GSTO1

Gene Summary

Gene:GSTO1; glutathione S-transferase omega 1
Aliases: P28, SPG-R, GSTO 1-1, GSTTLp28, HEL-S-21
Location:10q25.1
Summary:The protein encoded by this gene is an omega class glutathione S-transferase (GST) with glutathione-dependent thiol transferase and dehydroascorbate reductase activities. GSTs are involved in the metabolism of xenobiotics and carcinogens. The encoded protein acts as a homodimer and is found in the cytoplasm. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione S-transferase omega-1
Source:NCBIAccessed: 14 March, 2017

Ontology:

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 (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: GSTO1 (cancer-related)

Shaban NZ, Salem HH, Elsadany MA, et al.
Distribution of Glutathione S-Transferase Omega Gene Polymorphism with Different Stages of HBV Infection Including Hepatocellular Carcinoma in the Egyptian Population.
Asian Pac J Cancer Prev. 2016; 17(4):2145-50 [PubMed] Related Publications
BACKGROUND: Infection with hepatitis B virus (HBV) is a major global public health problem, with a wide spectrum of clinical manifestations. Human cytosolic glutathione-S-transferases (GSTs) include several classes such as alpha (A), mu (M), pi (P), sigma (S), zeta (Z), omega (O) and theta (T). The present study aimed to investigate the role of GST omega genes (GSTO1 and GSTO2) in different groups of patients infected with HBV.
MATERIALS AND METHODS: HBV groups were classified according to clinical history, serological tests and histological analysis into normal carriers (N), acute (A), chronic (CH), cirrhosis (CI) and hepatocellular carcinoma (HCC) cases. The study focused on determination of the genotypes of GST omega genes (GSTO1 and GSTO2) and GST activity and liver function tests.
RESULTS: The results showed that GSTO1 (A/A) was decreased in N, A, CH, CI and HCC groups compared to the C-group, while, GSTO1 (C/A) and GSTO1(C/C) genotypes were increased significantly in N, A, CH, CI and HCC groups. GSTO2 (A/A) was decreased in all studied groups as compared to the C-group but GSTO2(A/G) and GSTO2(G/G) genotypes were increased significantly. In addition, GST activities, albumin and TP levels were decreased in all studied groups compared to the C-group, while the activities of transaminases were increased to differing degrees.
CONCLUSIONS: The results indicate that GSTO genetic polymorphisms may be considered as biomarkers for determining and predicting the progression of HBV infection.

Zmorzyński S, Świderska-Kołacz G, Koczkodaj D, Filip AA
Significance of Polymorphisms and Expression of Enzyme-Encoding Genes Related to Glutathione in Hematopoietic Cancers and Solid Tumors.
Biomed Res Int. 2015; 2015:853573 [PubMed] Free Access to Full Article Related Publications
Antioxidant compounds such as glutathione and its enzymes have become the focus of attention of medical sciences. Glutathione, a specific tripeptide, is involved in many intercellular processes. The glutathione concentration is determined by the number of GAG repeats in gamma-glutamylcysteine synthetase. GAG polymorphisms are associated with an increased risk of schizophrenia, berylliosis, diabetes, lung cancer, and nasopharyngeal tumors. Cancer cells with high glutathione concentration are resistant to chemotherapy treatment. The oxidized form of glutathione is formed by glutathione peroxidases (GPXs). The changes in activity of GPX1, GPX2, and GPX3 isoforms may be associated with the development of cancers, for example, prostate cancer or even colon cancer. Detoxification of glutathione conjugates is possible due to activity of glutathione S-transferases (GSTs). Polymorphisms in GSTM1, GSTP1, and GSTO1 enzymes increase the risk of developing breast cancer and hepatocellular carcinoma. Gamma-glutamyl transpeptidases (GGTs) are responsible for glutathione degradation. Increased activity of GGT correlates with adverse prognosis in patients with breast cancer. Studies on genes encoding glutathione enzymes are continued in order to determine the correlation between DNA polymorphisms in cancer patients.

Deng X, Yang X, Cheng Y, et al.
GSTP1 and GSTO1 single nucleotide polymorphisms and the response of bladder cancer patients to intravesical chemotherapy.
Sci Rep. 2015; 5:14000 [PubMed] Free Access to Full Article Related Publications
SNPs may restrict cell detoxification activity and be a potential risk factor for cancer chemosensitivity. We evaluated the predictive value of these polymorphisms on the sensitivity of bladder cancer patients to epirubicin and mitomycin chemotherapy instillation as well as their toxicities. SNPs were analyzed by TaqMan genotyping assays in 130 patients treated with epirubicin and 114 patients treated with mitomycin. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method, and hazard ratios (HRs) and 95% confidence intervals (CIs) of the HRs were derived from multivariate Cox proportional hazard models. GSTP1 rs1695 and GSTO1 rs4925 were also associated with RFS in the epirubicin group. Patients carrying the GSTP1 AG+GG and GSTO1 AC+AA genotypes had an unfavorable RFS. Patients with the GSTP1 AA and GSTO1 CC genotypes had a reduced risk of recurrence after the instillation of epirubicin. In addition, patients with the GSTP1 rs1695 AA genotype had an increased risk of irritative voiding symptoms; while patients with the GSTO1 rs4925 CC genotype had a decreased risk of hematuria. Our results suggest that GSTP1 and GSTO1 polymorphisms are associated with epirubicin treatment outcomes as well as with epirubicin-related toxicity.

Qu K, Liu SS, Wang ZX, et al.
Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients.
World J Gastroenterol. 2015; 21(14):4310-22 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the effects of single nucleotide polymorphisms (SNPs) in glutathione S-transferase (GST) genes on survival of hepatocellular carcinoma (HCC) patients.
METHODS: Twelve tagging SNPs in GST genes (including GSTA1, GSTA4, GSTM2, GSTM3, GSTO1, GSTO2 and GSTP1) were genotyped using Sequenom MassARRAY iPLEX genotyping method in a cohort of 214 Chinese patients with resected HCC. The Cox proportional hazards model and log-rank test were performed to determine the SNPs related to outcome. Additionally, stratified analysis was performed at each level of the demographic and clinical variables. An SNP-gene expression association model was further established to investigate the correlation between SNP and gene expression.
RESULTS: Two SNPs (GSTO2: rs7085725 and GSTP1: rs4147581) were significantly associated with overall survival in HCC patients (P = 0.035 and 0.042, respectively). In stratified analysis, they were more significantly associated with overall survival in patients with younger age, male gender and cirrhosis. We further investigated cumulative effects of these two SNPs on overall survival in HCC patients. Compared with the patients carrying no unfavorable genotypes, those carrying 2 unfavorable genotypes had a 1.70-fold increased risk of death (P < 0.001). The cumulative effects were more significant in those patients with younger age, male gender and cirrhosis (HR = 2.00, 1.94 and 1.97, respectively; all P < 0.001). Additionally, we found that heavy smoking resulted in a significantly worse overall survival in those patients carrying variant alleles of rs7085725 (HR = 2.07, 95%CI: 1.13-3.76, P = 0.018). The distributions of GSTO2: rs7085725 and GSTP1: rs4147581 genotypes were associated with altered gene expression and contributed to influences on overall survival.
CONCLUSION: Our study provides the first evidence that GSTO2 and GSTP1 gene polymorphisms may serve as independent prognostic markers for HCC patients.

Rezazadeh D, Moradi MT, Kazemi A, Mansouri K
Childhood Pre-B acute lymphoblastic leukemia and glutathione S-transferase omega 1 and 2 polymorphisms.
Int J Lab Hematol. 2015; 37(4):530-5 [PubMed] Related Publications
INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy among children and makes up 23% of total childhood cancers worldwide. Pre-B ALL is one of the most common ALLs, comprising about 80% of childhood cases. A variety of genes are involved in metabolizing carcinogens. These gene polymorphisms can result in less efficient or overly-down metabolic pathways, which may contribute to the susceptibility to develop cancer. Glutathione S-transferase omega (GSTO) is a new known class among GSTs superfamily. GSTO1 and GSTO2 polymorphisms have been reported to be related to several types of disease. We assessed the association between GSTO1 and GSTO2 polymorphisms and childhood pre-B ALL risk in Iran.
METHODS: This case-control study analyzed GSTO1 A140D (rs. 4925) and GSTO2 N142D (rs. 156697) gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism method, in 100 patients and 120 healthy controls.
RESULTS: The genotype frequencies were not significantly different between patients and healthy controls. Odds ratio (95% confidence intervals) for mutant homozygotes were 1.54 (0.628-3.778) and 0.791 (0.349-1.793) for GSTO1 A140D and GSTO2 N142D, respectively.
CONCLUSION: This study found no significant association between Pre-B ALL and GSTO1 A140D and GSTO2 N142D polymorphisms.

Ren YB, Luo T, Li J, et al.
p28(GANK) associates with p300 to attenuate the acetylation of RelA.
Mol Carcinog. 2015; 54(12):1626-35 [PubMed] Related Publications
Oncoprotein p28(GANK), overexpressed in hepatocellular carcinomas (HCC), binds to RelA and retains NF-κB in the cytoplasm to suppress NF-κB transactivation. However, the mechanism has not yet been elucidated. In this study, we clarified the mechanism of NF-κB regulated by p28(GANK). p28(GANK) reduced TNF-α-induced nuclear translocation of RelA/NF-κB independent of HDAC3. p28(GANK) interacted with p300 to attenuate assembly of RelA with p300, which lessened acetylation of RelA on the lysine 310 sites. Moreover, overexpression of p28(GANK) attenuated the capability of NF-κB binding to the target gene IκBα promoter, but also weakened adriamycin-induced NF-κB pro-apoptotic gene Fas and FasL expression, which subsequently made p53-deficient tumor cells resistance to adriamycin. These results present mechanistic insight into the key role of p28(GANK) in post-translational regulation of RelA/NF-κB.

Tung MC, Wang YH, Yeh SD, et al.
Combined effects of GSTO1 and SULT1A1 polymorphisms and cigarette smoking on urothelial carcinoma risk in a Taiwanese population.
J Formos Med Assoc. 2014; 113(9):640-7 [PubMed] Related Publications
BACKGROUND/PURPOSE: Cigarette smoking is the main risk factor for urothelial carcinoma of the bladder (UCB). Glutathione S-transferase omega 1 (GSTO1) and sulfotransferase 1A1 (SULT1A1) have been reported to be associated with the metabolism of polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. The aim of the present study was to investigate the combined effects of polymorphisms in GSTO1 and SULT1A1 genes and cigarette smoking on UCB risk in a Taiwanese population.
METHODS: A total of 300 patients with histopathologically confirmed UCB and 233 cancer-free controls were recruited from the Department of Urology of Tung's Taichung Metro Harbor Hospital and Taipei Medical University Hospital. A comprehensive interview was conducted to collect personal information, including demographic characteristics and cigarette smoking status. A multivariate-adjusted logistic regression was performed to estimate the risk of UCB.
RESULTS: A significantly increased risk of UCB was observed in ever smokers [odds ratio (OR) = 2.3]. The Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene were associated with a significantly increased risk of UCB, with ORs of 1.8 [95% confidence interval (CI) = 1.2-2.6] and 2.1 (95% CI = 1.6-4.5), respectively. Significantly increased UCB risks were found in heavy smokers with the Ala/Ala genotype of the GSTO1 gene (OR = 4.2) and the Arg/Arg genotype of the SULT1A1 gene (OR = 6.8). Furthermore, a significant synergistic effect in an additive model (OR = 3.5) between the GSTO1 Ala/Ala genotype and the SULT1A1 Arg/Arg genotype on UCB risk was observed.
CONCLUSION: The present study provided epidemiological evidence for a significantly increased risk of UCB in ever smokers with the Ala/Ala genotype of the GSTO1 gene and the Arg/Arg genotype of the SULT1A1 gene.

Colunga A, Bollino D, Schech A, Aurelian L
Calpain-dependent clearance of the autophagy protein p62/SQSTM1 is a contributor to ΔPK oncolytic activity in melanoma.
Gene Ther. 2014; 21(4):371-8 [PubMed] Free Access to Full Article Related Publications
Oncolytic virotherapy is a promising strategy for reducing tumor burden through selective virus replication in rapidly proliferating cells. However, the lysis of slowly replicating cancer stem cells (CSCs), which maintain neoplastic clonality, is relatively modest and the potential contribution of programmed cell death pathways to oncolytic activity is still poorly understood. We show that the oncolytic virus ΔPK lyses CSC-enriched breast cancer and melanoma 3D spheroid cultures at low titers (0.1 pfu/cell) without resistance development and it inhibits the 3D growth potential (spheroids and agarose colonies) of melanoma and breast cancer cells. ΔPK induces calpain activation in both melanoma and breast cancer 3D cultures as determined by the loss of the p28 regulatory subunit, and 3D growth is restored by treatment with the calpain inhibitor PD150606. In melanoma, ΔPK infection also induces light chain 3 (LC3)-II accumulation and p62/SQSTM1 clearance, both markers of autophagy, and 3D growth is restored by treatment with the autophagy inhibitor chloroquine (CQ). However, expression of the autophagy-required protein Atg5 is not altered and CQ does not restore p62/SQSTM1 expression, suggesting that the CQ effect may be autophagy-independent. PD150606 restores expression of p62/SQSTM1 in ΔPK-infected melanoma cultures, suggesting that calpain activation induces anti-tumor activity through p62/SQSTM1 clearance.

Di Meo S, Airoldi I, Sorrentino C, et al.
Interleukin-30 expression in prostate cancer and its draining lymph nodes correlates with advanced grade and stage.
Clin Cancer Res. 2014; 20(3):585-94 [PubMed] Related Publications
PURPOSE: The interleukin (IL)-27 cytokine subunit p28, also called IL-30, has been recognized as a novel immunoregulatory mediator endowed with its own functions. These are currently the subject of discussion in immunology, but completely unexplored in cancer biology. We set out to investigate the role of IL-30 in prostate carcinogenesis and its effects on human prostate cancer (hPCa) cells.
EXPERIMENTAL DESIGN: IL-30 expression, as visualized by immunohistochemistry and real-time reverse transcriptase PCR on prostate and draining lymph nodes from 125 patients with prostate cancer, was correlated with clinicopathologic data. IL-30 regulation of hPCa cell viability and expression of selected gene clusters was tested by flow cytometry and PCR array.
RESULTS: IL-30, absent in normal prostatic epithelia, was expressed by cancerous epithelia with Gleason ≥ 7% of 21.3% of prostate cancer stage I to III and 40.9% of prostate cancer stage IV. IL-30 expression by tumor infiltrating leukocytes (T-ILK) was higher in stage IV that in stage I to III prostate cancer (P = 0.0006) or in control tissue (P = 0.0011). IL-30 expression in prostate draining lymph nodes (LN)-ILK was higher in stage IV than in stage I to III prostate cancer (P = 0.0031) or in control nodes (P = 0.0023). The main IL-30 sources were identified as CD68(+) macrophages, CD33(+)/CD11b(+) myeloid cells, and CD14(+) monocytes. In vitro, IL-30 stimulated proliferation of hPCa cells and also downregulated CCL16/LEC, TNFSF14/LIGHT, chemokine-like factor (CKLF), and particularly CKLF-like MARVEL transmembrane domain containing 3 (CMTM3) and greatly upregulated ChemR23/CMKLR.
CONCLUSIONS: We provide the first evidence that IL-30 is implicated in prostate cancer progression because (i) its expression by prostate cancer or T- and LN-ILK correlates with advanced disease grade and stage; and (ii) IL-30 exerts protumor activity in hPCa cells.

Skoric D, Ivana J, Tanja R, et al.
Methylenetetrahydrofolate reductase and glutathione S-tranferase gene polymorphisms in secondary mixed phenotype acute leukemia: a case report.
J Pediatr Hematol Oncol. 2014; 36(3):e152-4 [PubMed] Related Publications
BACKGROUND: Therapy-induced leukemia is a well-known clinical syndrome occurring as a late complication in patients treated with cytotoxic therapy.
OBSERVATION: We herein present results of analysis of common gene polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase (GST) genes in a 10-year-old boy who developed very rare type of cancer, mixed phenotype acute leukemia, 6 years after treatment of acute lymphoblastic leukemia.
CONCLUSIONS: Impairment in function of GST and MTHFR enzymes found in our patient may have contributed to the development of secondary mixed phenotype acute leukemia, although precise mechanism remains elusive.

Djukic TI, Savic-Radojevic AR, Pekmezovic TD, et al.
Glutathione S-transferase T1, O1 and O2 polymorphisms are associated with survival in muscle invasive bladder cancer patients.
PLoS One. 2013; 8(9):e74724 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To examine the association of six glutathione transferase (GST) gene polymorphisms (GSTT1, GSTP1/rs1695, GSTO1/rs4925, GSTO2/rs156697, GSTM1, GSTA1/rs3957357) with the survival of patients with muscle invasive bladder cancer and the genotype modifying effect on chemotherapy.
PATIENTS AND METHODS: A total of 105 patients with muscle invasive bladder cancer were included in the study. The follow-up lasted 5 years. The effect of GSTs polymorphisms on predicting mortality was analyzed by the Cox proportional hazard models, while Kaplan-Meier analysis was performed to assess differences in survival.
RESULTS: GSTT1 active, GSTO1 Asp140Asp or GSTO2 Asp142Asp genotypes were independent predictors of a higher risk of death among bladder cancer patients (HR = 2.5, P = 0.028; HR = 2.9, P = 0.022; HR = 3.9, P = 0.001; respectively) and significantly influenced the overall survival. There was no association between GSTP1, GSTM1 and GSTA1 gene variants with overall mortality. Only GSTO2 polymorphism showed a significant effect on the survival in the subgroup of patients who received chemotherapy (P = 0.006).
CONCLUSION: GSTT1 active genotype and GSTO1 Asp140Asp and GSTO2 Asp142Asp genotypes may have a prognostic/pharmacogenomic role in patients with muscle invasive bladder cancer.

Ada TG, Ada AO, Kunak SC, et al.
Association between glutathione S-transferase omega 1 A140D polymorphism in the Turkish population and susceptibility to non-small cell lung cancer.
Arh Hig Rada Toksikol. 2013; 64(2):61-7 [PubMed] Related Publications
Recent years have seen a growing evidence of ethnic differences in the frequency of glutathione S-transferase omega 1 (GSTO1) A140D gene polymorphism, which is associated with various cancers such as breast and liver. Until now however, no association has been investigated between the GSTO1 A140D polymorphism and lung cancer. The aim of our study was to see if there was one in the Turkish population. To do that, we identified GSTO1 A140D polymorphism in 214 unrelated healthy individuals and 172 patients with non-small cell lung cancer (NSCLC) using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of A/A (wild type), A/D (heterozygous mutant), and D/D (homozygous mutant) GSTO1 A140D genotypes in healthy subjects were 48%, 41%, and 11%, respectively. In NSCLC patients they were 48%, 45%, and 7%, respectively. We found no significant association between the GSTO1 A140D gene polymorphism and NSCLC or its histological subtypes, namely squamous cell carcinoma or adenocarcinoma. Furthermore, this polymorphism did not correlate with smoking. Our study is the first to show that the frequency of GSTO1 A140D gene polymorphism in the Turkish population is similar to other Caucasian populations and that this polymorphism is not associated with susceptibility to NSCLC.

Seibold P, Hall P, Schoof N, et al.
Polymorphisms in oxidative stress-related genes and mortality in breast cancer patients--potential differential effects by radiotherapy?
Breast. 2013; 22(5):817-23 [PubMed] Related Publications
We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.

Sanguansin S, Petmitr S, O-Charoenrat P, Pongstaporn W
Association of glutathione S-transferase omega gene polymorphisms with progression of head and neck cancer.
Mol Biol Rep. 2012; 39(12):10915-20 [PubMed] Related Publications
This study investigated the influence of glutathione S-transferase omega 1 (GSTO1) and GSTO2 gene polymorphisms on susceptibility and aggressiveness of head and neck squamous cell carcinoma (HNSCC). A case-control study consisting of 300 HNSCC cases and 299 age and sex- matched normal control was performed. Genotyping of GSTO1*A140D and GSTO2*N142D polymorphisms was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Our results revealed that the frequencies of GSTO1 and GSTO2 genotypes were not significantly different between HNSCC cases and controls. No significant differences were found in smoking or drinking status between cases and controls. However, HNSCC individuals with the GSTO1*D140 varient were significantly associated with nodal metastasis (OR = 0.53, 95 %CI = 0.31-0.91, P = 0.020) and advanced pathological stage (OR = 0.33,95 %CI = 0.15-0.70, P = 0.032), while no significant association was observed between GSTO2 genotype and clinicopathological features. Therefore, our findings suggest that the GSTO1*D140 variant genotype in individuals might play a protective role against the aggressiveness of HNSCC.

Luo X, Chen L, Dai J, et al.
Gankyrin gene deletion followed by proteomic analysis: insight into the roles of Gankyrin in tumorigenesis and metastasis.
BMC Med Genomics. 2012; 5:36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gankyrin was originally purified and characterized as the p28 component of the 26S proteasome, and later identified as an oncogenic protein in hepatocellular carcinomas (HCC). It has recently been found to be highly expressed in several other malignancies, and compelling evidence show gankyrin plays important roles in tumorigenesis. However, its mechanism of action remains unclear.
METHODS: In order to further clarify the functions of gankyrin and better understand its molecular mechanisms, we generated a gankyrin null cell line, HCT116 gankyrin-/- , by targeted homologous recombination in human colon cancer cells, and then employed two-dimensional electrophoresis (2-DE) based proteomic approaches followed by MS identification to investigate alterations in the proteome due to the gankyrin knockout. Western blot and qRT-PCR assays were also used to examine the protein and mRNA levels of some identified proteins.
RESULTS: Compared with wild-type control cells, gankyrin null cells were impaired in terms of their proliferation, migration and anchorage-independent growth. A total of 21 altered proteins were identified, which included 18 proteins that had not previously been reported to be related to gankyrin. Notably, eight metastasis-related proteins were identified. Western blot analyses confirmed that the changes in three examined proteins were consistent with 2-DE gel analysis.
CONCLUSIONS: In summary, we have generated a useful cell tool to clarify the functions of gankyrin. Our proteomic data provide novel information to better understand the roles and underlying mechanisms by which gankyrin is involved in tumorigenesis and cancer metastasis.

Henke A, Grace OC, Ashley GR, et al.
Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer.
PLoS One. 2012; 7(8):e42516 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIM: During prostate development, mesenchymal-epithelial interactions regulate organ growth and differentiation. In adult prostate, stromal-epithelial interactions are important for tissue homeostasis and also play a significant role in prostate cancer. In this study we have identified molecules that show a mesenchymal expression pattern in the developing prostate, and one of these showed reduced expression in prostate cancer stroma.
METHODOLOGY AND PRINCIPAL FINDINGS: Five candidate molecules identified by transcript profiling of developmental prostate mesenchyme were selected using a wholemount in situ hybridisation screen and studied Decorin (Dcn), Semaphorin6D (Sema6D), SPARC/Osteonectin (SPARC), Sprouty1 (Spry-1) and Tsukushi (Tsku). Expression in rat tissues was evaluated using wholemount in situ hybridisation (postnatal day (P) 0.5) and immunohistochemistry (embryonic day (E) E17.5, E19.5; P0.5; P6; 28 & adult). Four candidates (Decorin, SPARC, Spry-1, Tsukushi) were immunolocalised in human foetal prostate (weeks 14, 16, 19) and expression of Decorin was evaluated on a human prostate cancer tissue microarray. In embryonic and perinatal rats Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi were expressed with varying distribution patterns throughout the mesenchyme at E17.5, E19.5, P0.5 and P6.5. In P28 and adult prostates there was either a decrease in the expression (Semaphorin6D) or a switch to epithelial expression of SPARC, and Spry-1, whereas Decorin and Tsukushi were specific to mesenchyme/stroma at all ages. Expression of Decorin, SPARC, Spry-1 and Tsukushi in human foetal prostates paralleled that in rat. Decorin showed mesenchymal and stromal-specific expression at all ages and was further examined in prostate cancer, where stromal expression was significantly reduced compared with non-malignant prostate.
CONCLUSION AND SIGNIFICANCE: We describe the spatio-temporal expression of Decorin, Semaphorin6D, SPARC, Spry-1 and Tsukushi in developing prostate and observed similar mesenchymal expression patterns in rat and human. Additionally, Decorin showed reduced expression in prostate cancer stroma compared to non-malignant prostate stroma.

Doueiri R, Anupam R, Kvaratskhelia M, et al.
Comparative host protein interactions with HTLV-1 p30 and HTLV-2 p28: insights into difference in pathobiology of human retroviruses.
Retrovirology. 2012; 9:64 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Human T lymphotropic virus type-1 (HTLV-1) and type 2 (HTLV-2) are closely related human retroviruses, but have unique disease associations. HTLV-1 is the causative agent of an aggressive T-cell leukemia known as adult T-cell leukemia (ATL), HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory diseases. HTLV-2 infection has not been clearly associated with any disease condition. Although both viruses can transform T cells in vitro, the HTLV-1 provirus is mainly detected in CD4+ T cells whereas HTLV-2 is mainly detected in CD8+ T cells of infected individuals. HTLV-1 and HTLV-2 encode accessory proteins p30 and p28, respectively, which share partial amino acid homology and are required for viral persistence in vivo. The goal of this study was to identify host proteins interacting with p30 and p28 in order to understand their role in pathogenesis.
RESULTS: Affinity-tag purification coupled with mass spectrometric (MS) analyses revealed 42 and 22 potential interacting cellular partners of p30 and p28, respectively. Of these, only three cellular proteins, protein arginine methyltransferase 5 (PRMT5), hnRNP K and 60 S ribosomal protein L8 were detected in both p30 and p28 fractions. To validate the proteomic results, four interacting proteins were selected for further analyses using immunoblot assays. In full agreement with the MS analysis two cellular proteins REGγ and NEAF-interacting protein 30 (NIP30) selectively interacted with p30 and not with p28; heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) bound to p28 and not to p30; and PRMT5 interacted with both p30 and p28. Further studies demonstrated that reduced levels of PRMT5 resulted in decreased HTLV-2 viral gene expression whereas the viral gene expression of HTLV-1 was unchanged.
CONCLUSION: The comparisons of p30 and p28 host protein interaction proteome showed striking differences with some degree of overlap. PRMT5, one of the host proteins that interacted with both p30 and p28 differentially affected HTLV-1 and HTLV-2 viral gene expression suggesting that PRMT5 is involved at different stages of HTLV-1 and HTLV-2 biology. These findings suggest that distinct host protein interaction profiles of p30 and p28 could, in part, be responsible for differences in HTLV-1 and HTLV-2 pathobiology. This study provides new avenues of investigation into mechanisms of viral infection, tropism and persistence.

Beebe-Dimmer JL, Iyer PT, Nriagu JO, et al.
Genetic variation in glutathione S-transferase omega-1, arsenic methyltransferase and methylene-tetrahydrofolate reductase, arsenic exposure and bladder cancer: a case-control study.
Environ Health. 2012; 11:43 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ingestion of groundwater with high concentrations of inorganic arsenic has been linked to adverse health outcomes, including bladder cancer, however studies have not consistently observed any elevation in risk at lower concentrations. Genetic variability in the metabolism and clearance of arsenic is an important consideration in any investigation of its potential health risks. Therefore, we examined the association between genes thought to play a role in the metabolism of arsenic and bladder cancer.
METHODS: Single nucleotide polymorphisms (SNPs) in GSTO-1, As3MT and MTHFR were genotyped using DNA from 219 bladder cancer cases and 273 controls participating in a case-control study in Southeastern Michigan and exposed to low to moderate (<50 μg/L) levels of arsenic in their drinking water. A time-weighted measure of arsenic exposure was constructed using measures from household water samples combined with past residential history, geocoded and merged with archived arsenic data predicted from multiple resources.
RESULTS: While no single SNP in As3MT was significantly associated with bladder cancer overall, several SNPs were associated with bladder cancer among those exposed to higher arsenic levels. Individuals with one or more copies of the C allele in rs11191439 (the Met287Thr polymorphism) had an elevated risk of bladder cancer (OR = 1.17; 95% CI = 1.04-1.32 per 1 μg/L increase in average exposure). However, no association was observed between average arsenic exposure and bladder cancer among TT homozygotes in the same SNP. Bladder cancer cases were also 60% less likely to be homozygotes for the A allele in rs1476413 in MTHFR compared to controls (OR = 0.40; 95% CI = 0.18-0.88).
CONCLUSIONS: Variation in As3MT and MTHFR is associated with bladder cancer among those exposed to relatively low concentrations of inorganic arsenic. Further investigation is warranted to confirm these findings.

Qian YW, Chen Y, Yang W, et al.
p28(GANK) prevents degradation of Oct4 and promotes expansion of tumor-initiating cells in hepatocarcinogenesis.
Gastroenterology. 2012; 142(7):1547-58.e14 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is believed to arise from tumor-initiating cells (T-ICs), although little is known about their stem cell-like properties.
METHODS: We quantified levels of p28(GANK) (Gankyrin), OV6, and Oct4 in 130 human HCC samples using immunohistochemistry. Magnetic-activated cell sorting was used to isolate OV6+ HCC cells. T-IC properties were evaluated by quantitative reverse-transcription polymerase chain reaction, flow cytometry, and spheroid formation. We used a coimmunoprecipitation assay to study interactions among p28(GANK), Oct4, and WWP2. Tumorigenicity and pulmonary metastasis were examined in nonobese diabetic and severe combined immunodeficient mice.
RESULTS: In HCC samples, high levels of p28(GANK) correlated with expansion of OV6+ tumor cells; the combination of high levels of p28(GANK) and OV6 was associated with progression of HCC. p28(GANK) was predominantly expressed in liver T-ICs, isolated by magnetic sorting, and undifferentiated primary HCC spheroids. Increased levels of p28(GANK) in T-ICs increased their percentages in HCC samples, expression of stem cell genes, self-renewal potential, chemoresistance in vitro, and tumorigenicity and ability to develop into pulmonary metastases in mice. Conversely, knockdown of p28(GANK) reduced their T-IC properties. p28(GANK) likely activates liver T-ICs by impeding ubiquitination and degradation of the transcription factor Oct4 by WWP2. In support of this concept, levels of p28(GANK) correlated with those of Oct4 in HCC samples.
CONCLUSIONS: p28(GANK) activates and maintains liver T-ICs in HCCs by preventing degradation of Oct4. Inhibitors of p28(GANK) might therefore be developed to inactivate T-ICs and slow tumor progression.

Saadat M, Khalili M, Nasiri M, et al.
Clinical response to chemotherapy in locally advanced breast cancer was not associated with several polymorphisms in detoxification enzymes and DNA repair genes.
Biochem Biophys Res Commun. 2012; 419(1):117-9 [PubMed] Related Publications
The main aim of the present study was to investigate the association between several genetic polymorphisms (in glutathione S-transferase members and DNA repair genes) and clinical response to chemotherapy in locally advanced breast cancer. A sequential series of 101 patients were prospectively included in this study. Clinical assessment of treatment was accomplished by comparing initial tumor size with preoperative tumor size using revised RECIST guideline (version 1.1). Clinical response was regarded as a response or no response. There was no difference between non-responders and responders for the prevalence of genotypes of the study polymorphisms.

Liu L, Meng J, Zhang C, et al.
Effects on apoptosis and cell cycle arrest contribute to the antitumor responses of interleukin-27 mediated by retrovirus in human pancreatic carcinoma cells.
Oncol Rep. 2012; 27(5):1497-503 [PubMed] Related Publications
Interleukin (IL)-27, composed of p28 and Epstein-Barr virus-induced gene 3 (EBI3) subunits, has diverse functions in regulating immune systems. Human melanoma cells have been shown to express both IL-27 receptor subunits, and growth inhibition by IL-27 was detected. We investigated whether forced expression of the p28-linked EBI3 gene in human pancreatic carcinoma cells (AsPC1) by retroviral vector would produce IL-27-mediated antitumor effects and the related mechanisms. The data demonstrated that AsPC1 cells expressed both IL-27 receptor subunits, and tumor growth of AsPC1/IL-27 in mice was retarded compared with vector DNA-transduced tumors and survival of the mice was prolonged. Expression of cytokines such as interferon-γ, tumor necrosis factor-α and IL-1β in tumor specimens increased, while the secretion of IFN-γ and TNF-α from spleen cells of mice bearing IL-27-transfected tumors increased. Moreover, cell cycle arrest was induced in AsPC1/IL-27 inoculated mice with upregulated p21 expression and downregulated survivin expression. The appearance of apoptotic cells increased in tumor specimens of mice bearing IL-27-transfected tumors compared with the mice bearing DNA-transfected tumors by confirming the expression of apoptosis-related proteins and activated apoptotic pathways through detection of cleaved PARP. These results suggest that transfection of the IL-27 gene into human pancreatic carcinoma cells could produce antitumor effects in vivo and induction of cell cycle arrest and apoptosis could be the mechanism of IL-27 action in tumor regression.

Kukongviriyapan V
Genetic polymorphism of drug metabolizing enzymes in association with risk of bile duct cancer.
Asian Pac J Cancer Prev. 2012; 13 Suppl:7-15 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is the most common cancer in endemic areas of liver fluke infection. Although the liver fluke is recognized as a carcinogenic agent in cholangiocarcinogenesis, other factors may play important roles in bringing about the high prevalence of the cancer in populations of this region. Drug metabolizing enzymes (DME) are essential for detoxification of toxic and carcinogenic chemicals. Moreover, DME can play an alternative role by activating chemicals to more toxic metabolites. The large variation of DME activity among individuals is partly due to polymorphism of the genes encoding enzymes. Defective or variant alleles of DME genes may modify the risk of cancer in those who are exposeed to carcinogenic agents. The focus in this review is on DME genes which have been reported to be associated with CCA risk. These include CYP1A2, arylamine- N-acetyltransferase-1 (NAT1) and NAT2, NADPH-quinone oxidorecutase-1 (NQO1), glutathione-S-transferase M1 (GSTM1), GSTT1, GSTO1 and methylenetetrahydrofolate reductase (MTHFR). Mutant alleles which have been reportedly associated with an increased risk include CYP1A2*1F, GSTT1 null, GSTO1 and MTHFR 677C>T, whereas, slow NAT2 and NQO1*2 decrease risk and NAT1 variants and GSTM1 null have no effect. These genes modify the risk of cancer potentially by interaction and exposure with certain environmental conditions, thereby altering the metabolism of causative agents.

Hsu LI, Chen WP, Yang TY, et al.
Genetic polymorphisms in glutathione S-transferase (GST) superfamily and risk of arsenic-induced urothelial carcinoma in residents of southwestern Taiwan.
J Biomed Sci. 2011; 18:51 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Arsenic exposure is an important public health issue worldwide. Dose-response relationship between arsenic exposure and risk of urothelial carcinoma (UC) is consistently observed. Inorganic arsenic is methylated to form the metabolites monomethylarsonic acid and dimethylarsinic acid while ingested. Variations in capacity of xenobiotic detoxification and arsenic methylation might explain individual variation in susceptibility to arsenic-induced cancers.
METHODS: To estimate individual susceptibility to arsenic-induced UC, 764 DNA specimens from our long-term follow-up cohort in Southwestern Taiwan were used and the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and arsenic methylation enzymes including GSTO1 and GSTO2 were genotyped.
RESULTS: The GSTT1 null was marginally associated with increased urothelial carcinoma (UC) risk (HR, 1.91, 95% CI, 1.00-3.65), while the association was not observed for other GSTs. Among the subjects with cumulative arsenic exposure (CAE) ≥ 20 mg/L*year, the GSTT1 null genotype conferred a significantly increased cancer risk (RR, 3.25, 95% CI, 1.20-8.80). The gene-environment interaction between the GSTT1 and high arsenic exposure with respect to cancer risk was statistically significant (multiplicative model, p = 0.0151) and etiologic fraction was as high as 0.86 (95% CI, 0.51-1.22). The genetic effects of GSTO1/GSTO2 were largely confined to high arsenic level (CAE ≥ 20). Diplotype analysis showed that among subjects exposed to high levels of arsenic, the AGG/AGG variant of GSTO1 Ala140Asp, GSTO2 5'UTR (-183)A/G, and GSTO2 Asn142Asp was associated with an increased cancer risk (HRs, 4.91, 95% CI, 1.02-23.74) when compared to the all-wildtype reference, respectively.
CONCLUSIONS: The GSTs do not play a critical role in arsenic-induced urothelial carcinogenesis. The genetic effects of GSTT1 and GSTO1 on arsenic-induced urothelial carcinogenesis are largely confined to very high exposure level.

Dong LW, Yang GZ, Pan YF, et al.
The oncoprotein p28GANK establishes a positive feedback loop in β-catenin signaling.
Cell Res. 2011; 21(8):1248-61 [PubMed] Free Access to Full Article Related Publications
p28(GANK) (also known as PSMD10 or gankyrin) is a novel oncoprotein that is highly expressed in hepatocellular carcinoma (HCC). Through its interaction with various proteins, p28(GANK) mediates the degradation of the tumor suppressor proteins Rb and p53. Although p53 was reported to downregulate β-catenin, whether p28(GANK) is involved in the regulation of β-catenin remains uncertain. Here we report that both growth factors and Ras upregulate p28(GANK) expression through the activation of the phosphoinositide 3-kinase-AKT pathway. Upregulation of p28(GANK) expression subsequently enhanced the transcription activity of β-catenin. This effect was observed in p53-deficient cells, suggesting a p53-independent mechanism for the p28(GANK)-mediated activation of β-catenin. p28(GANK) overexpression also reduced E-cadherin protein levels, leading to increased release of free β-catenin into the cytoplasm from the cadherin-bound pool. Interestingly, exogenous expression of p28(GANK) resulted in elevated expression of the endogenous protein. We also observed that both β-catenin and c-Myc were transcriptional activators of p28(GANK), and a correlation between p28(GANK) overexpression and c-Myc, cyclin D1 and β-catenin activation in primary human HCC. Together, these results suggest that p28(GANK) expression is regulated by a positive feedback loop involving β-catenin, which may play a critical role in tumorigenesis and the progression of HCC.

Chung CJ, Pu YS, Su CT, et al.
Gene polymorphisms of glutathione S-transferase omega 1 and 2, urinary arsenic methylation profile and urothelial carcinoma.
Sci Total Environ. 2011; 409(3):465-70 [PubMed] Related Publications
Genetic polymorphisms in arsenic-metabolizing enzymes may be involved in the biotransformation of inorganic arsenic and may increase the risk of developing urothelial carcinoma (UC). The present study evaluated the roles of glutathione S-transferase omega 1 (GSTO1) and GSTO2 polymorphisms in UC carcinogenesis. A hospital-based case-control study was conducted. Questionnaire information and biological specimens were collected from 149 UC cases and 251 healthy controls in a non-obvious inorganic arsenic exposure area in Taipei, Taiwan. The urinary arsenic profile was determined using high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Genotyping for GSTO1 Ala140Asp and GSTO2 Asn142Asp was conducted using polymerase chain reaction-restriction fragment length polymerase. GSTO1 Glu208Lys genotyping was performed using high-throughput matrix-assisted laser desorption and ionization time-of-flight mass spectrometry. A significant positive association was found between total arsenic, inorganic arsenic percentage and monomethylarsonic acid percentage and UC, while dimethylarsinic acid percentage was significantly inversely associated with UC. The minor allele frequency of GSTO1 Ala140Asp, GSTO1 Glu208Lys and GSTO2 Asn142Asp was 18%, 1% and 26%, respectively. A significantly higher MMA% was found in people who carried the wild type of GSTO1 140 Ala/Ala compared to those who carried the GSTO1 140 Ala/Asp and Asp/Asp genotype (p=0.02). The homogenous variant genotype of GSTO2 142 Asp/Asp was inversely associated with UC risk (OR=0.17; 95% CI, 0.03 - 0.88; p=0.03). Large-scale studies will be required to verify the association between the single nucleotide polymorphisms of arsenic-metabolism-related enzymes and UC risk.

Chariyalertsak S, Purisa W, Sangrajrang S
Role of glutathione S-transferase omega gene polymorphisms in breast-cancer risk.
Tumori. 2009 Nov-Dec; 95(6):739-43 [PubMed] Related Publications
BACKGROUND/AIMS: Genetically influenced variations in the levels of activity and/or expression of some members of the glutathione S-transferase (GST) family have been identified as risk factors for cancer. One, GST omega (GSTO), has been found in a very limited number of studies. The aim of the present study was to investigate the influence of GSTO1 and GSTO2 polymorphisms on breast cancer risk.
METHODS: DNA isolated from the blood of 101 patients with breast cancer and 151 healthy controls was investigated for GSTO1 and GSTO2 polymorphisms by polymerase chain reaction-restriction-fragment length polymorphism.
RESULTS: Univariate and multivariate analyses showed no association between GSTO1 and GSTO2 genotypes and the risk of breast cancer. A higher prevalence of wild-type GSTO1 (A140/A140) was significantly correlated with advanced-stage breast cancer (OR = 0.1, 95% CI, 0.01-0.77), but the presence of the genotype did not correlate with patient age at diagnosis, menopausal status, tumor size, lymph node metastasis, or estrogen-receptor status. No association was found between GSTO2 genotype and clinicopathological features.
CONCLUSIONS: The results of the study suggest that GSTO1 and GSTO2 variants are not associated with breast cancer risk, but that wild-type GSTO1 (A140/A140) is likely among cases at an advanced stage.

Tang S, Yang G, Meng Y, et al.
Overexpression of a novel gene gankyrin correlates with the malignant phenotype of colorectal cancer.
Cancer Biol Ther. 2010; 9(2):88-95 [PubMed] Related Publications
Gankyrin, a small and highly conserved protein which is identical to the p28 gene product, was found to be related with the malignant phenotypes in liver and esophageal carcinoma. However, the roles of gankyrin in colorectal carcinoma (CRC) are still unknown. In the present study, the gankyrin mRNA and protein expression in human CRC cell lines and clinical tissue samples were evaluated and correlated with clinicopathological features. Possible mechanisms by which gankyrin regulates the malignant phenotype of CRC cells were also investigated. The results demonstrated that gankyrin was obviously overexpressed in CRC tissues and cell lines compared to controls, and gankyrin expression was correlated with TNM stages and metastasis of CRC. Overexpression of gankyrin by PhkitNeo-hGankyrin plasmid transfected into Lovo cells could promote the cell proliferation and tumorigenicity. This finding was further strengthened by experiments that suppressing gankyrin expression by siRNA exerted the opposite effects on CRC cells SW620. In addition, our present study showed that the co-expression of cyclinD1 and beta-catenin were positive correlation with the alteration of gankyrin expression. This data suggested that gankyrin played significant roles in the pathogenesis of human CRC, and might be an important therapeutic target for CRC.

Andonova IE, Justenhoven C, Winter S, et al.
No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk.
Breast Cancer Res Treat. 2010; 121(2):497-502 [PubMed] Related Publications
Breast cancer is a complex disease and in recent years a number of breast cancer susceptibility genes have been identified, but the role of low penetrance susceptibility genes has not been completely resolved. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes involved in the detoxification of chemical carcinogens and environmental pollutants and play an important role in cell defense mechanisms against oxidative stress. They have been in the spot light for the investigation of a potential association with breast cancer risk but so far, sparse or even no data for a potential contribution of GSTA2, GSTM2, GSTO, and GSTZ to breast cancer risk are available. We genotyped GSTA2_448_C > G (rs2180314), GSTA2_742_A > C (rs6577), GSTM2_-832_T > C (rs638820), GSTO1_-1242_G > A (rs2164624), GSTO1_419_A > C (rs4925), GSTO2_-183_A > G (rs2297235), GSTO2_342_A > G (rs156697), GSTZ1_-4378_A > G (rs1046428), and GSTZ1_94_G > A (rs3177427) by MALDI-TOF MS in the German GENICA breast cancer case-control collection of 1021 cases and 1015 controls and performed breast cancer risk association in general and with respect to the stratifications: menopausal status, family history of breast or ovarian cancer, use of oral contraceptives, use of hormone therapy, body mass index, and smoking as well as histopathological tumor characteristics including hormone receptor status, grade, histology, and node status. We did not observe any breast cancer risk associations and conclude that it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility.

Nagai H, Oniki S, Fujiwara S, et al.
Antitumor activities of interleukin-27 on melanoma.
Endocr Metab Immune Disord Drug Targets. 2010; 10(1):41-6 [PubMed] Related Publications
The worldwide incidence of malignant melanoma has been steadily increasing, and it has become a major public health problem in many countries. Melanoma has been considered as a prototypical "immunogenic" tumor on the basis of clinical observations showing that primary lesions can spontaneously regress and that immunosuppressed individuals have an increased incidence of melanoma. Thus, various immunological therapies have been intensively conducted for the treatment of melanoma. Interleukin(IL)-27 is a IL-12-related heterodimeric cytokine composed of p28 and EBV-induced gene 3 subunits that are structurally related to the p35 and p40 subunits of IL-12, respectively. Recent studies reveal that IL-27 exhibits not only potent antitumor immune activities via cytotoxic T lymphocytes or natural killer cells but also an antiangiogenic effect. We recently clarified that IL-27 possesses an antiproliferative activity on melanoma cells. This review summarizes anti-tumor responses induced by IL-27 and novel anti-melanoma activities of IL-27.

Dai RY, Chen Y, Fu J, et al.
p28GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity.
Cell Res. 2009; 19(11):1243-57 [PubMed] Related Publications
It has been shown that oncoprotein p28(GANK), which is consistently overexpressed in human hepatocellular carcinoma (HCC), plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28(GANK) inhibits apoptosis in HCC cells induced by the endoplasmic reticulum (ER) stress. During ER stress, p28(GANK) enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell's ability to cope with the stress conditions. Furthermore, p28(GANK) upregulates glucose-regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28(GANK) increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B (NF-kappaB) activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28(GANK) inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28(GANK) has potential implications for HCC progression under the ER stress conditions.

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