Gene Summary

Gene:HSP90AB1; heat shock protein 90 alpha family class B member 1
Aliases: HSP84, HSPC2, HSPCB, D6S182, HSP90B
Summary:This gene encodes a member of the heat shock protein 90 family; these proteins are involved in signal transduction, protein folding and degradation and morphological evolution. This gene encodes the constitutive form of the cytosolic 90 kDa heat-shock protein and is thought to play a role in gastric apoptosis and inflammation. Alternative splicing results in multiple transcript variants. Pseudogenes have been identified on multiple chromosomes. [provided by RefSeq, Dec 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:heat shock protein HSP 90-beta
Source:NCBIAccessed: 16 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Mutation
  • Cell Proliferation
  • Viral Regulatory and Accessory Proteins
  • Xenograft Models
  • Up-Regulation
  • Receptor, erbB-2
  • Young Adult
  • Ovarian Cancer
  • Acute Myeloid Leukaemia
  • Messenger RNA
  • Proteomics
  • Gene Expression Regulation
  • Deoxycytidine
  • Chromosome 6
  • Case-Control Studies
  • DNA-Binding Proteins
  • Cell Cycle
  • Lung Cancer
  • Immunohistochemistry
  • Annexin A1
  • Phosphorylation
  • Protein Binding
  • Transcription Factors
  • HSP90 Heat-Shock Proteins
  • TOR Serine-Threonine Kinases
  • Risk Factors
  • Enzyme Inhibitors
  • citreoviridin
  • Gastrointestinal Stromal Tumors
  • Stomach Cancer
  • Staging
  • Cancer Gene Expression Regulation
  • Benzoquinones
  • cdc25 Phosphatases
  • Base Sequence
  • Proteins
  • Apoptosis
  • Alleles
  • Biomarkers, Tumor
  • Tumor Suppressor Proteins
  • Valproic Acid
  • Single Nucleotide Polymorphism
  • Non-Small Cell Lung Cancer
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

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: HSP90AB1 (cancer-related)

Cui F, Zan X, Li Y, et al.
Grifola frondosa Glycoprotein GFG-3a Arrests S phase, Alters Proteome, and Induces Apoptosis in Human Gastric Cancer Cells.
Nutr Cancer. 2016; 68(2):267-79 [PubMed] Related Publications
GFG-3a is a novel glycoprotein previously purified from the fermented mycelia of Grifola frondosa with novel sugar compositions and protein sequencing. The present study aims to investigate its effects on the cell cycle, differential proteins expression, and apoptosis of human gastric cancer SGC-7901 cells. Our findings revealed that GFG-3a induced the cell apoptosis and arrested cell cycle at S phase. GFG-3a treatment resulted in the differential expression of 21 proteins in SGC-7901 cells by upregulating 10 proteins including RBBP4 associated with cell cycle arrest and downregulating 11 proteins including RUVBL1, NPM, HSP90AB1, and GRP78 involved in apoptosis and stress response. qRT-PCR and Western blot analysis also suggested that GFG-3a could increase the expressions of Caspase-8/-3, p53, Bax, and Bad while decrease the expressions of Bcl2, Bcl-xl, PI3K, and Akt1. These results indicated that the stress response, p53-dependent mitochondrial-mediated, Caspase-8/-3-dependent, and PI3k/Akt pathways were involved in the GFG-3a-induced apoptosis process in SGC-7901 cells. These findings might provide a basis to prevent or treat human gastric cancer with GFG-3a and understand the tumor-inhibitory molecular mechanisms of mushroom glycoproteins.

Hu CW, Hsu CL, Wang YC, et al.
Temporal Phosphoproteome Dynamics Induced by an ATP Synthase Inhibitor Citreoviridin.
Mol Cell Proteomics. 2015; 14(12):3284-98 [PubMed] Free Access to Full Article Related Publications
Citreoviridin, one of toxic mycotoxins derived from fungal species, can suppress lung cancer cell growth by inhibiting the activity of ectopic ATP synthase, but has limited effect on normal cells. However, the mechanism of citreoviridin triggering dynamic molecular responses in cancer cells remains unclear. Here, we performed temporal phosphoproteomics to elucidate the dynamic changes after citreoviridin treatment in cells and xenograft model. We identified a total of 829 phosphoproteins and demonstrated that citreoviridin treatment affects protein folding, cell cycle, and cytoskeleton function. Furthermore, response network constructed by mathematical modeling shows the relationship between the phosphorylated heat shock protein 90 β and mitogen-activated protein kinase signaling pathway. This work describes that citreoviridin suppresses cancer cell growth and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling by site-specific dephosphorylation of HSP90AB1 on Serine 255 and provides perspectives in cancer therapeutic strategies.

Liu LL, Zhao H, Ma TF, et al.
Identification of valid reference genes for the normalization of RT-qPCR expression studies in human breast cancer cell lines treated with and without transient transfection.
PLoS One. 2015; 10(1):e0117058 [PubMed] Free Access to Full Article Related Publications
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is a powerful technique for examining gene expression changes during tumorigenesis. Target gene expression is generally normalized by a stably expressed endogenous reference gene; however, reference gene expression may differ among tissues under various circumstances. Because no valid reference genes have been documented for human breast cancer cell lines containing different cancer subtypes treated with transient transfection, we identified appropriate and reliable reference genes from thirteen candidates in a panel of 10 normal and cancerous human breast cell lines under experimental conditions with/without transfection treatments with two transfection reagents. Reference gene expression stability was calculated using four algorithms (geNorm, NormFinder, BestKeeper and comparative delta Ct), and the recommended comprehensive ranking was provided using geometric means of the ranking values using the RefFinder tool. GeNorm analysis revealed that two reference genes should be sufficient for all cases in this study. A stability analysis suggests that 18S rRNA-ACTB is the best reference gene combination across all cell lines; ACTB-GAPDH is best for basal breast cancer cell lines; and HSPCB-ACTB is best for ER+ breast cancer cells. After transfection, the stability ranking of the reference gene fluctuated, especially with Lipofectamine 2000 transfection reagent in two subtypes of basal and ER+ breast cell lines. Comparisons of relative target gene (HER2) expression revealed different expressional patterns depending on the reference genes used for normalization. We suggest that identifying the most stable and suitable reference genes is critical for studying specific cell lines under certain circumstances.

Ozgur A, Tutar L, Tutar Y
Regulation of Heat Shock Proteins by miRNAs in human breast cancer.
Microrna. 2014; 3(2):118-35 [PubMed] Related Publications
Metabolic rates of cancer cells are faster compared to normal cells. This faster rate yields aberrant protein folding and causes loss of protein function. Therefore, cancer cells need more Heat Shock Proteins (HSPs) for proper substrate- protein folding on oncogenic pathways. Pseudogenes regulate tumor suppressors and oncogenes, and pseudogenes are deregulated in cancer progression. Further, alterations in miRNA expression have been identified in different cancer types. MiRNAs also have both oncogenic and tumour-suppressive roles in breast cancer post-transcriptional gene regulation. Breast cancer is a genetic disease and we performed miRNA analysis in human breast cancer cell lines to identify miRNAs in association with HSPs and pseudogenes by employing CellMiner; a web-based suite. CellMiner integrates several databases and help analysing microarray metadata. The experimental data provide a platform for researchers to compare macromolecules' relationships in NCI-60 cell lines. Breast cancer associated miRNAs gathered from literature and analyzed by employing this suite, significantly correlated HSP genes and pseudogenes in the breast cancer are determined as; HSPA13, HSP90AB1, TRAP1, HSPB1, DNAJB4, HSPD1 and HSP90AA4P, HSPB1P1, DNAJC8P1, HSPD1P9 respectively. HSPs involved in breast cancer are regulated by several miRNAs and miRNA regulators from CellMiner data found as hsa-miR-17, hsa-miR-22, hsa-miR-93, hsa-miR-106a, hsa-miR-125b, hsa-miR-130a, and hsamiR- 141. Cross check of the determined miRNAs and target HSPs was performed by target site prediction software. Comparison of the experimental data from CellMiner and software predicted data indicate differences. CellMiner data provide a vast miRNA types compared to prediction softwares-web tools data and reported miRNAs in the literature. Therefore, reported key miRNAs in this work that are not studied earlier may help cancer researchers to uncover novel posttranslational regulation mechanisms. Cancer cells use HSP network as an escape mechanism from apoptosis, therefore inhibition of associated HSPs by modulating miRNAs may provide a novel therapy for the tumorigenesis.

El-Mallawany NK, Day N, Ayello J, et al.
Differential proteomic analysis of endemic and sporadic Epstein-Barr virus-positive and negative Burkitt lymphoma.
Eur J Cancer. 2015; 51(1):92-100 [PubMed] Related Publications
BACKGROUND: Burkitt lymphoma (BL) is the most common non-Hodgkin lymphoma in children worldwide and the most common paediatric malignancy in sub-Saharan Africa. The endemic (eBL) and sporadic (sBL) variants have distinct epidemiologic and virologic characteristics. Although gene expression studies have defined the transcriptional profiles of both, their proteomic signatures have not been studied.
METHODS: We compared the proteomic expression profiles using differential mass spectrometry-based isotope tag for relative and absolute quantitation (iTRAQ) analysis of a cell line representing Epstein-Barr virus (EBV)+ eBL, EBV+ and EBV- sBL, and EBV+/- normal B cells from healthy donors.
RESULTS: In total, there were 144 differentially expressed proteins with a statistically significant false discovery rate (FDR) of ⩽0.2. Results revealed over-expression of specific proteins with well-established links to lymphomagenesis such as TUBB2C (FDR 0.05), UCHL1 (FDR 0.05) and HSP90AB1 (FDR 0.1). Distinct characteristics based upon the epidemiologic and virologic subtypes of BL were also identified. In sBL, PCNA (FDR 0.05) and SLC3A2 (FDR 0.1) were significantly over-expressed. In eBL, C1QBP (FDR 0.1) and ENO1 (FDR 0.25) were significantly over-expressed. Comparison of EBV+ to EBV- BL cell lines and B cells revealed significant over-expression of DDX3X (FDR 0.1). Proteins were validated using Western blot analysis.
CONCLUSION: Our results suggest unique signal transduction pathways associated with EBV infection and epidemiological subtype of BL that may contribute to lymphomagenesis. These proteomic findings provide potential diagnostic, prognostic and therapeutic links to BL.

Severson PL, Vrba L, Stampfer MR, Futscher BW
Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells.
Mutat Res Genet Toxicol Environ Mutagen. 2014; 775-776:48-54 [PubMed] Free Access to Full Article Related Publications
Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutations were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. The results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.

Biaoxue R, Shuanying Y, Wei L, et al.
Co-overexpression of Hsp90-β and annexin A1 with a significantly positive correlation contributes to the diagnosis of lung cancer.
Expert Rev Mol Diagn. 2014; 14(8):1067-79 [PubMed] Related Publications
AIM: Hsp90-β and annexin A1 have been demonstrated to be associated with tumorigenesis. However, the effect of Hsp90-β and annexin A1 in lung cancer remains poorly understood. In this research, the correlation of Hsp90-β and annexin A1 in lung cancer patients were analyzed.
METHODS: The expression levels of Hsp90-β and annexin A1 were examined by immunohistochemistry and ELISA.
RESULTS: Lung cancer tissues and serum exhibited higher co-expression of Hsp90-β and annexin A1 than control groups (p < 0.05). Hsp90-β and annexin A1 could discriminate lung cancer from the control groups (sensitivity of Hsp90-β was 80.2% in tissues and 96% in serum; specificity of Hsp90-β was 80% in tissues and 83.33% in serum; sensitivity of annexin A1 was 68.76% in tissues and 95.23% in serum; specificity of annexin A1 was 75% in tissues and 85.7% in serum) and multi-index combined detection had a better diagnostic value.
CONCLUSION: The expression levels of Hsp90-β and annexin A1 positively correlated and such co-overexpression of Hsp90-β and annexin A1 contributed to lung cancer diagnosis.

Coskunpinar E, Akkaya N, Yildiz P, et al.
The significance of HSP90AA1, HSP90AB1 and HSP90B1 gene polymorphisms in a Turkish population with non-small cell lung cancer.
Anticancer Res. 2014; 34(2):753-7 [PubMed] Related Publications
BACKGROUND/AIM: Heat-shock proteins (HSPs) are molecular chaperones which modify the structures and interactions of other proteins. The aim of our study was to investigate HSP90AA1, HSP90AB1 and HSP90B1 gene polymorphisms in patients with non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS: Ninety-seven patients with NSCLC and 97 healthy controls were included in the study. Real-time polymerase chain reaction was used for genotyping.
RESULTS: The frequency of mutant CC genotype for HSP90AA1 (rs4947C/T), mutant AA genotype for HSP90AB1 (rs13296A/G) and mutant CC genotype for HSP90B1 (rs2070908 C/G) was significantly higher in the patient group than in controls (p=0.019, p=0.004 and p=0.036, respectively). The frequency of patients with homozygote mutant allele was also significantly higher than that of controls and possessing of the mutant genotype increased the risk for disease by approximately 2.9, 4.8, 1.9 for HSP90AA1, HSP90AB1 and HSP90B1, respectively. The present study appears to be the first of its kind to report data on these gene polymorphisms in patients with NSCLC in the Turkish population.

Tanaka K, Eskin A, Chareyre F, et al.
Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2.
Clin Cancer Res. 2013; 19(14):3856-70 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The growth and survival of neurofibromatosis type 2 (NF2)-deficient cells are enhanced by the activation of multiple signaling pathways including ErbBs/IGF-1R/Met, PI3K/Akt, and Ras/Raf/Mek/Erk1/2. The chaperone protein HSP90 is essential for the stabilization of these signaling molecules. The aim of the study was to characterize the effect of HSP90 inhibition in various NF2-deficient models.
EXPERIMENTAL DESIGN: We tested efficacy of the small-molecule NXD30001, which has been shown to be a potent HSP90 inhibitor. The antiproliferative activity of NXD30001 was tested in NF2-deficient cell lines and in human primary schwannoma and meningioma cultures in vitro. The antitumor efficacy of HSP90 inhibition in vivo was verified in two allograft models and in one NF2 transgenic model. The underlying molecular alteration was further characterized by a global transcriptome approach.
RESULTS: NXD30001 induced degradation of client proteins in and suppressed proliferation of NF2-deficient cells. Differential expression analysis identified subsets of genes implicated in cell proliferation, cell survival, vascularization, and Schwann cell differentiation whose expression was altered by NXD30001 treatment. The results showed that NXD30001 in NF2-deficient schwannoma suppressed multiple pathways necessary for tumorigenesis.
CONCLUSIONS: HSP90 inhibition showing significant antitumor activity against NF2-related tumor cells in vitro and in vivo represents a promising option for novel NF2 therapies.

Forthun RB, Sengupta T, Skjeldam HK, et al.
Cross-species functional genomic analysis identifies resistance genes of the histone deacetylase inhibitor valproic acid.
PLoS One. 2012; 7(11):e48992 [PubMed] Free Access to Full Article Related Publications
The mechanisms of successful epigenetic reprogramming in cancer are not well characterized as they involve coordinated removal of repressive marks and deposition of activating marks by a large number of histone and DNA modification enzymes. Here, we have used a cross-species functional genomic approach to identify conserved genetic interactions to improve therapeutic effect of the histone deacetylase inhibitor (HDACi) valproic acid, which increases survival in more than 20% of patients with advanced acute myeloid leukemia (AML). Using a bidirectional synthetic lethality screen revealing genes that increased or decreased VPA sensitivity in C. elegans, we identified novel conserved sensitizers and synthetic lethal interactors of VPA. One sensitizer identified as a conserved determinant of therapeutic success of HDACi was UTX (KDM6A), which demonstrates a functional relationship between protein acetylation and lysine-specific methylation. The synthetic lethal screen identified resistance programs that compensated for the HDACi-induced global hyper-acetylation, and confirmed MAPKAPK2, HSP90AA1, HSP90AB1 and ACTB as conserved hubs in a resistance program for HDACi that are drugable in human AML cell lines. Hence, these resistance hubs represent promising novel targets for refinement of combinatorial epigenetic anti-cancer therapy.

Giessrigl B, Krieger S, Rosner M, et al.
Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells.
Hum Mol Genet. 2012; 21(21):4615-27 [PubMed] Related Publications
Pancreas cancer cells escape most treatment options. Heat shock protein (Hsp)90 is frequently over-expressed in pancreas carcinomas and protects a number of cell-cycle regulators such as the proto-oncogene Cdc25A. We show that inhibition of Hsp90 with geldanamycin (GD) destabilizes Cdc25A independent of Chk1/2, whereas the standard drug for pancreas carcinoma treatment, gemcitabine (GEM), causes Cdc25A degradation through the activation of Chk2. Both agents applied together additively inhibit the expression of Cdc25A and the proliferation of pancreas carcinoma cells thereby demonstrating that both Cdc25A-destabilizing/degrading pathways are separated. The role of Hsp90 as stabilizer of Cdc25A in pancreas carcinoma cells is further supported by two novel synthetic inhibitors 4-tosylcyclonovobiocic acid and 7-tosylcyclonovobiocic acid and specific Hsp90AB1 (Hsp90β) shRNA. Our data show that targeting Hsp90 reduced the resistance of pancreas carcinoma cells to treatment with GEM.

Thoreen CC, Chantranupong L, Keys HR, et al.
A unifying model for mTORC1-mediated regulation of mRNA translation.
Nature. 2012; 485(7396):109-13 [PubMed] Free Access to Full Article Related Publications
The mTOR complex 1 (mTORC1) kinase nucleates a pathway that promotes cell growth and proliferation and is the target of rapamycin, a drug with many clinical uses. mTORC1 regulates messenger RNA translation, but the overall translational program is poorly defined and no unifying model exists to explain how mTORC1 differentially controls the translation of specific mRNAs. Here we use high-resolution transcriptome-scale ribosome profiling to monitor translation in mouse cells acutely treated with the mTOR inhibitor Torin 1, which, unlike rapamycin, fully inhibits mTORC1 (ref. 2). Our data reveal a surprisingly simple model of the mRNA features and mechanisms that confer mTORC1-dependent translation control. The subset of mRNAs that are specifically regulated by mTORC1 consists almost entirely of transcripts with established 5' terminal oligopyrimidine (TOP) motifs, or, like Hsp90ab1 and Ybx1, with previously unrecognized TOP or related TOP-like motifs that we identified. We find no evidence to support proposals that mTORC1 preferentially regulates mRNAs with increased 5' untranslated region length or complexity. mTORC1 phosphorylates a myriad of translational regulators, but how it controls TOP mRNA translation is unknown. Remarkably, loss of just the 4E-BP family of translational repressors, arguably the best characterized mTORC1 substrates, is sufficient to render TOP and TOP-like mRNA translation resistant to Torin 1. The 4E-BPs inhibit translation initiation by interfering with the interaction between the cap-binding protein eIF4E and eIF4G1. Loss of this interaction diminishes the capacity of eIF4E to bind TOP and TOP-like mRNAs much more than other mRNAs, explaining why mTOR inhibition selectively suppresses their translation. Our results clarify the translational program controlled by mTORC1 and identify 4E-BPs and eIF4G1 as its master effectors.

Cheng Q, Chang JT, Geradts J, et al.
Amplification and high-level expression of heat shock protein 90 marks aggressive phenotypes of human epidermal growth factor receptor 2 negative breast cancer.
Breast Cancer Res. 2012; 14(2):R62 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Although human epidermal growth factor receptor 2 (HER2) positive or estrogen receptor (ER) positive breast cancers are treated with clinically validated anti-HER2 or anti-estrogen therapies, intrinsic and acquired resistance to these therapies appears in a substantial proportion of breast cancer patients and new therapies are needed. Identification of additional molecular factors, especially those characterized by aggressive behavior and poor prognosis, could prioritize interventional opportunities to improve the diagnosis and treatment of breast cancer.
METHODS: We compiled a collection of 4,010 breast tumor gene expression data derived from 23 datasets that have been posted on the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. We performed a genome-scale survival analysis using Cox-regression survival analyses, and validated using Kaplan-Meier Estimates survival and Cox Proportional-Hazards Regression survival analyses. We conducted a genome-scale analysis of chromosome alteration using 481 breast cancer samples obtained from The Cancer Genome Atlas (TCGA), from which combined expression and copy number data were available. We assessed the correlation between somatic copy number alterations and gene expression using analysis of variance (ANOVA).
RESULTS: Increased expression of each of the heat shock protein (HSP) 90 isoforms, as well as HSP transcriptional factor 1 (HSF1), was correlated with poor prognosis in different subtypes of breast cancer. High-level expression of HSP90AA1 and HSP90AB1, two cytoplasmic HSP90 isoforms, was driven by chromosome coding region amplifications and were independent factors that led to death from breast cancer among patients with triple-negative (TNBC) and HER2-/ER+ subtypes, respectively. Furthermore, amplification of HSF1 was correlated with higher HSP90AA1 and HSP90AB1 mRNA expression among the breast cancer cells without amplifications of these two genes. A collection of HSP90AA1, HSP90AB1 and HSF1 amplifications defined a subpopulation of breast cancer with up-regulated HSP90 gene expression, and up-regulated HSP90 expression independently elevated the risk of recurrence of TNBC and poor prognosis of HER2-/ER+ breast cancer.
CONCLUSIONS: Up-regulated HSP90 mRNA expression represents a confluence of genomic vulnerability that renders HER2 negative breast cancers more aggressive, resulting in poor prognosis. Targeting breast cancer with up-regulated HSP90 may potentially improve the effectiveness of clinical intervention in this disease.

Beck HC, Petersen J, Nielsen SJ, et al.
Proteomic profiling of human colon cancer cells treated with the histone deacetylase inhibitor belinostat.
Electrophoresis. 2010; 31(16):2714-21 [PubMed] Related Publications
The anticancer drug belinostat is a hydroxamate histone deacetylase inhibitor that has shown significant antitumour activity in various tumour models and also in clinical trials. In this study, we utilized a proteomic approach in order to evaluate the effect of this drug on protein expression in the human colon cancer cell line HCT116. Protein extracts from untreated HCT116 cells, and cells grown for 24 h in the presence of 1 and 10 muM belinostat were analysed by 2-D gel electrophoresis. Proteins were visualized by colloidal Coomassie blue staining and quantitative analysis of gel images revealed 45 unique differentially expressed proteins that were identified by LC-MSMS analysis. Among these proteins, of particular interest are the downregulated proteins nucleophosmin and stratifin, and the upregulated proteins nucleolin, gelsolin, heterogeneous nuclear ribonucleoprotein K, annexin 1, and HSP90B that all were related to the proto-oncogene proteins p53, Myc, activator protein 1, and c-fos protein. The modulation of these proteins is consistent with the observations that belinostat is able to inhibit clonogenic cell growth of HCT116 cells and the biological role of these proteins will be discussed.

Fu J, Bian L, Zhao L, et al.
Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues.
Acta Biochim Biophys Sin (Shanghai). 2010; 42(8):568-74 [PubMed] Related Publications
Increased attention has been paid to the determination of the potential biomarker and therapeutic target for ovarian cancer in recent years. However, the normalization of quantitative real-time PCR is important to obtain accurate gene expression data. We investigated the stability of 20 reference genes in ovarian tissues under different conditions to determine the most adequate for this application. The study characterized the expression of 20 possible reference genes among 52 ovarian tissue samples involving the normal, non-malignant, and primary ovarian carcinomas. One-way analysis of variance (ANOVA) method was used to compare the candidate gene changes brought about by the disease progression. The stability and suitability of the genes with no statistic difference were further validated employing geNorm and NormFinder softwares. Results showed that the expression levels of the 20 reference genes varied, while the RPL4, RPLP0, HSPCB, TPT1, RPL13A, 18S rRNA, PPIA, TBP, and GUSB kept statistic stability despite different ovarian tissue conditions. RPL4, RPLP0, and HSPCB were demonstrated as the most stable reference genes and the combination of the RPLP0 and RPL4 should be recommended as a much more reliable normalization strategy.

Tsumuraya M, Kato H, Miyachi K, et al.
Comprehensive analysis of genes involved in the malignancy of gastrointestinal stromal tumors.
Anticancer Res. 2010; 30(7):2705-15 [PubMed] Related Publications
BACKGROUND: During tumorigenesis of gastrointestinal stromal tumors (GISTs), the most frequent changes are reported to be gain-of-function mutations in the C-KIT proto-oncogene. However, we speculated that additional genetic alterations are required for the progression of GISTs.
PATIENTS AND METHODS: Using 15 cases diagnosed with GISTs, we searched for novel indicator genes by microarray analyses using an Oligo GEArray(R) PI3K-AKT Signaling Pathway Microarray Kit. In addition, we analyzed the mutational status of C-KIT and the proliferation status indicated by the Ki-67 index.
RESULTS: The tumor localizations of the 15 GISTs were as follows: 8 in the stomach; 2 in the small intestine; 2 in the mesentery; 1 in the duodenum; 1 in the rectum; and 1 in liver. Regarding the C-KIT gene analysis, mutations in exon 11 were detected in 11 out of 13 patients. In 1 out of the 13 patients, mutations were detected in both exons 11 and 13. No genetic abnormalities were identified in 1 patient. The Ki-67 labeling indices were significantly lower for the low-risk and intermediate-risk groups than for the high-risk group (p=0.0440). No specific genes were overexpressed in the >1% Ki-67 group. Regarding the primary lesion sites, the following 6 genes were overexpressed in tumors in the stomach: RBL2, RHOA, SHC1, HSP90AB1, ACTB and BAS2C.
CONCLUSION: Gene analysis is currently only useful for diagnostic assessment and predicting therapeutic effects. However, it may be possible for new malignancy-related factors to be identified by comparing and investigating gene expression levels and other factors using such analyses.

Li WH, Miao XH, Qi ZT, et al.
Proteomic analysis of differently expressed proteins in human hepatocellular carcinoma cell lines HepG2 with transfecting hepatitis B virus X gene.
Chin Med J (Engl). 2009; 122(1):15-23 [PubMed] Related Publications
BACKGROUND: Hepatitis B virus encoded X protein (HBx) is a trans-activating protein that may be involved in hepatocarcinogenesis, although few natural effectors of HBx that participate in this process have been identified. We screened, by comparative proteomics method, effectors of HBx associated with hepatocarcinogenesis.
METHODS: HBx positive and negative HepG2 cells were constructed and expression patterns of cellular proteins were obtained by high resolution, two dimensional electrophoresis. Comprehensive analyses of proteins associated with hepatocellular carcinoma (HCC) were focused on the differently expressed proteins (more than two-fold increase or decrease, P < 0.05) from HBx positive and negative HepG2 cells. For peptide mass fingerprinting, protein spots with different intensity between HBx positive and negative HepG2 cells were directly cut out of gels and processed for matrix assisted, laser desorption/ionization, time of flight mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) analysis.
RESULTS: The mean number of protein spots for HBx negative and HBx positive HepG2 cells were 2095 +/- 137 and 2188 +/- 105, respectively. The analysis of paired cells showed 75 spots with significant differences in expression between HBx negative and HBx positive cells: 37 spots corresponding to 32 different proteins; 25 proteins were upregulated, 7 downregulated. We found 7 proteins not previously reported differentially expressed in HBx positive HepG2 cells. Variations in protein accumulation were confirmed for four (HSP90AB1, BCL2 associated athanogene 2, nucleophosmin and chloride intracellular channel 1) by Western blotting in HBx positive HepG2 cells.
CONCLUSIONS: Numerous effectors of HBx that may promote the development of HCC are identified, of which 7 are newly noted in HepG2 cells. Several of these effectors of HBx may help in elucidating the roles of HBx in hepatocarcinogenesis and diagnostics or targets for therapeutic intervention.

Bucci B, Misiti S, Cannizzaro A, et al.
Fractionated ionizing radiation exposure induces apoptosis through caspase-3 activation and reactive oxygen species generation.
Anticancer Res. 2006 Nov-Dec; 26(6B):4549-57 [PubMed] Related Publications
BACKGROUND: Radiation therapy (RT) is a well established therapeutic modality for the treatment of solid tumors. In particular, post-operative RT is considered the standard treatment adjuvant to surgery since its ability to prolong median survival of patients with malignant astrocytoma has been shown; nevertheless the ionizing radiation (IR) treatment fails in a considerable number of astrocytoma patients.
MATERIALS AND METHODS: Using an ADF human astrocytoma cell line the molecular mechanisms involved in the DNA damage induced by fractionated irradiation (FIR) and single IR treatment have been investigated.
RESULTS: FIR and single IR treatment inhibited the growth of the ADF human astrocytoma cell line. FACS analysis revealed that FIR treatment, but not single IR treatment, induced growth inhibition associated with the induction of apoptosis. Apoptosis was related to caspase-3 activation and reactive oxygen species (ROS) generation. ROS formation depends on the up-regulation of the cytochrome P450 enzyme gene. On the contrary, 12.5 Gy induced necrotic cell death up-regulating the HSPD1, HSPCB, HSPCA and HSPB1 genes.
CONCLUSION: FIR treatment induced cell death through caspase-3 and ROS-mediated apoptosis.

Takahashi H, Nemoto T, Yoshida T, et al.
Cancer diagnosis marker extraction for soft tissue sarcomas based on gene expression profiling data by using projective adaptive resonance theory (PART) filtering method.
BMC Bioinformatics. 2006; 7:399 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent advances in genome technologies have provided an excellent opportunity to determine the complete biological characteristics of neoplastic tissues, resulting in improved diagnosis and selection of treatment. To accomplish this objective, it is important to establish a sophisticated algorithm that can deal with large quantities of data such as gene expression profiles obtained by DNA microarray analysis.
RESULTS: Previously, we developed the projective adaptive resonance theory (PART) filtering method as a gene filtering method. This is one of the clustering methods that can select specific genes for each subtype. In this study, we applied the PART filtering method to analyze microarray data that were obtained from soft tissue sarcoma (STS) patients for the extraction of subtype-specific genes. The performance of the filtering method was evaluated by comparison with other widely used methods, such as signal-to-noise, significance analysis of microarrays, and nearest shrunken centroids. In addition, various combinations of filtering and modeling methods were used to extract essential subtype-specific genes. The combination of the PART filtering method and boosting--the PART-BFCS method--showed the highest accuracy. Seven genes among the 15 genes that are frequently selected by this method--MIF, CYFIP2, HSPCB, TIMP3, LDHA, ABR, and RGS3--are known prognostic marker genes for other tumors. These genes are candidate marker genes for the diagnosis of STS. Correlation analysis was performed to extract marker genes that were not selected by PART-BFCS. Sixteen genes among those extracted are also known prognostic marker genes for other tumors, and they could be candidate marker genes for the diagnosis of STS.
CONCLUSION: The procedure that consisted of two steps, such as the PART-BFCS and the correlation analysis, was proposed. The results suggest that novel diagnostic and therapeutic targets for STS can be extracted by a procedure that includes the PART filtering method.

Asaka S, Fujimoto T, Akaishi J, et al.
Genetic prognostic index influences patient outcome for node-positive breast cancer.
Surg Today. 2006; 36(9):793-801 [PubMed] Related Publications
PURPOSE: To establish a novel genetic prognostic index among node-positive breast cancer patients.
METHODS: Using a cDNA microarray, the gene expression profiles of 20 primary breast cancers that had metastasis to four or more axillary lymph nodes were examined. Ten patients survived disease-free for more than 5 years (5S), while ten patients died of breast cancer within 5 years of surgery (5D).
RESULTS: A set of genes characterizing each group was identified. Sixteen genes were underexpressed in 5D compared to 5S, and 15 genes were underexpressed in 5S in comparison to 5D. The prognostic index (PI) was established, which could predict the postoperative outcome with five genes that were commonly underexpressed in the 5D group; these genes encoded granulin (GRN), heat shock 90 kDa protein 1 beta (HSPCB), large tumor suppressor homolog 1 (LATS1), valosin-containing protein (VCP), and LIM-and-SH3 protein1 (LASP1).
CONCLUSION: These five genes might play an important role in deciding the behavior of node-positive breast cancer. The PI system could thus predict the prognosis of node-positive breast cancer, and might therefore be able to provide valuable information for the prognosis of breast cancer patients.

Yu X, Harris SL, Levine AJ
The regulation of exosome secretion: a novel function of the p53 protein.
Cancer Res. 2006; 66(9):4795-801 [PubMed] Related Publications
The p53 protein responds to stress signals by regulating the transcription of a variety of genes. Some of these genes encode secreted proteins that may be involved in the communication between adjacent cells. In this study, a proteomics approach was employed to identify proteins secreted by cells in a p53-dependent manner after DNA damage. In addition to the known transcriptional targets of p53, a set of proteins encoded by genes that are not transcriptional targets of p53 were found to increase in the culture medium after p53 activation. These proteins exit the cell via small, secreted vesicles called exosomes and exosome production by cells was found to be regulated by the p53 response. A p53-regulated gene product, TSAP6, was shown to enhance exosome production in cells undergoing a p53 response to stress. Thus, the p53 pathway regulates the production of exosomes into the medium and these vesicles can communicate with adjacent cells and even cells of the immune system.

Man TK, Lu XY, Jaeweon K, et al.
Genome-wide array comparative genomic hybridization analysis reveals distinct amplifications in osteosarcoma.
BMC Cancer. 2004; 4:45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Osteosarcoma is a highly malignant bone neoplasm of children and young adults. It is characterized by extremely complex karyotypes and high frequency of chromosomal amplifications. Currently, only the histological response (degree of necrosis) to therapy represent gold standard for predicting the outcome in a patient with non-metastatic osteosarcoma at the time of definitive surgery. Patients with lower degree of necrosis have a higher risk of relapse and poor outcome even after chemotherapy and complete resection of the primary tumor. Therefore, a better understanding of the underlying molecular genetic events leading to tumor initiation and progression could result in the identification of potential diagnostic and therapeutic targets.
METHODS: We used a genome-wide screening method - array based comparative genomic hybridization (array-CGH) to identify DNA copy number changes in 48 patients with osteosarcoma. We applied fluorescence in situ hybridization (FISH) to validate some of amplified clones in this study.
RESULTS: Clones showing gains (79%) were more frequent than losses (66%). High-level amplifications and homozygous deletions constitute 28.6% and 3.8% of tumor genome respectively. High-level amplifications were present in 238 clones, of which about 37% of them showed recurrent amplification. Most frequently amplified clones were mapped to 1p36.32 (PRDM16), 6p21.1 (CDC5L, HSPCB, NFKBIE), 8q24, 12q14.3 (IFNG), 16p13 (MGRN1), and 17p11.2 (PMP22 MYCD, SOX1,ELAC27). We validated some of the amplified clones by FISH from 6p12-p21, 8q23-q24, and 17p11.2 amplicons. Homozygous deletions were noted for 32 clones and only 7 clones showed in more than one case. These 7 clones were mapped to 1q25.1 (4 cases), 3p14.1 (4 cases), 13q12.2 (2 cases), 4p15.1 (2 cases), 6q12 (2 cases), 6q12 (2 cases) and 6q16.3 (2 cases).
CONCLUSIONS: This study clearly demonstrates the utility of array CGH in defining high-resolution DNA copy number changes and refining amplifications. The resolution of array CGH technology combined with human genome database suggested the possible target genes present in the gained or lost clones.

Andersen CL, Jensen JL, Ørntoft TF
Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets.
Cancer Res. 2004; 64(15):5245-50 [PubMed] Related Publications
Accurate normalization is an absolute prerequisite for correct measurement of gene expression. For quantitative real-time reverse transcription-PCR (RT-PCR), the most commonly used normalization strategy involves standardization to a single constitutively expressed control gene. However, in recent years, it has become clear that no single gene is constitutively expressed in all cell types and under all experimental conditions, implying that the expression stability of the intended control gene has to be verified before each experiment. We outline a novel, innovative, and robust strategy to identify stably expressed genes among a set of candidate normalization genes. The strategy is rooted in a mathematical model of gene expression that enables estimation not only of the overall variation of the candidate normalization genes but also of the variation between sample subgroups of the sample set. Notably, the strategy provides a direct measure for the estimated expression variation, enabling the user to evaluate the systematic error introduced when using the gene. In a side-by-side comparison with a previously published strategy, our model-based approach performed in a more robust manner and showed less sensitivity toward coregulation of the candidate normalization genes. We used the model-based strategy to identify genes suited to normalize quantitative RT-PCR data from colon cancer and bladder cancer. These genes are UBC, GAPD, and TPT1 for the colon and HSPCB, TEGT, and ATP5B for the bladder. The presented strategy can be applied to evaluate the suitability of any normalization gene candidate in any kind of experimental design and should allow more reliable normalization of RT-PCR data.

Gotoh K, Nonoguchi K, Higashitsuji H, et al.
Apg-2 has a chaperone-like activity similar to Hsp110 and is overexpressed in hepatocellular carcinomas.
FEBS Lett. 2004; 560(1-3):19-24 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. We constructed subtracted cDNA libraries enriched with genes overexpressed in HCCs. Among the 17 genes identified were molecular chaperones, Hsp110, Hsp90B, and Hsp70-1. Expression of the Hsp110 family members was further analyzed, and increased transcript levels of Hsp110 and Apg-2, but not Apg-1, were found in 12 and 14, respectively, of 18 HCCs. Immunohistochemical analysis demonstrated the overexpression of the proteins in tumor cells. Apg-2 had chaperone ability similar to Hsp110 in a thermal denaturation assay using luciferase, and showed anti-apoptotic activity. These results suggest that the Hsp110 family members play important roles in hepatocarcinogenesis through their chaperoning activities.

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