Gene Summary

Gene:UCHL1; ubiquitin C-terminal hydrolase L1
Aliases: NDGOA, PARK5, PGP95, SPG79, PGP9.5, Uch-L1, HEL-117, PGP 9.5, HEL-S-53
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, HGNC, Ensembl, GeneCard, Gene
Protein:ubiquitin carboxyl-terminal hydrolase isozyme L1
Source:NCBIAccessed: 01 September, 2019


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 (1994-2019)
Graph generated 01 September 2019 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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)

Gu Y, Lv F, Xue M, et al.
The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation.
J Exp Clin Cancer Res. 2018; 37(1):258 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Neuroblastoma (NB) is the most common pediatric solid tumor that originates from neural crest-derived sympathoadrenal precursor cells that are committed to development of sympathetic nervous system. The well differentiated histological phenotype of NB tumor cells has been reportedly associated with favorable patient outcome. Retinoic acid (RA) can effectively induce NB cell differentiation, thereby being used in the clinic as a treatment agent for inducing the differentiation of high-risk NB. However, the underlying molecular mechanisms of regulating differentiation remain elusive.
METHODS: The correlation between clinical characteristics, survival and the deubiquitinating enzyme ubiquitin C-terminal hydrolase 1 (UCHL1) expression were assessed using a neuroblastic tumor tissue microarray, and then validated in three independent patient datasets. The different expression of UCHL1 in ganglioneuroblastoma, ganglioneuroma and NB was detected by immunohistochemistry, mass spectra and immunoblotting analysis, and the correlation between UCHL1 expression and the differentiated histology was analyzed, which was also validated in three independent patient datasets. Furthermore, the roles of UCHL1 in NB cell differentiation and proliferation and the underlying mechanisms were studied by using short hairpin RNA and its inhibitor LDN57444 in vitro.
RESULTS: Based on our neuroblastic tumor tissue microarrays and three independent validation datasets (Oberthuer, Versteeg and Seeger), we identified that UCHL1 served as a prognostic marker for better clinical outcome in NB. We further demonstrated that high UCHL1 expression was associated with NB differentiation, indicated by higher UCHL1 expression in ganglioneuroblastomas/ganglioneuromas and well-differentiated NB than poorly differentiated NB, and the positive correlation between UCHL1 and differentiation markers. As expected, inhibiting UCHL1 by knockdown or LDN57444 could significantly inhibit RA-induced neural differentiation of NB tumor cells, characterized by decreased neurite outgrowth and neural differentiation markers. This effect of UCHL1 was associated with positively regulating RA-induced AKT and ERK1/2 signaling activation. What's more, knockdown of UCHL1 conferred resistance to RA-induced growth arrest.
CONCLUSION: Our findings identify a pivotal role of UCHL1 in NB cell differentiation and as a prognostic marker for survival in patients with NB, potentially providing a novel therapeutic target for NB.

Alexandrescu S, Paulson V, Dubuc A, et al.
PHOX2B is a reliable immunomarker in distinguishing peripheral neuroblastic tumours from CNS embryonal tumours.
Histopathology. 2018; 73(3):483-491 [PubMed] Related Publications
AIMS: The PHOX2B gene regulates neuronal maturation in the brain stem nuclei associated with cardiorespiratory function and in the autonomic sympathetic and enteric nervous system. PHOX2B expression is a reliable immunomarker for peripheral neuroblastic tumours; however, no systematic evaluation of central nervous system (CNS) embryonal tumours was included in the studies. We encountered two cases in which the differential diagnosis included neuroblastoma and CNS embryonal tumour, and we hypothesised that PHOX2B immunostain would be helpful in establishing the diagnosis.
METHODS AND RESULTS: PHOX2B immunostain was performed on 29 paediatric cases, with adequate controls: one retroperitoneal embryonal tumour in a child with retinoblastoma (index 1), one posterior fossa embryonal tumour in a child with a neuroblastoma (index 2), seven medulloblastomas, four atypical teratoid/rhabdoid tumours (ATRT), four retinoblastomas, six pineoblastomas, four embryonal tumours with multilayered rosettes (ETMR) and two CNS embryonal tumours, not elsewhere classified. Cell lineage immunomarkers (GFAP, OLIG2, synaptophysin, NeuN, CRX, PGP 9.5), immunosurrogates for molecular alterations (beta-catenin, INI1, Lin-28), array CGH and OncoPanel were performed as needed. Medulloblastomas, ATRTs, ETMRs, retinoblastomas and CNS embryonal tumours not elsewhere classified were essentially negative for PHOX2B. Two of six pineoblastomas had significant PHOX2B expression, while the rest were negative. Index 1 was negative for PHOX2B and PGP 9.5 and positive for CRX, consistent with retinoblastoma. Index 2 had diffuse PHOX2B expression, MYCN amplification and no copy number changes of medulloblastoma, in keeping with neuroblastoma.
CONCLUSION: PHOX2B antibody is helpful in distinguishing between peripheral neuroblastic and CNS embryonal tumours, which are immunonegative, with the caveat that a subset of pineoblastomas has significant expression.

Yang G, Fan G, Zhang T, et al.
Upregulation of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Mediates the Reversal Effect of Verapamil on Chemo-Resistance to Adriamycin of Hepatocellular Carcinoma.
Med Sci Monit. 2018; 24:2072-2082 [PubMed] Free Access to Full Article Related Publications
BACKGROUND The aim of this study was to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in the reversal effect of verapamil (VER) on chemo-resistance to Adriamycin (ADM) in treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS HCC cell lines SMMC-7721 and BEL-7402 were used as model cell lines. High-throughput transcriptome sequencing based on Illumina technology was used to screen whether UCHL1 mediated the reversal effect of VER on chemo-resistance. Quantitative real-time PCR (qRT-PCR) was performed to determine the expression level of UCHL1 mRNA in HCC cells, and western blot analysis was performed to examine the protein expression of UCHL1 protein in HCC cells. Immunohistochemistry assay was performed to determine the protein expression of UCHL1 in tissue samples from patients presenting with either positive or negative responses to the reversal therapeutic regimen of VER. Moreover, cell models with UCHL1 knockdown and overexpression were established to examine the reversal effect of VER on chemo-resistance to ADM in HCC cells. Cell apoptosis was determined by flow cytometry following Annexin V-PI staining. RESULTS The expression levels of UCHL1 genes correlated with the level of apoptosis induced by ADM+VER. Overexpression of UCHL1 genes promoted apoptosis in cells treated with VER+ADM. UCHL1 knockdown using siRNA weakened the effect of ADM+VER, indicating that ADM+VER promotes HCC cell apoptosis and that UCHL1 genes participate in VER-mediated promotion in tumor cell apoptosis. CONCLUSIONS Upregulation of UCHL1 enhanced the reversal effect of VER on chemo-resistance to ADM and promoted cell apoptosis. The underlying mechanism of the function of UCHL1 and the signaling pathway involved in its effect are to be investigated in our future research.

Nanok C, Jearanaikoon P, Proungvitaya S, Limpaiboon T
Aberrant methylation of HTATIP2 and UCHL1 as a predictive biomarker for cholangiocarcinoma.
Mol Med Rep. 2018; 17(3):4145-4153 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is the most common primary liver cancer in Northeastern Thailand where liver fluke infection is highly endemic. Although aberrant DNA methylation in CCA has been reported by several investigators, little is known regarding the associations between them. In the present study, the results obtained from our previously published methylation array were analyzed and 10 candidate genes involved in DNA repair [protein phosphatase 4 catalytic subunit (PPP4C)], apoptosis [runt related transcription factor 3 (RUNX3), interferon regulatory factor 4 (IRF4), ubiquitin C‑terminal hydrolase L1 (UCHL1) and tumor protein p53 inducible protein 3 (TP53I3)], cell proliferation [cyclin D2 (CCND2) and Ras association domain family member 1 (RASSF1)], drug metabolism [aldehyde dehydrogenase 1 family member A3 (ALDH1A3) and solute carrier family 29 member 1 (SLC29A1)] and angiogenesis [human immunodeficiency virus‑1 tat interactive protein 2 (HTATIP2)] were selected for quantification of their methylation levels in 54 CCA and 19 adjacent normal tissues using methylation‑sensitive high‑resolution melting. The associations between the methylation status of the individual genes and clinical parameters were statistically analyzed. High methylation levels were observed in UCHL1, IRF4, CCND2, HTATIP2 and TP53I3. The median methylation level of UCHL1 was 57.3% (range, 3.15 to 88.7%) and HTATIP2 was 13.6% (range, 7.5 to 36.7%). By contrast, low methylation of HTATIP2 and UCHL1 was identified in adjacent normal tissues. The methylation status of HTATIP2 and UCHL1 was associated with patients' overall survival. CCA patients with high methylation of HTATIP2 and low methylation of UCHL1 exhibited longer overall survival. In addition, multivariate Cox regression analysis demonstrated that UCHL1 methylation was an independent factor for CCA with hazard ratio of 1.81 (95% confidence interval, 1.01‑3.25) in high methylation group. The combination of HTATIP2 and UCHL1 methylation status strongly supported their potential predictive biomarker in which patients with CCA who had high methylation of HTATIP2 and low methylation of UCHL1 showed longer overall survival than those with low HTATIP2 methylation and high UCHL1 methylation. In conclusion, the present study revealed the value of aberrant DNA methylation of HTATIP2 and UCHL1, which may serve as a potential predictive biomarker for CCA.

Fang Y, Shen X
Ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications.
Cancer Metastasis Rev. 2017; 36(4):669-682 [PubMed] Related Publications
Protein ubiquitination and deubiquitination participate in a number of biological processes, including cell growth, differentiation, transcriptional regulation, and oncogenesis. Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), includes four members: UCH-L1/PGP9.5 (protein gene product 9.5), UCH-L3, UCHL5/UCH37, and BRCA1-associated protein-1 (BAP1). Recently, more attention has been paid to the relationship between the UCH family and malignancies, which play different roles in the progression of different tumors. It remains controversial whether UCHL1 is a tumor promoter or suppressor. UCHL3 and UCH37 are considered to be tumor promoters, while BAP1 is considered to be a tumor suppressor. Studies have showed that UCH enzymes influence several signaling pathways that play crucial roles in oncogenesis, tumor invasion, and migration. In addition, UCH families are associated with tumor cell sensitivity to therapeutic modalities. Here, we reviewed the roles of UCH enzymes in the development of tumors, highlighting the potential consideration of UCH enzymes as new interesting targets for the development of anticancer drugs.

Liu H, Zhou T, Wang B, et al.
Identification and functional analysis of a potential key lncRNA involved in fat loss of cancer cachexia.
J Cell Biochem. 2018; 119(2):1679-1688 [PubMed] Related Publications
Cancer cachexia is a devastating, multifactorial, and irreversible syndrome characterized by skeletal muscle reduction with or without fat loss. Although much attention has been focused on muscle wasting, fat loss may occur earlier and accelerate muscle wasting in cachexia. The cause of 20% of cancer related death makes it urgent to discover molecular mechanisms behind cancer cachexia. Here we applied weighted gene co-expression network analysis (WGCNA) to identify cachexia related gene modules using differentially expressed 3289 genes and 59 long non-coding RNAs based on microarray data of cachectic and non-cachectic subcutaneous adipose tissue. Subsequently, 16 independent modules were acquired and GSAASeqSP Toolset confirmed that black module was significantly associated with fat loss in cancer cachexia. Top 50 hub-genes in black module contained only one lncRNA, VLDLR antisense RNA 1 (VLDLR-AS1). We then explored the function of black module from the view of VLDLR-AS1-connected genes in the network. GO enrichment and KEGG pathways analysis revealed LDLR-AS1-connected genes were involved in Wnt signaling pathway, small GTPase mediated signal transduction, epithelial-mesenchymal transition and so on. Through construction of competing endogenous RNAs (ceRNAs) regulation network, we showed that VLDLR-AS1 may function with hsa-miR-600 to regulate gene GOLGA3, DUSP14, and UCHL1, or interact with hsa-miR-1224-3p to modulate the expression of gene GOLGA3, ZNF219, RNF141, and CALU. After literature validation, we predicted that VLDLR-AS1 most likely interacted with miR-600 to regulate UCH-L1 through Wnt/β-catenin signaling pathway. However, further experiments are still required to validate mechanisms of VLDLR-AS1 in fat reduction of cancer cachexia.

Nakashima R, Goto Y, Koyasu S, et al.
UCHL1-HIF-1 axis-mediated antioxidant property of cancer cells as a therapeutic target for radiosensitization.
Sci Rep. 2017; 7(1):6879 [PubMed] Free Access to Full Article Related Publications
Hypoxia-inducible factor 1 (HIF-1) has been recognized as an important mediator of the reprogramming of carbohydrate metabolic pathways from oxidative phosphorylation to accelerated glycolysis. Although this reprogramming has been associated with the antioxidant and radioresistant properties of cancer cells, gene networks triggering the HIF-1-mediated reprogramming and molecular mechanisms linking the reprogramming with radioresistance remain to be determined. Here, we show that Ubiquitin C-terminal hydrolase-L1 (UCHL1), which we previously identified as a novel HIF-1 activator, increased the radioresistance of cancer cells by producing an antioxidant, reduced glutathione (GSH), through HIF-1-mediated metabolic reprogramming. A luciferase assay to monitor HIF-1 activity demonstrated that the overexpression of UCHL1, but not its deubiquitination activity-deficient mutant (UCHL1 C90S), upregulated HIF-1 activity by stabilizing the regulatory subunit of HIF-1 (HIF-1α) in a murine breast cancer cell line, EMT6. UCHL1 overexpression induced the reprogramming of carbohydrate metabolism and increased NADPH levels in a pentose phosphate pathway (PPP)-dependent manner. The UCHL1-mediated reprogramming elevated intracellular GSH levels, and consequently induced a radioresistant phenotype in a HIF-1-dependent manner. The pharmacological inhibition of PPP canceled the UCHL1-mediated radioresistance. These results collectively suggest that cancer cells acquire antioxidant and radioresistant phenotypes through UCHL1-HIF-1-mediated metabolic reprogramming including the activation of PPP and provide a rational basis for targeting this gene network for radiosensitization.

Luo Y, He J, Yang C, et al.
UCH-L1 promotes invasion of breast cancer cells through activating Akt signaling pathway.
J Cell Biochem. 2018; 119(1):691-700 [PubMed] Free Access to Full Article Related Publications
As a de-ubiquitin enzyme, ubiquitin C-terminal hydrolase (UCH)-L1 has been shown to be overexpressed in several human cancers. However, the function of UCH-L1 in invasion of breast cancers is still unclear. Here we report that the expression of UCH-L1 is significantly higher in cancer cells with higher invasive ability. While ectopic UCH-L1 expression failed to alter cell proliferation in MCF-7 cells, it caused a significant upregulation of cellular invasion. Furthermore, siRNA mediated knockdown of UCH-L1 led to suppression of invasion in UCH-L1 overexpressing MCF-7 cells. In order to identify molecular mechanisms underlying these observations, a novel in vitro proximity-dependent biotin identification method was developed by fusing UCH-L1 protein with a bacterial biotin ligase (Escherichia coli BirA R118G, BioID). Streptavidin magnetic beads pulldown assay revealed that UCH-L1 can interact with Akt in MCF-7 cells. Pulldown assay with His tagged recombinant UCH-L1 protein and cell lysate from MCF-7 cells further demonstrated that UCH-L1 preferentially binds to Akt2 for Akt activation. Finally, we demonstrated that overexpression of UCH-L1 led to activation of Akt as evidenced by upregulation of phosphorylated Akt. Thus, these findings demonstrated that UCH-L1 promotes invasion of breast cancer cells and might serve as a potential therapeutic target for treatment of human patients with breast cancers.

Stephen JK, Chen KM, Merritt J, et al.
Methylation markers differentiate thyroid cancer from benign nodules.
J Endocrinol Invest. 2018; 41(2):163-170 [PubMed] Related Publications
PURPOSE: The incidence of thyroid cancer (TC) is increasing. Cytology by itself cannot distinguish TC from some benign nodules especially in certain subtypes of TC. Our immediate goal is to identify DNA methylation markers for early detection of TC and to molecularly differentiate TC subtypes from benign nodules.
METHODS: Promoter methylation status of 21 candidate genes was examined on formalin-fixed paraffin-embedded tissue (FFPE) utilizing quantitative methylation-specific polymerase chain reaction (QMSP) in a retrospective cohort of 329 patients (56% white, 29% African American, 61% female) comprising 71 normal thyroid, 83 benign nodules [follicular adenomas (FA)], 90 follicular TC (FTC) and 85 papillary TC (PTC). All genes were analyzed individually (Kruskal-Wallis and Wilcoxon rank sum tests) and in combination (logistic regression models) to identify genes whose methylation levels might best separate groups.
RESULTS: Combination gene panels TPO and UCHL1 (ROC = 0.607, sensitivity 78%) discriminated FTC from FA, and RASSF1 and TPO (ROC = 0.881, sensitivity 78%) discriminated FTC from normal. Methylation of TSHR distinguished PTC from FTC (ROC = 0.701, sensitivity 84%) and PTC from FA (ROC = 0.685, sensitivity 70%). The six gene panel of TIMP3, RARB2, SERPINB5, RASSF1, TPO and TSHR, which differentiates PTC from normal thyroid, had the best combination sensitivity (91%) and specificity (81%) of the panels addressing discrimination of cancer tissue.
CONCLUSIONS: Aberrant gene methylation used in combination panels may be useful clinically in differentiating FTC and PTC from benign nodules. If confirmed in additional studies, these findings could help reduce the over diagnosis of thyroid cancer and surgeries related to over diagnosis.

Song YL, Yu R, Qiao XW, et al.
Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors.
Sci Rep. 2017; 7(1):2205 [PubMed] Free Access to Full Article Related Publications
Prognostic biomarkers for the pancreatic neuroendocrine tumors are needed. Proteomic study on insulinoma has been rarely reported. We identified the differential expression of proteins between insulinoma and their paired tissues by proteomic analysis, and evaluated the prognostic significance of specific proteins in pancreatic neuroendocrine tumors including insulinoma. The differential expression of select proteins was validated in more than 300 tumors using immunohistochemical staining and western blot. Methylation of UCH-L1 promoter in tumors was examined by methylation specific PCR and validated by sequencing. The concurrent expression of UCH-L1 and α-internexin was correlated with the prognosis in 2 independent collectives of patients with tumors. Sixty-two and 219 proteins were significantly down-regulated and up-regulated in insulinomas, respectively. Demethylation of UCH-L1 promoter was associated with UCH-L1 expression in tumors (p = 0.002). The concurrent expression of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors was significantly associated with better overall survival and disease-free survival in the combination of both cohorts (log rank p = 3.90 × 10

Sanchez-Diaz PC, Chang JC, Moses ES, et al.
Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is associated with stem-like cancer cell functions in pediatric high-grade glioma.
PLoS One. 2017; 12(5):e0176879 [PubMed] Free Access to Full Article Related Publications
Pediatric high-grade gliomas represent 8-12% of all primary tumors of the nervous system in children. Five-year survival for these pediatric aggressive tumors is poor (15-35%) indicating the need to develop better treatments for pediatric high-grade gliomas. In this work we used SF188 and SJ-GBM2 cell lines to study the function of the ubiquitin carboxyl-terminal esterase L1 (UCHL1), a deubiquitinase de-regulated in several cancers, in pediatric high-grade gliomas. UCHL1 depletion in SF188 and SJ-GBM2 glioma cells was associated with decreased cell proliferation and invasion, along with a reduced ability to grow in soft agar and to form spheres (i.e. self-renewal measure). A 70% reduction in Wnt signaling was also observed in the SF188 and SJ-GBM2 UCHL1 knockdowns (KDs) using a TCF-dependent TOPflash reporter assay. Transcriptome comparisons of UCHL1 KDs versus vector control identified a list of 306 differentially expressed genes (at least 2-fold change; p <0.05) which included genes known to be involved in cancer like ACTA2, POSTN, LIF, FBXL7, FBXW11, GDF15, HEY2, but also potential novel genes such us IGLL5, ABCA4, AQP3, AQP4, CALB1, and ALK. Bioinformatics gene ontology (GO) analysis of these 306 genes revealed significant enrichment in "signal peptides", "extracellular matrix"and "secreted proteins" GO Terms. "Angiogenesis and blood vessel development", "neuron differentiation/development", cell adhesion", and "cell migration" also showed significant enrichment in our GO analysis. Top canonical pathways identified by Ingenuity Pathway Analysis (IPA) included "Clathrin-mediated Endocytosis Signaling" (p = 5.14x10-4), "Virus Entry via Endocytic Pathways" (p = 6.15x 10-4), and "High Mobility Group-Box 1 (HMGB1) Signaling" (p = 6.15x10-4). While FGF2, IL1B, TNF and PDGFB were predicted as top upstream regulators (p < 2x10-16) of the UCHL1 KD-associated transcriptome. Aberrant expression of UCHL1 in pediatric high-grade gliomas may promote cell invasion, transformation, and self-renewal properties, at least in part, by modulating Wnt/Beta catenin activity. UCHL1 might act as an oncogene in glioma within the gene network that imparts stem-like characteristics to these cancer cells.

Seo EY, Jin SP, Sohn KC, et al.
UCHL1 Regulates Melanogenesis through Controlling MITF Stability in Human Melanocytes.
J Invest Dermatol. 2017; 137(8):1757-1765 [PubMed] Related Publications
Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is involved in many signaling pathways via the ubiquitin-proteasome system. UCHL1 is expressed in the human skin and serves as a neuronal marker; however, its functions in melanogenesis remain unknown. Here, we investigated the role of UCHL1 in melanogenesis and elucidated the underlying mechanism using human melanocytes. UCHL1 downregulation by small interfering RNA resulted in upregulation of microphthalmia-associated transcription factor (MITF), tyrosinase, dopachrome tautomerase, tyrosinase-related protein-1, and melanin. In contrast, overexpression of UCHL1 in melanocytes via adenovirus transfection led to downregulation of tyrosinase, dopachrome tautomerase, and tyrosinase-related protein-1 and decreased melanin contents. Furthermore, UCHL1 reduced the protein, but not mRNA, levels of MITF, the upstream regulator of tyrosinase, dopachrome tautomerase, and tyrosinase-related protein-1. Inhibition of de novo protein synthesis and treatment of normal human primary epidermal melanocytes with proteasome inhibitor MG132 revealed that UCHL1 negatively regulates the stability of MITF by binding to the ubiquitinated protein. Finally, overexpression of MITF via an adenovirus restored the level of melanogenesis reduced by UCHL1. Collectively, our findings indicate a role of UCHL1 in regulating skin pigmentation. Suppression of MITF activity by UCHL1 via protein degradation might aid in the development of new therapeutic approaches for melanoma or dyspigmentation disorders.

Wang GY, Nazarian RM, Zhao L, et al.
Protein gene product 9.5 (PGP9.5) expression in benign cutaneous mesenchymal, histiocytic, and melanocytic lesions: comparison with cellular neurothekeoma.
Pathology. 2017; 49(1):44-49 [PubMed] Related Publications
Cellular neurothekeoma (CNTK) frequently enters the differential diagnosis of a benign dermal cellular proliferation. Diagnosis often relies on immunohistochemistry including the use of protein gene product 9.5 (PGP9.5). A previous study demonstrated PGP9.5 expression across a wide variety of soft tissue neoplasms. We explored the utility of this antibody in distinguishing CNTK from other benign dermal-based lesions. A cohort of CNTK (n=7) and benign cutaneous lesions of neural (n=28), fibrohistiocytic (n=23), fibroblastic (n=25), histiocytic (n=18), myofibroblastic (n=7), smooth muscle (n=14), and melanocytic (n=12) differentiations were immunostained with PGP9.5. Staining was graded by H-score and compared with CNTK. A significantly higher H-score was found in CNTK compared with the fibrohistiocytic (p=0.0001), histiocytic (p=0.0016), myofibroblastic (p=0.0003), smooth muscle (p<0.0001), and melanocytic (p=0.0004) groups, with the exceptions of plexiform fibrohistiocytic tumour, xanthoma, and xanthogranuloma. No significant difference was found when comparing CNTK with fibroblastic and neural lesions, with the exceptions of neurofibroma and perineurioma. In conclusion, PGP9.5 is helpful in distinguishing CNTK from most benign cutaneous fibrohistiocytic, histiocytic, myofibroblastic, smooth muscle, and melanocytic lesions. In addition to CNTK and neural lesions, PGP9.5 is also expressed in benign fibroblastic lesions, and therefore distinction of these lesions should not be based on PGP9.5 positivity.

Wen W, Liu G, Jin K, Hu X
TGF-β1 induces PGP9.5 expression in CAFs to promote the growth of colorectal cancer cells.
Oncol Rep. 2017; 37(1):115-122 [PubMed] Related Publications
Numerous studies indicate that the interaction between cancer-associated fibroblasts (CAFs) and tumors is manifested in the entire process of colorectal cancer (CRC) cell development, in which TGF-β1 plays a key role and has a significant effect on promoting the activation of CAFs. However, there are few studies on the mechanisms involved in the activation of CAFs by TGF-β1 to produce an influence on tumor cells. TGF-β1 was added to CAFs for further culture, and the expression of α-SMA was significantly enhanced as shown by immunofluorescence assay. Western blot analysis was performed, and the results showed that TGF-β1 promoted expression of PGP9.5 in a time-dependent manner. After siRNA was used to inhibit the expression of Smad2 or Smad3, the TGF-β1-induced PGP9.5 expression in CAFs was obviously suppressed. In addition, TGF-β1 was also found to promote the expression of PGP9.5 through the ERK1/2 and PI3K pathways. CAFs were cultured on the upper layer of a Transwell plate and TGF-β1 was added. Simultaneously, CRC cells were cultured on the lower layer. The biological behaviors of the cancer cells were detected. According to the results, TGF-β1 promoted the proliferation and invasion of CRC cells and inhibited their apoptosis while activating CAFs. This effect was achieved by induction of the expression of PGP9.5. However, when PGP9.5 was inhibited, the impact of TGF-β1 on tumor cells after activation of CAFs was not fully blocked. Therefore, TGF-β1 can promote PGP9.5 expression in CAFs to facilitate the growth of cancer cells. This finding aids in the identification of new targets for treating CRC.

Kozlowska A, Kwiatkowski P, Oponowicz A, et al.
Myenteric plexuses atrophy in the vicinity of colorectal cancer tissue is not caused by apoptosis or necrosis.
Folia Histochem Cytobiol. 2016; 54(2):99-107 [PubMed] Related Publications
INTRODUCTION: The previously performed studies showed that the presence of colorectal cancer (CRC) tumor is associated with the atrophy of myenteric plexuses in the vicinity of cancer invasion; however, the possible mechanisms of this phenomenon are not known. The aim of the present study was to determine whether the atrophic changes of the enteric nervous system (ENS) within an intestine wall of the CRC patients were caused by apoptosis or necrosis and whether they were associated with changes in the number of galanin-immunore-active (GAL-Ir) neurons.
MATERIAL AND METHODS: Samples of the large intestine wall located close to the CRC invasion and control, distally-located part of the colon, were collected from 9 CRC patients. The size of ENS plexuses and the number of neurons were compared. Triple immunofluorescent staining was used to visualize the co-expression of caspase 3 (CASP3) or caspase 8 (CASP8) with GAL and protein gene-product 9.5 (PGP 9.5, panneuronal marker) in the submucosal and myenteric ENS plexuses. The cells expressing myeloperoxidase (MPO, marker of neutrophils) and CD68 (marker of macrophages) were detected by immunohistochemistry around/in myenteric plexuses (MPs) and in the muscularis externa of the colon wall in the vicinity of tumor invasion.
RESULTS: Myenteric plexuses in the vicinity of the CRC tissue were significantly smaller and had lower number of neurons per plexus than distantly located plexuses. The number of CASP8- and CASP3-Ir neurons in the ENS plexuses was similar in the colon wall both close to and distally from tumor invasion. The number of CASP8-Ir neurons within MPs located close to CRC invasion was higher than of CASP3-Ir neurons. The percentage of neurons co-expressing CASP8 and GAL in myenteric plexuses close and distantly from tumor was three-fold lower than of those co-expressing CASP3 and GAL. The mean number of neutrophils and macrophages inside and around myenteric plexuses located close to tumor invasion was higher or similar, respectively, as compared with adjacent muscularis externa.
CONCLUSIONS: The atrophy of myenteric plexuses in the vicinity of CRC invasion is not caused by apoptosis or necrosis. The differences in the proportions of neurons expressing galanin and the studied caspases suggest as yet unknown role of this neuropeptide in the mechanisms of neuron's atrophy in MPs located close to CRC tumor.

Laco J, Mottl R, Höbling W, et al.
Cyclin D1 Expression in Ectomesenchymal Chondromyxoid Tumor of the Anterior Tongue.
Int J Surg Pathol. 2016; 24(7):586-94 [PubMed] Related Publications
Ectomesenchymal chondromyxoid tumor (ECT) is a rare benign tumor of uncertain lineage, which almost exclusively affects the anterior tongue. Herein, we report 2 cases of ECT occurring in 58- and 56-year-old males on the right and on the left side of the dorsum of the anterior tongue, measuring 18 mm and 10 mm, respectively. Despite positive resection margin in one case, none of the tumors recurred during follow-up of 6 and 5 years. Microscopically, both tumors had lobular architecture with a mixture of solid, microcystic, and chondromyxoid areas. The tumor cells were polygonal or elongated and showed mild atypia in one case. Immunohistochemically, both tumors showed diffuse expression of vimentin and focal positivity of CD10 and of smooth muscle actin. Regarding neural tissue-related markers, there was nearly diffuse expression of CD56 and neuron-specific enolase and focal positivity of PGP 9.5 in both cases and variable expression of CD57, synaptophysin, glial fibrillary acidic protein, and S-100 protein. Interestingly, we observed diffuse expression of SOX10 in one case. In both tumors, diffuse strong nuclear expression of cyclin D1 was present, without CCND1/IGH translocation or CCND1 amplification. The EWSR1 gene rearrangement was not detected. To the best of our knowledge, expression of SOX10, which may support neural crest origin of this peculiar lesion, has not been reported in ECT. The significance of strong cyclin D1 expression remains to be further investigated.

Bracalente C, Ibañez IL, Berenstein A, et al.
Reprogramming human A375 amelanotic melanoma cells by catalase overexpression: Upregulation of antioxidant genes correlates with regression of melanoma malignancy and with malignant progression when downregulated.
Oncotarget. 2016; 7(27):41154-41171 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) are implicated in tumor transformation. The antioxidant system (AOS) protects cells from ROS damage. However, it is also hijacked by cancers cells to proliferate within the tumor. Thus, identifying proteins altered by redox imbalance in cancer cells is an attractive prognostic and therapeutic tool. Gene expression microarrays in A375 melanoma cells with different ROS levels after overexpressing catalase were performed. Dissimilar phenotypes by differential compensation to hydrogen peroxide scavenging were generated. The melanotic A375-A7 (A7) upregulated TYRP1, CNTN1 and UCHL1 promoting melanogenesis. The metastatic A375-G10 (G10) downregulated MTSS1 and TIAM1, proteins absent in metastasis. Moreover, differential coexpression of AOS genes (EPHX2, GSTM3, MGST1, MSRA, TXNRD3, MGST3 and GSR) was found in A7 and G10. Their increase in A7 improved its AOS ability and therefore, oxidative stress response, resembling less aggressive tumor cells. Meanwhile, their decrease in G10 revealed a disruption in the AOS and therefore, enhanced its metastatic capacity.These gene signatures, not only bring new insights into the physiopathology of melanoma, but also could be relevant in clinical prognostic to classify between non aggressive and metastatic melanomas.

Pagano JS, Shackelford J
UCH-L1 in DLBCL: marker or target?
Blood. 2016; 127(12):1524-5 [PubMed] Free Access to Full Article Related Publications
In this issue of Blood, Bedekovics et al have demonstrated that a multifunctional molecule of the ubiquitin system ubiquitin C-terminal hydrolase L1 (UCH-L1) is induced in diffuse large B-cell lymphomas (DLBCLs), and that levels of this molecule are higher in germinal center (GC) B-cell DLBCL (GCB-DLBCL) compared with activated B-cell DLBCL (ABC-DLBCL) and predict poor outcomes.

Jin Y, Zhang W, Xu J, et al.
UCH-L1 involved in regulating the degradation of EGFR and promoting malignant properties in drug-resistant breast cancer.
Int J Clin Exp Pathol. 2015; 8(10):12500-8 [PubMed] Free Access to Full Article Related Publications
Ubiquitin carboxy terminal hydrolase-L1 (UCHL1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Our previous research showed that UCH-L1 and EGFR could regulate the expression of P-gp, CD147 and MMPs in multi-drug resistance (MDR) breast cancer cells, respectively. But it is still unclear whether direct regulation exists between the UCH-L1 and EGFR in MDR breast cancer. In order to clarify this, MDR human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We added ubiquitin proteasome inhibitor MG-132 into the culture of MCF7/Adr cells and transfected pIRES2-UCH-L1-EGFP plasmid into MCF7 cells, respectively. Using quantitative real-time polymerase chain reaction and western blot analyses, we found accompanying over-expression of UCH-L1, EGFR was up-regulated in both MCF7/ADR and MCF7 cells. Preliminary results indicated the degradation of EGFR might be regulated by ubiquitin level. So we speculated that up-regulated UCH-L1 could promote expression level of EGFR, thereby enhance the invasion and metastasis abilities of tumor cells. Moreover, to further explore the role of UCH-L1 and EGFR, we investigated the expression of UCH-L1, EGFR and P-gp in 65 local advanced breast cancer cases by immunohistochemistry assay. The result showed that the patients not responding to chemotherapy had higher UCH-L1, EGFR and P-gp expression levels and more lymph nodes metastasis. The Kaplan-Meier survival analysis showed that the patients with elevated UCH-L1 expression after chemotherapy presented shorter overall survival and disease free survival times than those with down-regulated or unchanged expression of UCH-L1. Our findings suggest that UCH-L1 may be an indicator of chemotherapy-response and poor-survival in breast cancer. UCH-L1 might be an appropriate target for improving chemo-resistant breast cancer therapy.

Bedekovics T, Hussain S, Feldman AL, Galardy PJ
UCH-L1 is induced in germinal center B cells and identifies patients with aggressive germinal center diffuse large B-cell lymphoma.
Blood. 2016; 127(12):1564-74 [PubMed] Free Access to Full Article Related Publications
Gene expression profiling has identified 2 major subclasses of diffuse large B-cell lymphoma (DLBCL). Cases resembling germinal center (GC) B cells (GCB-DLBCL) generally occur in younger patients, have a distinct molecular pathophysiology, and have improved outcomes compared with those similar to activated post-GC cells (activated B-cell DLBCL). We previously found that the ubiquitin hydrolase UCH-L1 is frequently overexpressed in mature B-cell malignancies and is a potent oncogene in mice. The cause for its overexpression in lymphoma, and whether it impacts the outcome of patients with DLBCL is unknown. Here, we show that UCH-L1 reflects GC lineage in lymphoma and is an oncogenic biomarker of aggressive GCB-DLBCL. We find that UCH-L1 is specifically induced in GC B cells in mice and humans, and that its expression correlates highly with the GCB subtype in DLBCL. We also find that UCH-L1 cooperates with BCL6 in a mouse model of GC B-cell lymphoma, but not with the development of multiple myeloma derived from post-GC cells. Despite the typically good outcomes of GCB-DLBCL, increased UCHL1 identifies a subgroup with early relapses independent of MYC expression, suggesting biological diversity in this subset of disease. Consistent with this, forced Uchl1 overexpression had a substantial impact on gene expression in GC B cells including pathways of cell cycle progression, cell death and proliferation, and DNA replication. These data demonstrate a novel role for UCH-L1 outside of the nervous system and suggest its potential use as a biomarker and therapeutic target in DLBCL.

Agarwal A, Pradhan R, Kumari N, et al.
Molecular Characteristics of Large Parathyroid Adenomas.
World J Surg. 2016; 40(3):607-14 [PubMed] Related Publications
INTRODUCTION: The clinical entity of large parathyroid adenomas (LPTAs) has not been well defined. It is speculated that LPTAs would have biochemical, histological, and molecular characteristics different from small adenomas. Our study aimed to find out occurrence of atypia and carcinomas in large parathyroid lesions and the presence of distinct molecular abnormalities in LPTAs.
MATERIALS AND METHODS: We divided the parathyroid lesions into large (>7 g, i.e., LPTAs) and small (<7 g) adenomas. We performed parafibromin, APC (adenomatous polyposis coli), galectin 3, and PGP9.5 (protein gene product 9.5) analysis by immunohistochemistry in adenomas without atypia, atypical adenomas, and carcinomas.
RESULTS: Mean serum calcium, alkaline phosphatase, and intact PTH were significantly higher in large parathyroid tumor group. The presence of both atypical adenoma and carcinoma was higher in large parathyroid tumor group. There was higher percentage of atypia in patients with LPTAs >10 g (33%), and 68% of tumors showed at least one marker suggestive of malignancy in this group. Detailed analysis of immunohistochemical features of LPTA >10 g revealed that six patients showed complete loss of parafibromin immunoreactivity (out of these four showed atypia), while seven showed partial loss. In histopathologically proven malignancy (n = 9), six patients showed complete loss of parafibromin staining, 5 (55%) APC negativity, and 45% showed both galectin 3 and PGP9.5 positivity. Three out of these showed all IHC markers s/o malignancy, and all of them had evidence of metastases or recurrence. 32% of atypical adenoma and 13% of atypical adenoma showed complete loss of parafibromin staining, however none developed metastases or recurrence in follow-up (median follow-up 40 months). Loss of parafibromin staining (complete or partial) was higher in LPTA group (56%) than that in small adenoma (39%); however, it was not statistically significant. APC, galectin 3, and PGP9.5 markers suggestive were higher in LPTA group but were not significant.
CONCLUSION: LPTAs may show some morphological and immunohistochemical features suggestive of malignancy and can be considered a separate entity. However, the immunohistochemical markers are unable to clearly segregate those LPTAs that may show premalignant potential. Further, we would like to recommend that LPTAs showing complete parafibromin loss together with atypia should be kept under close follow-up.

Friedrich RE, Behrendt CA, Glatzel M, Hagel C
Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1.
Anticancer Res. 2015; 35(12):6509-16 [PubMed] Related Publications
UNLABELLED: Neurofibroma constitutes a heterogeneous group of solid tumours occurring sporadically or in association with syndromes. The aspect of these peripheral nerve sheath tumours may vary considerably, with disseminated tumours covering various parts of the body or nodular/diffuse plexiform neurofibroma that can grow to an impressive size. Although neurofibromas have vascular density comparable to that of normal tissue, they have tendency to bleed upon surgery which is poorly understood. Herein we investigated whether this finding may result from alterations of peripheral vasculature innervation. Different types of neurofibroma and controls were evaluated with special reference to nerve fibre topography and vessel density.
MATERIALS AND METHODS: Seventy-six formalin-fixed and paraffin-embedded tissue samples (63 neurofibromas and 13 skin biopsies) were retrieved from the archives of the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf. Nerve fibres and blood vessels were differentiated immunohistochemically on 10-μm-thick tumour slices using antibodies against smooth muscle actin (arteries), protein gene product 9.5 (PGP9.5) and neurofilament (nerve fibres). Skin samples served as controls. Nerve fibre and vessel densities were quantified morphometrically.
RESULTS: Nerve fibre density varied considerably. However, vascular innervation did not statistically significantly differ between the different tumour sub-groups and controls. Vessel density was not significantly increased in tumours compared to skin biopsies. Within the tumour sub-groups, diffuse plexiform neurofibroma presented a significantly higher vascular density than atypical neurofibroma (p=0.006).
CONCLUSION: Blood vessel density and vascular innervation in the whole cohort of neurofibromas did not significantly differ from that of controls. Thus, the source of prolonged and intense bleeding of neurofibroma during surgical procedures cannot be explained by increased vessel density or loss of innervation, but may be attributed to other factors such as alterations in the structure of the vascular wall.

Oka S, Shiraishi K, Matsuyama H
Microsurgical Anatomy of the Spermatic Cord and Spermatic Fascia: Distribution of Lymphatics, and Sensory and Autonomic Nerves.
J Urol. 2016; 195(6):1841-7 [PubMed] Related Publications
PURPOSE: An understanding of the microsurgical anatomy of the spermatic cord and spermatic fascia is important for surgeons during microsurgical varicocelectomy and denervation. We examined the distribution of the lymphatics, and the sensory and autonomic nerves of the spermatic cord.
MATERIALS AND METHODS: We collected spermatic cords from 11 men undergoing orchiectomy for localized testicular tumors and we biopsied a third of the spermatic fascia from 36 men undergoing microsurgical varicocelectomy. Immunohistochemical staining of the pan-neuronal marker PGP 9.5 (protein gene product 9.5), the sensory nociceptor marker CPRP (calcitonin gene-related peptide), the sympathetic marker TH (tyrosine hydroxylase), the parasympathetic marker VIP (vasoactive intestinal polypeptide) and the lymphatic marker D2-40 was performed. We counted the number of nerves and lymphatics.
RESULTS: PGP 9.5 staining revealed dense nerve distributions in the spermatic cord and fascia. Sensory and autonomic nerve fibers were basically co-localized in the same nerve. Of the nerves 50% were identified near the vas deferens and 20% were identified in the spermatic fascia. Sensory and sympathetic nerve fibers represented most of the nerves but a few parasympathetic nerve fibers were observed. Of the lymphatics 36 per patient were identified in the spermatic cord but only a few were identified in the spermatic fascia.
CONCLUSIONS: Sensory and sympathetic nerves accounted for the majority of the nerves. Although the functional aspects of the nerves remain undetermined, information on the distribution of nerves and lymphatics is useful when dealing with nerves and preserving lymphatics during microsurgical varicocelectomy or denervation.

Shang D, Han T, Xu X, Liu Y
Decitabine induces G2/M cell cycle arrest by suppressing p38/NF-κB signaling in human renal clear cell carcinoma.
Int J Clin Exp Pathol. 2015; 8(9):11140-8 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: The anti-neoplastic effects of decitabine, an inhibitor of DNA promoter methylation, are beneficial for the treatment of renal cell carcinoma (RCC); however, the mechanism of action of decitabine is unclear. We analyzed gene expression profiling and identified specific pathways altered by decitabine in RCC cells.
METHODS: Four human RCC cell lines (ACHN, Caki-1, Caki-1, and A498) were used in this study; growth suppression of RCC cells by decitabine was analyzed using the WST-1 assay. Apoptosis and cell cycle arrest were examined using flow cytometric analysis. Gene expression of RCC cells induced by decitabine was evaluated with cDNA microarray, and potential biological pathways were selected using Ingenuity Pathway Analysis. The activity of the p38-NF-κB pathway regulated by decitabine was confirmed by Western blotting.
RESULTS: Decitabine suppresses the proliferation of RCC cells in vitro. Although decitabine did not significantly induce apoptosis, decitabine caused cell cycle arrest at G2/M in a dose-dependent manner. Gene expression regulated by decitabine in RCC cells was investigated using microarray analysis. Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), interferon inducible protein 27 (IFI27), and cell division cycle-associated 2 (CDCA2) may be involved in growth suppression of RCC cells by decitabine. The phosphorylation of p38-NF-κB pathway was suppressed by decitabine in RCC cells.
CONCLUSIONS: We investigated gene expression profiling and pathways modulated by decitabine in RCC cells. Decitabine was shown to suppress the growth of RCC cells via G2/M cell cycle arrest and the p38-NF-κB signaling pathway may play a role in the anti-neoplastic effect of decitabine in RCC cells.

Mu QJ, Li HL, Yao Y, et al.
Chromodomain Helicase/ATPase DNA-Binding Protein 1-Like Gene (CHD1L) Expression and Implications for Invasion and Metastasis of Breast Cancer.
PLoS One. 2015; 10(11):e0143030 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L), also known as ALC1 (amplified in liver cancer 1 gene), is a new oncogene amplified in many solid tumors. Whether this gene plays a role in invasion and metastasis of breast cancer is unknown.
METHODS: Immunohistochemistry was performed to detect the expression of CHD1L in patients with invasive ductal carcinoma and normal mammary glands. Chemotaxis, wound healing, and Transwell invasion assays were also performed to examine cell migration and invasion. Western blot analysis was conducted to detect the expression of CHD1L, MMP-2, MMP-9, pAkt/Akt, pARK5/ARK5, and pmTOR/mTOR. Moreover, ELISA was carried out to detect the expression levels of MMP-2 and MMP-9. Nude mice xenograft model was used to detect the invasion and metastasis of breast cancer cell lines.
RESULTS: CHD1L overexpression was observed in 112 of 268 patients (41.8%). This overexpression was associated with lymph node metastasis (P = 0.008), tumor differentiation (P = 0.020), distant metastasis (P = 0.026), MMP-2 (P = 0.035), and MMP-9 expression (P = 0.022). In the cell experiment, reduction of CHD1L inhibited the invasion and metastasis of breast cancer cells by mediating MMP-2 and MMP-9 expression. CHD1L knockdown via siRNA suppressed EGF-induced pAkt, pARK5, and pmTOR. This knockdown inhibited the metastasis of breast cancer cells into the lungs of SCID mice.
CONCLUSIONS: CHD1L promoted the invasion and metastasis of breast cancer cells via the PI3K/Akt/ARK5/mTOR/MMP signaling pathway. This study identified CHD1L as a potential anti-metastasis target for therapeutic intervention in breast cancer.

Wang G, Zhang W, Zhou B, et al.
The diagnosis value of promoter methylation of UCHL1 in the serum for progression of gastric cancer.
Biomed Res Int. 2015; 2015:741030 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant promoter methylation has been considered as a potential molecular marker for gastric cancer (GC). However, the role of methylation of FLNC, THBS1, and UCHL1 in the development and progression of GC has not been explored.
METHODS: The promoter methylation status of UCHL1, FLNC, THBS1, and DLEC1 was assessed by quantitative methylation-specific PCR (QMSP) in the serum of 82 GC patients, 46 chronic atrophic gastritis (CAG) subjects, and 40 healthy controls.
RESULTS: All four genes had significantly higher methylation levels in GC patients than in CAG and control subjects. However, only UCHL1 methylation was significantly correlated with the tumor stage and lymph node metastasis. While THBS1 methylation was altered in an age-dependent manner, FLNC methylation was correlated with differentiation and Helicobacter pylori infection. DLEC1 methylation was only associated with tumor size. Moreover, methylated UCHL1 with or without THBS1 in the serum was found to be significantly associated with a poor prognosis.
CONCLUSION: The promoter methylation degree of FLNC, THBS1, UCHL1, and DLEC1 in serum could tell the existence of GC and only UCHL1 in the serum was also associated with poor prognosis of GC.

Waraya M, Yamashita K, Ema A, et al.
Exclusive Association of p53 Mutation with Super-High Methylation of Tumor Suppressor Genes in the p53 Pathway in a Unique Gastric Cancer Phenotype.
PLoS One. 2015; 10(10):e0139902 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A comprehensive search for DNA methylated genes identified candidate tumor suppressor genes that have been proven to be involved in the apoptotic process of the p53 pathway. In this study, we investigated p53 mutation in relation to such epigenetic alteration in primary gastric cancer.
METHODS: The methylation profiles of the 3 genes: PGP9.5, NMDAR2B, and CCNA1, which are involved in the p53 tumor suppressor pathway in combination with p53 mutation were examined in 163 primary gastric cancers. The effect of epigenetic reversion in combination with chemotherapeutic drugs on apoptosis was also assessed according to the tumor p53 mutation status.
RESULTS: p53 gene mutations were found in 44 primary gastric tumors (27%), and super-high methylation of any of the 3 genes was only found in cases with wild type p53. Higher p53 pathway aberration was found in cases with male gender (p = 0.003), intestinal type (p = 0.005), and non-infiltrating type (p = 0.001). The p53 pathway aberration group exhibited less recurrence in lymph nodes, distant organs, and peritoneum than the p53 non-aberration group. In the NUGC4 gastric cancer cell line (p53 wild type), epigenetic treatment augmented apoptosis by chemotherapeutic drugs, partially through p53 transcription activity. On the other hand, in the KATO III cancer cell line (p53 mutant), epigenetic treatment alone induced robust apoptosis, with no trans-activation of p53.
CONCLUSION: In gastric cancer, p53 relevant and non-relevant pathways exist, and tumors with either pathway type exhibited unique clinical features. Epigenetic treatments can induce apoptosis partially through p53 activation, however their apoptotic effects may be explained largely by mechanism other than through p53 pathways.

Lee CH, Pan KL, Tang YC, et al.
LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation.
Oncotarget. 2015; 6(28):25188-201 [PubMed] Free Access to Full Article Related Publications
Previously, we identified global epigenetic aberrations in smoking-associated oral squamous cell carcinoma (OSCC). We hypothesized that cigarette exposure triggers OSCC through alteration of the methylome of oral cells. Here we report that cigarette smoke condensate (CSC) significantly changes the genomic 5-methyldeoxycytidine content and nuclear accumulation of DNA methyltransferase 1 (DNMT1) and DNMT3A in human untransformed oral cells. By using integrated analysis of cDNA and methylation arrays of the smoking-associated dysplastic oral cell line and OSCC tumors, respectively, we identified four epigenetic targets--UCHL1, GPX3, LXN, and LDOC1--which may be silenced by cigarette. Results of quantitative methylation-specific PCR showed that among these four genes, LDOC1 promoter was the most sensitive to CSC. LDOC1 promoter hypermethylation and gene silencing followed 3 weeks of CSC treatment. LDOC1 knockdown led to a proliferative response and acquired clonogenicity of untransformed oral cells. Immunohistochemistry showed that LDOC1 was downregulated in 53.3% (8/15) and 57.1% (20/35) of premalignant oral tissues and early stage OSCCs, respectively, whereas 76.5% (13/17) of normal oral tissues showed high LDOC1 expression. Furthermore, the microarray data showed that LDOC1 expression had decreased in the lung tissues of current smokers compared with that in those of never smokers and had significantly decreased in the lung tumors of smokers compared with that in normal lung tissues. Our data suggest that CSC-induced promoter methylation may contribute to LDOC1 downregulation, thereby conferring oncogenic features to oral cells. These findings also imply a tumor suppressor role of LDOC1 in smoking-related malignancies such as OSCC and lung cancer.

Abdelmaksoud-Dammak R, Saadallah-Kallel A, Miladi-Abdennadher I, et al.
CpG methylation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) and P53 mutation pattern in sporadic colorectal cancer.
Tumour Biol. 2016; 37(2):1707-14 [PubMed] Related Publications
The ubiquitin-proteasome system plays an essential regulatory role in various cellular processes. Besides its involvement in normal cellular functions, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders, including cancer. Aberrant methylation of the CpG islands has been reported as an alternative way to inactivate gene expression involved in the ubiquitination process and thus protein degradation in tumor tissues. In this study, we aimed to determine the CpG methylation pattern of the UCHL1 promoter, as well as the mutation spectrum and the expression pattern of P53 in sporadic colorectal cancer (CRC) from Tunisian patients. We found that UCHL1 was methylated in 68.57 % and correlated significantly with lymph node metastasis (P = 0.029) and transcriptional silencing in tumor tissues (P = 0.013). Mutation screening of exons 5-9 of P53 showed that 42.85 % of cases harbor somatic mutation and are positively correlated with the methylated pattern of UCHL1 (P = 0.001). Furthermore, cytoplasmic accumulation of P53 was strongly associated with the unmethylated UCHL1 profile (P = 0.006), supporting the relationship between these two proteins in CRC.

Wang W, Zou L, Zhou D, et al.
Overexpression of ubiquitin carboxyl terminal hydrolase-L1 enhances multidrug resistance and invasion/metastasis in breast cancer by activating the MAPK/Erk signaling pathway.
Mol Carcinog. 2016; 55(9):1329-42 [PubMed] Related Publications
Multidrug resistant (MDR) cancer cells overexpressing P-glycoprotein (P-gp) exhibit enhanced invasive/metastatic ability as compared with the sensitive cells. We aimed to clarify the mechanism underlying this observation and found that during the development of drug resistance to adriamycin in MCF7 cells, the elevated expression of UCH-L1 coincides with the up-regulation of MDR1, CD147, MMP2, and MMP9 as well as increased cellular migration/invasion. Overexpression of UCH-L1 in MCF7 cells up-regulated MDR1, CD147, MMP2, and MMP9, which conferred MDR and promoted migration/invasion. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Immunohistochemistry in 203 breast cancer samples revealed that UCH-L1 expression is positively correlated with P-gp, CD147, MMP2, and MMP9 expression and standard tumor spread indicators. Kaplan-Meier survival analysis indicated a correlation between UCH-L1 expression and shorter recurrent and survival times. Moreover, UCH-L1-overexpressing clones treated with U0126 (an Erk1/2-specific inhibitor) significantly decreased the expression of MDR1, CD147, MMP2, and MMP9. These data indicate that UCH-L1 may assume a dual role, because it had intrinsic stimulatory effects on tumor migration/invasion and increased MDR. © 2015 Wiley Periodicals, Inc.

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