aim of this study was to examine the UCH-L1 expression in primary breast cancer and to determine its relevance as a potential prognostic marker.
METHODS: We investigated both UCH-L1 mRNA expression in microarray data from 182 primary mammary carcinomas and UCH-L1 protein expression using a tissue microarray containing samples from 1,622 breast cancer patients.
RESULTS: With both methods, high UCH-L1 expression correlated significantly with negative oestrogen receptor and progesterone receptor status and advanced tumour stage. Moreover by Kaplan-Meier analysis, high UCH-L1 mRNA and protein expression correlated with a significantly shorter overall survival.
CONCLUSION: The data of our study suggest that high levels of UCH-L1 expression indicate a more aggressive tumour behaviour and might represent a potential target in breast cancer treatment.

Tanaka T, Kuramitsu Y, Wang Y, et al.
Glyoxalase 1 as a candidate for indicating the metastatic potential of SN12C human renal cell carcinoma cell clones.
Oncol Rep. 2013; 30(5):2365-70 [PubMed] Related Publications
Three clones with differential metastatic potential were established from the parental SN12C human renal cell carcinoma (HRCC). We previously reported that in the two high metastatic SN12C clones, two isoforms of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH‑L1) showed decreased expression by using two-dimensional electrophoresis (2‑DE) covering a pH range (pH 3.0‑10.0) followed by liquid chromatography‑tandem mass spectrometry. However, in the case of the low metastatic clone, the spot volume for UCH‑L1 was almost the same as for the parental SN12C. In the present study, we found one protein spot which was correlated with the metastatic potential of SN12C clones by using 2‑DE over a narrow pH range (pH 4.0‑7.0). The protein glyoxalase 1 (GLO1) appeared to be directly proportional to the metastatic potential of the SN12C clones. GLO1 was the only protein which consistently varied according to the metastatic potentials of SN12C clones. GLO1 was increased in high metastatic cell lines by western blot analysis. These findings suggest that GLO1 is associated with the metastatic potential of SN12C HRCC clones. We expanded our experimental range to include clones of scirrhous gastric cancer cell lines (OCUM‑2M, OCUM‑2D and OCUM‑2MLN) and similar results were obtained, thereby further strengthening our original findings.

Tomita T
PGP 9.5 immunocytochemical staining for pancreatic endocrine tumors.
Islets. 2013 May-Jun; 5(3):122-8 [PubMed] Free Access to Full Article Related Publications
AIMS/HYPOTHESIS: Protein gene product 9.5 (PGP 9.5) is a marker for neuroendocrine cells but has not been used for pancreatic islet cells and pancreatic endocrine tumors (PETs). Antibodies for PGP 9.5 are now commercially available for immunocytochemical study, with which immunostaining may be able to differentiate between benign and malignant PETs.
RESULTS: All 4 kinds of normal islet cells were positively immunostained for PGP 9.5-moderately positive for β-cells and strongly positive for δ-cells, whereas ganglion cells were immunostained more strongly than islet cells. Nine of 12 insulinomas were moderately to strongly positive for PGP 9.5. Two glucagonomas, 3 of 6 pancreatic polypeptidomas (PPomas), 3 of 9 gastrinomas, and 2 of 4 non-functioning PETs were negative for PGP 9.5.
MATERIALS AND METHODS: Thirty-four PETs were immunocytochemically stained for PGP 9.5 using a rabbit polyclonal antibody together with immunostaining for 4 pancreatic hormones, chromogranin A (CgA), and gastrin. PETs consisted of 12 insulinomas, 2 glucagonomas, 1 somatostatinoma (SRIFoma), 6 PPomas, 9 gastrinomas, and 4 non-functioning PETs.
CONCLUSION/INTERPRETATION: PGP 9.5 immunostaining was universally positive for 4 kinds of islet cells and was moderately to strongly positive for 9 of 12 (75%) insulinomas. All 22 non-β-cell PETs were negative or weakly positive for PGP 9.5, and thus negative or weakly positive PGP 9.5 immunostaining may be used as a marker for potential malignancy and poor prognosis for non-β-cell PETs.

Lleras RA, Smith RV, Adrien LR, et al.
Unique DNA methylation loci distinguish anatomic site and HPV status in head and neck squamous cell carcinoma.
Clin Cancer Res. 2013; 19(19):5444-55 [PubMed] Free Access to Full Article Related Publications
PURPOSE: We have used a genome-wide approach to identify novel differentially methylated CpG dinucleotides that are seen in different anatomic sites of head and neck squamous cell carcinoma (HNSCC), as well as those that might be related to HPV status in the oropharynx.
EXPERIMENTAL DESIGN: We conducted genome-wide DNA methylation profiling of primary tumor samples and corresponding adjacent mucosa from 118 HNSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY, using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M-value).
RESULTS: When datasets were individually analyzed by anatomic site of the primary tumor, we identified 293 differentially methylated CpG loci in oral cavity squamous cell carcinoma (SCC), 219 differentially methylated CpG loci in laryngeal SCC, and 460 differentially methylated in oropharyngeal SCC. A subset of these differentially methylated CpG loci was common across all anatomic sites of HNSCC. Stratification by HPV status revealed a significantly higher number of differentially methylated CpG loci in HPV+ patients.
CONCLUSION: Novel epigenetic biomarkers derived from clinical HNSCC specimens can be used as molecular classifiers of this disease, revealing many new avenues of investigation for this disease.

Tian F, Yip SP, Kwong DL, et al.
Promoter hypermethylation of tumor suppressor genes in serum as potential biomarker for the diagnosis of nasopharyngeal carcinoma.
Cancer Epidemiol. 2013; 37(5):708-13 [PubMed] Related Publications
PURPOSE: Promoter hypermethylation of tumor suppressor genes may serve as a promising biomarker for the diagnosis of cancer. Cell-free circulating DNA (cf-DNA) shares hypermethylation status with primary tumors. This study investigated promoter hypermethylation of five tumor suppressor genes as markers in the detection of nasopharyngeal carcinoma (NPC) in serum samples.
METHODS: cf-DNA was extracted from serum collected from 40 NPC patients and 41 age- and sex-matched healthy subjects. The promoter hypermethylation status of the five genes (RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1) was assessed by methylation-specific PCR after sodium bisulfite conversion. Differences in the methylation status of these five genes between NPC patients and healthy subjects were compared.
RESULTS: The concentration of cf-DNA in the serum of NPC patients was significantly higher than that in normal controls. The five tumor suppressor genes - RASSF1, CDKN2A, DLEC1, DAPK1 and UCHL1 - were found to be methylated in 17.5%, 22.5%, 25.0%, 51.4% and 64.9% of patients, respectively. The combination of four-gene marker - CDKN2A, DLEC1, DAPK1 and UCHL1 - had the highest sensitivity and specificity in predicting NPC.
CONCLUSION: Screening DNA hypermethylation of tumor suppressor genes in serum was a promising approach for the diagnosis of NPC.

Karim R, Tummers B, Meyers C, et al.
Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte's innate immune response.
PLoS Pathog. 2013; 9(5):e1003384 [PubMed] Free Access to Full Article Related Publications
Persistent infection of basal keratinocytes with high-risk human papillomavirus (hrHPV) may cause cancer. Keratinocytes are equipped with different pattern recognition receptors (PRRs) but hrHPV has developed ways to dampen their signals resulting in minimal inflammation and evasion of host immunity for sustained periods of time. To understand the mechanisms underlying hrHPV's capacity to evade immunity, we studied PRR signaling in non, newly, and persistently hrHPV-infected keratinocytes. We found that active infection with hrHPV hampered the relay of signals downstream of the PRRs to the nucleus, thereby affecting the production of type-I interferon and pro-inflammatory cytokines and chemokines. This suppression was shown to depend on hrHPV-induced expression of the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in keratinocytes. UCHL1 accomplished this by inhibiting tumor necrosis factor receptor-associated factor 3 (TRAF3) K63 poly-ubiquitination which lead to lower levels of TRAF3 bound to TANK-binding kinase 1 and a reduced phosphorylation of interferon regulatory factor 3. Furthermore, UCHL1 mediated the degradation of the NF-kappa-B essential modulator with as result the suppression of p65 phosphorylation and canonical NF-κB signaling. We conclude that hrHPV exploits the cellular protein UCHL1 to evade host innate immunity by suppressing PRR-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response. This identifies UCHL1 as a negative regulator of PRR-induced immune responses and consequently its virus-increased expression as a strategy for hrHPV to persist.

Wulfänger J, Biehl K, Tetzner A, et al.
Heterogeneous expression and functional relevance of the ubiquitin carboxyl-terminal hydrolase L1 in melanoma.
Int J Cancer. 2013; 133(11):2522-32 [PubMed] Related Publications
The expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short-term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity-dependent growth promoting function of UCHL1 via the activation of the mitogen-activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose-dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K-Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients.

Lien HC, Wang CC, Lin CH, et al.
Differential expression of ubiquitin carboxy-terminal hydrolase L1 in breast carcinoma and its biological significance.
Hum Pathol. 2013; 44(9):1838-48 [PubMed] Related Publications
Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that hydrolyzes ubiquitin. Previous reports have shown both tumorigenic and antitumorigenic roles for UCHL1. However, the expression patterns of UCHL1 protein, an area that is critical for validating its clinicopathologic roles among subtypes of breast cancer, is still lacking. Here we examined the expression of UCHL1 by immunohistochemistry in 243 breast carcinomas of various subtypes. We found expression of UCHL1 in 8.3% of invasive ductal carcinomas but not in other carcinoma subtypes, except for metaplastic carcinomas of the breast, which showed UCHL1 staining in 61.9% of cases, with the sarcomatous components being more intensely stained. UCHL1 expression in invasive ductal carcinomas significantly correlated with a high histologic grade (P = .001), the triple-negative phenotype (P = .02), and the basal-like phenotype (P <.001); furthermore, it was associated with poorer overall survival by univariate and multivariate analyses. Knockdown of UCHL1 in an invasive Snail variant-transfected MCF7 cells with high endogenous UCHL1 protein level significantly reduced invasion and anchorage-independent growth. Conclusively, our results demonstrate a role for UCHL1 in aggressive phenotypes in breast carcinoma. The high expression of UCHL1 in metaplastic carcinomas of the breast, which is pathogenically related to epithelial-mesenchymal transition, may implicate an association between UCHL1 expression and the epithelial-mesenchymal transition in breast cancer.

Fellenberg J, Sähr H, Liu L, et al.
Rescue of silenced UCHL1 and IGFBP4 expression suppresses clonogenicity of giant cell tumor-derived stromal cells.
Cancer Lett. 2013; 336(1):61-7 [PubMed] Related Publications
Giant cell tumor (GCT) of bone is a generally benign tumor with a locally aggressive behavior. Histologically, GCTs consist of multinucleated giant cells, mononuclear histiocytes and the neoplastic fibroblast-like stromal cells (GCTSC). Growing evidence exists that GCTSCs develop from mesenchymal stem cells (MSCs), but little is known about the underlying molecular mechanisms. In previous studies we observed inactivation of the ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene in primary GCTSC due to strong DNA hypermethylation, indicating that epigenetic silencing might be involved in neoplastic transformation of MSCs. Here we investigated further candidate genes and identified strong hypermethylation of the insulin-like growth factor binding protein 4 (IGFBP4) promoter, resulting in IGFBP4 downregulation in GCTs compared to MSCs. Overexpression of UCHL1 and IGFBP4 by stable transfection of GCTSC did not influence cell viability, proliferation, migration and chemosensitivity compared to parental cells. However, colony-formation was significantly decreased suggesting that rescue of UCHL1 and IFGBP4 suppresses clonogenicity of GCT stromal cells. The observation of reduced expression of the stem-cell-specific transcription factors OCT4 and SOX2 in these cell lines further supported our findings. Epigenetic silencing of UCHL1 and IGFBP4 in GCTs might thus be a crucial event during the malignant transformation of MSCs in the context of GCT development and represent promising targets for the development of new diagnostic and therapeutic strategies.

Lo Furno D, Pellitteri R, Graziano AC, et al.
Differentiation of human adipose stem cells into neural phenotype by neuroblastoma- or olfactory ensheathing cells-conditioned medium.
J Cell Physiol. 2013; 228(11):2109-18 [PubMed] Related Publications
Olfactory ensheathing cells (OECs) are known to be capable of continuous neurogenesis throughout lifetime and are a source of multiple trophic factors important in central nervous system regeneration. B104 neuroblastoma cells are recognized to induce differentiation of neural stem cells into oligodendrocyte precursor cells. Therefore, the aim of this study was to verify if conditioned medium (CM) obtained from OECs or B104 cells was capable of inducing differentiation of adipose tissue-derived mesenchymal stem cells (AT-MSCs) to a neuronal phenotype. In order to this goal, immunocytochemical procedures and flow cytometry analysis were used and some neural markers, as nestin, protein gene product 9.5 (PGP 9.5), microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP), and neuron cell surface antigen (A2B5) were examined 24 h and 7 days after the treatment. The results showed that both OECs- or B104-CM treated AT-MSCs express markers of progenitor and mature neurons (nestin, PGP 9.5 and MAP2) in time-dependent manner, display morphological features resembling neuronal cells, and result negative for GFAP and A2B5, astrocyte and oligodendrocyte markers, respectively. This study demonstrated that AT-MSCs can be influenced by the environment, indicating that these cells can respond to environmental cues also versus a neuronal phenotype.

Kato N, Yamamoto H, Adachi Y, et al.
Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids.
World J Gastroenterol. 2013; 19(11):1718-27 [PubMed] Free Access to Full Article Related Publications
AIM: To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers.
METHODS: DNA was extracted from undiluted pancreatic and biliary fluids. As a surrogate for a genome-wide hypomethylation assay, levels of long interspersed nuclear element-1 (LINE-1) methylation were analyzed using bisulfite pyrosequencing. CpG island hypermethylation of 10 tumor-associated genes, aryl-hydrocarbon receptor repressor, adenomatous polyposis coli, calcium channel, voltage dependent, T type α1G subunit, insulin-like growth factor 2, O-6-methyl-guanine-DNA methyltransferase, neurogenin 1, CDKN2A, runt-related transcription factor 3 (RUNX3), secreted frizzled-related protein 1, and ubiquitin carboxyl-terminal esterase L1 (UCHL1), was analyzed using MethyLight. To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1, human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 μmol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h. After the treatment, UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction.
RESULTS: Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease (58.7% ± 4.3% vs 61.7% ± 2.2%, P = 0.027; 53.8% ± 6.6% vs 57.5% ± 1.7%, P = 0.007); however, LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids (45.4% ± 5.5% vs 58.7% ± 4.3%, P < 0.001). CpG island hypermethylation of tumor-associated genes was detected at various frequencies, but it was not correlated with LINE-1 hypomethylation. Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic (67%) or biliary (70%) fluids from patients with pancreatobiliary cancer. As a single marker, hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers, respectively (100% specificity). Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic (87% sensitivity and 100% specificity) and pancreatobiliary (97% sensitivity and 100% specificity) cancers. Treatment with a demethylating agent, 5-AZA-2'-deoxycytidine, restored UCHL1 expression in pancreatobiliary cancer cell lines.
CONCLUSION: Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers.

Shahdoust M, Hajizadeh E, Mozdarani H, Chehrei A
Finding genes discriminating smokers from non-smokers by applying a growing self-organizing clustering method to large airway epithelium cell microarray data.
Asian Pac J Cancer Prev. 2013; 14(1):111-6 [PubMed] Related Publications
BACKGROUND: Cigarette smoking is the major risk factor for development of lung cancer. Identification of effects of tobacco on airway gene expression may provide insight into the causes. This research aimed to compare gene expression of large airway epithelium cells in normal smokers (n=13) and non-smokers (n=9) in order to find genes which discriminate the two groups and assess cigarette smoking effects on large airway epithelium cells.
MATERIALS AND METHODS: Genes discriminating smokers from non-smokers were identified by applying a neural network clustering method, growing self-organizing maps (GSOM), to microarray data according to class discrimination scores. An index was computed based on differentiation between each mean of gene expression in the two groups. This clustering approach provided the possibility of comparing thousands of genes simultaneously.
RESULTS: The applied approach compared the mean of 7,129 genes in smokers and non-smokers simultaneously and classified the genes of large airway epithelium cells which had differently expressed in smokers comparing with non-smokers. Seven genes were identified which had the highest different expression in smokers compared with the non-smokers group: NQO1, H19, ALDH3A1, AKR1C1, ABHD2, GPX2 and ADH7. Most (NQO1, ALDH3A1, AKR1C1, H19 and GPX2) are known to be clinically notable in lung cancer studies. Furthermore, statistical discriminate analysis showed that these genes could classify samples in smokers and non-smokers correctly with 100% accuracy. With the performed GSOM map, other nodes with high average discriminate scores included genes with alterations strongly related to the lung cancer such as AKR1C3, CYP1B1, UCHL1 and AKR1B10.
CONCLUSIONS: This clustering by comparing expression of thousands of genes at the same time revealed alteration in normal smokers. Most of the identified genes were strongly relevant to lung cancer in the existing literature. The genes may be utilized to identify smokers with increased risk for lung cancer. A large sample study is now recommended to determine relations between the genes ABHD2 and ADH7 and smoking.

Brinkmann K, Zigrino P, Witt A, et al.
Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA.
Cell Rep. 2013; 3(3):881-91 [PubMed] Related Publications
The BH3-only protein NOXA represents one of the critical mediators of DNA-damage-induced cell death. In particular, its involvement in cellular responses to cancer chemotherapy is increasingly evident. Here, we identify a strategy of cancer cells to escape genotoxic chemotherapy by increasing proteasomal degradation of NOXA. We show that the deubiquitylating enzyme UCH-L1 is a key regulator of NOXA turnover, which protects NOXA from proteasomal degradation by removing Lys(48)-linked polyubiquitin chains. In the majority of tumors from patients with melanoma or colorectal cancer suffering from high rates of chemoresistance, NOXA fails to accumulate because UCH-L1 expression is epigenetically silenced. Whereas UCH-L1/NOXA-positive tumor samples exhibit increased sensitivity to genotoxic chemotherapy, downregulation of UCH-L1 or inhibition of its deubiquitylase activity resulted in reduced NOXA stability and resistance to genotoxic chemotherapy in both human and C. elegans cells. Our data identify the UCH-L1/NOXA interaction as a therapeutic target for overcoming cancer chemoresistance.

Trifa F, Karray-Chouayekh S, Jmaa ZB, et al.
Frequent CpG methylation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) in sporadic and hereditary Tunisian breast cancer patients: clinical significance.
Med Oncol. 2013; 30(1):418 [PubMed] Related Publications
Aberrant methylation of the CpG islands in promoter regions is one of the mechanisms for inactivation of tumor suppressor genes in many human cancers including breast carcinoma. In this study, we aimed to assess, by methylation-specific PCR, the CpG methylation pattern of the UCHL1 promoter in 94 sporadic and 44 hereditary breast cancers from Tunisian patients. The percentage of UCHL1 methylation was 67 % in sporadic and 82 % in hereditary breast cancer cases. In sporadic cases, UCHL1 methylation correlated with poor response to treatment (P = 0.042) and progesterone receptor status (P = 0.036), whereas in patients with hereditary predisposition, the only significant association was found with Her2 expression (P = 0.024). Moreover, in patients with sporadic breast cancer, the UCHL1 unmethylated pattern conferred a prolonged overall survival time in particular in the group of patients with advanced TNM stage of the disease (P log rank = 0.04). Aberrant CpG methylation of the UCHL1 promoter was significantly associated with transcriptional silencing of this tumor suppressor gene in sporadic breast cancer tissues (P = 0.001). On the other hand, the UCHL1 unmethylated pattern correlated with P53 positivity in primary sporadic tumors (P = 0.032), supporting the functional link between the two tumor suppressors in breast tumorigenesis.

Gunia S, Erbersdobler A, Koch S, et al.
Protein gene product 9.5 is diagnostically helpful in delineating high-grade renal cell cancer involving the renal medullary/sinus region from invasive urothelial cell carcinoma of the renal pelvis.
Hum Pathol. 2013; 44(5):712-7 [PubMed] Related Publications
The classification of poorly differentiated carcinomas involving the renal medullary/sinus region might be challenging on conventional histomorphologic grounds alone. However, delineation of high-grade renal cell carcinomas such as collecting duct (Bellini) carcinoma from urothelial cell carcinoma of the renal pelvis is critical, as it conveys important therapeutic implications. We assessed the so far neglected differential diagnostic role of protein gene product 9.5, a neuropeptide involved in intracellular proteolysis, in terms of differentiating invasive urothelial cell carcinomas of the renal pelvis from high-grade renal cell carcinomas infiltrating the renal medullary/sinus region. To this aim, 21 invasive urothelial cell carcinomas of the renal pelvis and 27 high-grade renal cell carcinomas (8 renal cell carcinomas with sarcomatoid dedifferentiation and 5 type 1 and 7 type 2 papillary renal cell carcinomas as well as 7 collecting duct carcinomas) were stained with antibodies directed against protein gene product 9.5, CD10, vimentin, CEA, p63, CK5/6, CK7, CK20, PAX2, PAX8, CD117 (c-Kit), AE1/3, α-methyl CoA racemase, actin, and desmin. Briefly, strong protein gene product 9.5 expression was observed in 6 (86%) of 7 collecting duct carcinomas, 8 (67%) of 12 papillary renal cell carcinomas, and 2 (25%) of 8 renal cell carcinomas with sarcomatoid dedifferentiation. Conversely, none of the 21 urothelial cell carcinomas investigated showed protein gene product 9.5 expression. Our findings suggest that protein gene product 9.5, particularly if used in conjunction with p63 and CK5/6, might be helpful in differentiating high-grade renal cell carcinomas from urothelial cell carcinomas of the renal pelvis, whereas its specificity with respect to the histologic subtyping of renal cell carcinomas seems to be low. However, because of the limited number of study cases enrolled in our investigation, our findings need to be validated in the future.

Pérez-Magán E, Campos-Martín Y, Mur P, et al.
Genetic alterations associated with progression and recurrence in meningiomas.
J Neuropathol Exp Neurol. 2012; 71(10):882-93 [PubMed] Related Publications
Meningiomas are the most common primary brain tumors; they arise from the coverings of the brain. Although meningiomas are generally benign, some are more clinically aggressive, as reflected by their histopathological features or by their unexpected recurrence. We hypothesized that recurrent histologically benign meningiomas might have genetic features in common with those showing a more aggressive histology. By comparing gene expression profiles associated with meningioma progression and recurrence in 128 tumor samples (i.e. 83 benign World Health Organization [WHO] Grade I, 37 atypical WHO Grade II, and 8 anaplastic WHO Grade III) from 121 patients, we identified a 49-gene signature of meningioma aggressivity. This signature classified the tumors into 2 groups showing different clinical and pathological behaviors. The signature was composed of genes involved in the cell cycle (TMEM30B, CKS2, and UCHL1) and other pathways previously described as being altered in meningiomas, that is, WNT (SFRP1 and SFRP4) and transforming growth factor-β pathways (LTBP2 and LMO4). Overall, gene downregulation was observed in advanced and recurrent samples versus benign and original ones. We propose that this gene repression may be caused by gene promoter hypermethylation, as in the case of UCHL1 and SFRP1, suggesting that this epigenetic event, together with loss of specific chromosomal regions, may play an important role in meningioma progression and recurrence.

Malvasi A, Cavallotti C, Nicolardi G, et al.
NT, NPY and PGP 9.5 presence in myomeytrium and in fibroid pseudocapsule and their possible impact on muscular physiology.
Gynecol Endocrinol. 2013; 29(2):177-81 [PubMed] Related Publications
The uterine myoma pseudocapsule is a neurovascular bundle surrounding fibroid, containing neuropeptides, probably involved in uterine scar healing. We studied neurotensin (NT), neuropeptide tyrosine (NPY), and protein gene product 9.5 (PGP 9.5) nerve fibres in the pseudocapsule neurovascular bundle of intramural uterine fibroids on 67 no pregnant women by intracapsular myomectomy sparing the neurovascular bundle, sampling full thickness specimens of the pseudocapsule of uterine fibroids (PUF) and normal myometrium (NM) obtained from the fundus uteri (FU) and the uterine body (UB). The samples were sent for histological and immunofluorescent analyses and compared by morphometrical quantification. The Conventional Unit (C.U.) difference of NT, NPY, and PGP 9.5 nerve fibres was statistically analyzed. Our results showed that NT, NPY, and PGP 9.5 neurofibers are almost equally present in PUF as in NM of a no pregnant uterus. As all of these neuropeptides are present in the uterine muscle and can affect muscle contractility, uterine peristalsis and muscular healing. A myomectomy respecting the pseudocapsule neurofibers should facilitate smooth muscle scarring and promote restoration of normal uterine peristalsis with a possible positive influence on fertility.

Glogowska A, Stetefeld J, Weber E, et al.
Epidermal growth factor cytoplasmic domain affects ErbB protein degradation by the lysosomal and ubiquitin-proteasome pathway in human cancer cells.
Neoplasia. 2012; 14(5):396-409 [PubMed] Free Access to Full Article Related Publications
The cytoplasmic domains of EGF-like ligands, including EGF cytoplasmic domain (EGFcyt), have important biological functions. Using specific constructs and peptides of human EGF cytoplasmic domain, we demonstrate that EGFcyt facilitates lysosomal and proteasomal protein degradation, and this coincided with growth inhibition of human thyroid and glioma carcinoma cells. EGFcyt and exon 22-23-encoded peptide (EGF22.23) enhanced procathepsin B (procathB) expression and procathB-mediated lysosomal degradation of EGFR/ErbB1 as determined by inhibitors for procathB and the lysosomal ATPase inhibitor BafA1. Presence of mbEGFctF, EGFcyt, EGF22.23, and exon 23-encoded peptides suppressed the expression of the deubiqitinating enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1). This coincided with hyperubiquitination of total cellular proteins and ErbB1/2 and reduced proteasome activity. Upon small interfering RNA-mediated silencing of endogenously expressed UCH-L1, a similar hyperubiquitinylation phenotype, reduced ErbB1/2 content, and attenuated growth was observed. The exon 23-encoded peptide region of EGFcyt was important for these biologic actions. Structural homology modeling of human EGFcyt showed that this molecular region formed an exposed surface loop. Peptides derived from this EGFcyt loop structure may aid in the design of novel peptide therapeutics aimed at inhibiting growth of cancer cells.

Friedrich RE, Holstein AF, Middendorff R, Davidoff MS
Vascular wall cells contribute to tumourigenesis in cutaneous neurofibromas of patients with neurofibromatosis type 1. A comparative histological, ultrastructural and immunohistochemical study.
Anticancer Res. 2012; 32(5):2139-58 [PubMed] Related Publications
UNLABELLED: Neurofibromas are benign nerve sheath tumours. They occur sporadically, singly or few in number, and in neurofibromatosis type 1 (NF1), an autosomal inherited disease. These tumours are composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, and fibroblasts. The local control of tumour growth in NF1 is poorly understood. Identification of cell markers could provide new information on the processes that are involved in tumour growth.
MATERIALS AND METHODS: NF1 patients were diagnosed according to the revised NF1 diagnostic criteria proposed by the US National Institute of Health. Fifteen cutaneous neurofibromas from eight patients (origin: trunk and face) were excised, immediately immersion-fixed in Bouin's fixative and embedded in paraffin. Six micrometre thin sections were incubated with a variety of neuronal markers, connective tissue and glial cell markers, neurotrophic factors and their receptors. In addition, material was fixed, embedded and further processed for light and electron microscopic studies.
RESULTS: The tumours were composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, compartmentalising cells and fibroblasts. Neuronal markers were identified in axons (neuron-specific protein gene product 9.5, PGP9.5), in several cell types (neurofilament protein-200 kDa, NF-200) and glial cells (protein S-100, S-100). In glial cells the immunoreactivity for fibroblast surface protein (FSP) was scanty, low for cyclic 2,3-nucleotide 3'-phosphodiesterase (CNPase), strong for glucose transporter 1 (Glut-1) but lacking for glial fibrillary acidic protein (GFAP). Schwann cells and so-called compartmentalising cells exhibited immunoreactivity for neurotrophin receptor protein TrkA (TrkA) and glial cell-derived neurotrophic factor (GDNF). GDNF receptor α-1 (GFR-α1) exhibited distinct immunoreactivity in single axons, in Schwann cells, and with lower intensity in some perineurial sheet cells. No immunoreactivity was observed for the low-affinity neurotrophin receptor protein p75(NTR), high-affinity receptor protein TrkB (TrkB), high-affinity receptor protein TrkC (TrkC), the neurotrophin 3 (NT-3), and the brain-derived neurotrophic factor (BDNF).
CONCLUSION: Human cutaneous neurofibromas displayed a pattern of neurotrophic factors and their receptor immunoreactivity, which is characteristic of differentiated non-malignant tumours, and exhibited some differences from that established in developing and differentiated control Schwann cells (probably involved in the pathogenesis of the neurofibromas), as well as tumour cells in the process of differentiation. Neurofibromas are highly vascularized tumours and possess activated endothelial cells and pericytes. We presume that most of the hyperplastic structural components of a neurofibroma are generated from activated pericytes and smooth muscle cells of the small tumour vessels which possess qualities of adult stem cells.

Park JW, Baek IH, Kim YT
Preliminary study analyzing the methylated genes in the plasma of patients with pancreatic cancer.
Scand J Surg. 2012; 101(1):38-44 [PubMed] Related Publications
BACKGROUND AND AIMS: CpG islands of the promoter region of some genes are methylated in pancreatic cancer tissue and the detection of this methylation has been suggested to be useful in the diagnosis of various cancers. The aim of this study was to investigate whether the detection of methylated CpG islands in plasma can be used in the diagnosis of pancreatic cancer.
MATERIAL AND METHODS: Plasma DNA was collected from patients with pancreatic cancer, chronic pancreatitis, and healthy controls. The methylation status of six genes, UCHL1, NPTX2, SARP2, ppENK, p16, and RASSF1A, was checked by methylation-specific PCR and was subsequently confirmed by direct sequencing after bisulfite treatment.
RESULTS: CpG island methylation was detectable in 13 of 16 patients (81.3%) with pancreatic cancer, 1 of 29 healthy controls (3.5%), and 8 of 13 patients with chronic pancreatitis (61.5%). The mean number of genes with CpG island methylation was 1.6±1.2 in pancreatic cancer, 0.04±0.19 in healthy controls, and 1.2±1.1 in chronic pancreatitis. Among six genes, p16 was more specifically methylated in pancreatic cancer compared with chronic pancreatitis (p=0.016). The methylation status was not correlated with smoking history, tumor size, or cancer stage.
CONCLUSIONS: The detection of methylated genes in the plasma may have a role in differentiating between pancreatic cancers and healthy controls but not between pancreatic cancer and chronic pancreatitis.

Brown S, O'Neill C, Suliburk J, et al.
Parathyroid carcinoma: increasing incidence and changing presentation.
ANZ J Surg. 2011 Jul-Aug; 81(7-8):528-32 [PubMed] Related Publications
BACKGROUND: Parathyroid carcinoma has been regarded as an exceedingly rare disease worldwide, responsible for less than 1% of cases of primary hyperparathyroidism. However, there have been anecdotal reports recently of an increasing number of patients presenting with parathyroid carcinoma. The aim of this study was to examine the changing incidence and presentation of parathyroid cancer within a single centre.
PATIENTS AND METHODS: This is a retrospective case series. Data were obtained from the University of Sydney Endocrine Surgical Unit database, as well as a review of hospital records. All pathology was independently reviewed.
RESULTS: Over the 52-year period of the study from 1958 to 2010, there were 21 cases of confirmed parathyroid cancer. Only three cases were reported in the first 30 years of the study with the majority of cases (n = 11) presenting in the last 5 years. Despite the exponential increase in presentations, no significant differences in demographics or mode of presentation were found.
CONCLUSION: Possible reasons for the dramatic increase in parathyroid cancer include increased screening, an increase in referrals for parathyroid surgery overall associated with the availability of minimally invasive techniques, changes in diagnostic techniques with immunohistochemistry for parafibromin and protein gene product 9.5 (PGP9.5) or possibly a true increase in the incidence of the disease.

Xiang T, Li L, Yin X, et al.
The ubiquitin peptidase UCHL1 induces G0/G1 cell cycle arrest and apoptosis through stabilizing p53 and is frequently silenced in breast cancer.
PLoS One. 2012; 7(1):e29783 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear.
METHODOLOGY/PRINCIPAL FINDINGS: We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90S-expressed cells.
CONCLUSIONS/SIGNIFICANCE: UCHL1 exerts its tumor suppressive functions by inducing G0/G1cell cycle arrest and apoptosis in breast tumorigenesis, requiring its deubiquitinase activity. Its frequent silencing by promoter CpG methylation may serve as a potential tumor marker for breast cancer.

Zong J, Guo C, Liu S, et al.
Proteomic research progress in lymphatic metastases of cancers.
Clin Transl Oncol. 2012; 14(1):21-30 [PubMed] Related Publications
Lymph node metastasis (LNM) is recognised as an important factor involved in malignant tumour progression by interfering with a favourable prognosis. It is involved in a variety of cancers. Proteins are believed to play important roles in the LNM of cancers. The rapid achievements of state-of-the-art proteomic techniques have emerged as the key technologies successfully applied to identify markers for cancers at high-throughput level by providing novel targets and creating possible therapeutic interventions in cancer research. This review summarises recent progress in proteomic research in hepatocarcinoma, gastric cancer, oesophageal cancer, colorectal cancer, breast cancer, lung cancer and nasopharyngeal cancer. Actin, heat-shock proteins (HSPs), annexins, cytokeratin 10 (CK10), CK19, protein gene product 9.5 (PGP9.5) and protein disulfide isomerase (PDI) are the most common proteins in lymphatic metastases of cancers revealed by proteomic and protein functional studies. Other protein candidates specifically associated with LNMs of certain cancers are also summarised and discussed.

Mitsui Y, Shiina H, Hiraki M, et al.
Tumor suppressor function of PGP9.5 is associated with epigenetic regulation in prostate cancer--novel predictor of biochemical recurrence after radical surgery.
Cancer Epidemiol Biomarkers Prev. 2012; 21(3):487-96 [PubMed] Related Publications
BACKGROUND: The expression level of protein G product 9.5 (PGP9.5) is downregulated because of promoter CpG hypermethylation in several tumors. We speculated that impaired regulation of PGP9.5 through epigenetic pathways is associated with the pathogenesis of prostate cancer.
METHODS: CpG methylation of the PGP9.5 gene was analyzed in cultured prostate cancer cell lines, 226 localized prostate cancer samples from radical prostatectomy cases, and 80 benign prostate hyperplasia (BPH) tissues.
RESULTS: Following 5-aza-2'-deoxycytidune treatment, increased PGP9.5 mRNA transcript expression was found in the LNCaP and PC3 cell lines. With bisulfite DNA sequencing, partial methylation of the PGP9.5 promoter was shown in LNCaP whereas complete methylation was found in PC3 cells. After transfection of PGP9.5 siRNA, cell viability was significantly accelerated in LNCaP but not in PC3 cells as compared with control siRNA transfection. Promoter methylation of PGP9.5 was extremely low in only one of 80 BPH tissues, whereas it was found in 37 of 226 prostate cancer tissues. Expression of the mRNA transcript of PGP9.5 was significantly lower in methylation (+) than methylation (-) prostate cancer tissues. Multivariate analysis of biochemical recurrence (BCR) after an radical prostatectomy revealed pT category and PGP9.5 methylation as prognostically relevant. Further stratification with the pT category in addition to methylation status identified a stepwise reduction of BCR-free probability.
CONCLUSION: This is the first clinical and comprehensive study of inactivation of the PGP9.5 gene via epigenetic pathways in primary prostate cancer.
IMPACT: CpG methylation of PGP9.5 in primary prostate cancer might become useful as a molecular marker for early clinical prediction of BCR after radical prostatectomy.

Xu J, Erdreich-Epstein A, Gonzalez-Gomez I, et al.
Novel cell lines established from pediatric brain tumors.
J Neurooncol. 2012; 107(2):269-80 [PubMed] Free Access to Full Article Related Publications
The paucity of cell culture models for childhood brain tumors prompted us to establish pediatric cell lines for use in biological experiments and preclinical developmental therapeutic studies. Three cell lines were established, CHLA-200 (GBM), CHLA-259 (anaplastic medulloblastoma) and CHLA-266 (atypical teratoid rhabdoid tumor, AT/RT). Consistent with an AT/RT origin, CHLA-266 lacked INI1 expression and had monosomy 22. All lines had unique DNA short tandem repeat "fingerprints" matching that of the patient's tumor tissue and were adherent on tissue culture plastic, but differed in morphology and doubling times. CHLA-200 had a silent mutation in TP53. CHLA-259 and CHLA-266 had wild-type TP53. All three lines were relatively resistant to multiple drugs when compared to the DAOY medulloblastoma cell line, using the DIMSCAN fluorescence digital image microscopy cytotoxicity assay. RNA expression of MYC and MYCN were quantified using RT-PCR (Taqman). CHLA-200 expressed MYC, DAOY and CHLA-259 expressed MYCN, and CHLA-266 expressed both MYCN and MYC. CHLA-200 was only tumorigenic subcutaneously, but CHLA-259 and CHLA-266 were tumorigenic both subcutaneously and in brains of NOD/SCID mice. Immunohistochemistry of the xenografts revealed GFAP staining in CHLA-200 and PGP 9.5 staining in CHLA-259 and CHLA-266 tumors. As expected, INI1 expression was lacking in CHLA-266 (AT/RT). These three new cell lines will provide useful models for research of pediatric brain tumors.

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