HSPA1B

Gene Summary

Gene:HSPA1B; heat shock 70kDa protein 1B
Aliases: HSP70-2, HSP70.2, HSP70-1B
Location:6p21.3
Summary:This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:heat shock 70 kDa protein 1B
HPRD
Source:NCBIAccessed: 11 August, 2015

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 (1990-2015)
Graph generated 11 August 2015 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: HSPA1B (cancer-related)

Negroni L, Taouji S, Arma D, et al.
Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.
Mol Cell Proteomics. 2014; 13(12):3473-83 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen(®), and AMMP(®)) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253.

Singh S, Suri A
Targeting the testis-specific heat-shock protein 70-2 (HSP70-2) reduces cellular growth, migration, and invasion in renal cell carcinoma cells.
Tumour Biol. 2014; 35(12):12695-706 [PubMed] Related Publications
Renal cell carcinoma (RCC) represents one of the most resistant tumors to radiotherapy and chemotherapy. Current therapies for the RCC patients are limited owing to lack of diagnosis and therapeutic treatments. Testis-specific heat-shock protein 70-2 (HSP70-2), a member of HSP70 chaperone family, has been shown to be associated with various cancers. In the present study, we investigated the putative role of HSP70-2 in various malignant properties of the RCC cells. HSP70-2 messenger RNA (mRNA) and protein expression was investigated in A704, ACHN, and Caki-1 cells derived from the RCC patients. We assessed the expression of HSP70-2 gene and protein by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The expression of HSP70-2 protein was further validated by performing indirect immunofluorescence (IIF) and flow cytometry. The malignant properties of high-grade invasive A704 and Caki-1 cells, such as cellular proliferation, colony formation, migration, invasion, and wound healing, were evaluated by silencing the expression of HSP70-2 gene in these cells. Statistical significance was defined using Student's t test. Our RT-PCR and Western blotting data showed the expression of HSP70-2 in all RCC cells. Our results showed that HSP70-2 was predominantly expressed in cytoplasm and found to be colocalized with endoplasmic reticulum, mitochondria, Golgi body, and plasma membrane but not the nuclear envelope. Knockdown of HSP70-2 expression with specific short hairpin RNA (shRNA) demonstrated significant reduction in cell growth and colony formation. Further, a marked reduction in cell migration and invasion was also observed, indicating the potential role of HSP70-2 in metastasis. Collectively, our data suggest that HSP70-2 plays a key role in cancerous growth and invasive potential of RCC cells. Thus, HSP70-2 could serve as a novel potential therapeutic target for the RCC.

Kuang D, Chen W, Song YZ, et al.
Association between the HSPA1B ±1267A/G polymorphism and cancer risk: a meta-analysis of 14 case-control studies.
Asian Pac J Cancer Prev. 2014; 15(16):6855-61 [PubMed] Related Publications
BACKGROUND: Previous epidemiological studies have suggested a potential role of the HSPA1B±1267A/G polymorphism in risk of developing cancer. However, the results were inconsistent. Therefore, we performed this meta-analysis to summarize the possible association with cancer risk.
MATERIALS AND METHODS: We retrieved relevant articles from PubMed, EMBASE, ISI Web of Science, Chinese Biomedical Literature and Chinese National Knowledge Infrastructure. Studies were selected using specific criteria. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess those associations. All analyses were performed using STATA software.
RESULTS: Fourteen case-control studies, including 1, 834 cancer cases and 2, 028 controls were included in this meta-analysis. Overall, the results indicated that the G allele of HSPA1B gene ±1267A/G was significantly associated with an increased cancer risk in all genetic models (G vs A: OR=1.51, 95%CI 1.17-1.95, p=0.001; GG vs AA: OR=2.93, 95%CI 1.50-5.74, p=0.002; AG vs AA: OR=1.48, 95%CI 1.10-1.98, p=0.009; GG/AG vs AA: OR=1.69, 95%CI 1.22-2.33, p=0.001; GG vs
AG/AA: OR=2.31, 95%CI 1.24-4.32, p=0.009). In the subgroup analysis stratified by ethnicity, a significant association was identified in Caucasians (G vs A: OR=1.35, 95%CI 1.08-1.69, p=0.008; GG/AG vs AA: OR=1.36, 95%CI 1.09-1.70, p=0.007), but not in Asians. In the stratified analysis by cancer types, individuals with the G allele showed an increased risk of hepatocellular carcinoma compared with carriers of the A allele (OR=2.40, 95%CI 1.47-3.91, p< 0.001). Inversely, individuals with the GG genotype showed a decreased risk of gastric cancer compared with carriers of the AG/GG genotypes (GG vs
AG/AA: OR=0.39, 95%CI 0.20-0.70, p=0.007).
CONCLUSIONS: This meta-analysis suggests associations between the HSPA1B ±1267A/G polymorphism and risk of cancer. However, this association might be Caucasian-specific and the G allele of this polymorphism probably increases risk of hepatocellular carcinoma while decreasing risk of gastric cancer. Further well-designed studies based on larger sample sizes are needed to validate these findings.

He L, Deng T, Luo HS
Heat shock protein 70 gene polymorphisms and cancer risk: a meta-analysis.
ScientificWorldJournal. 2014; 2014:540309 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The polymorphisms in the three main heat shock protein 70 (HSP70-1, HSP70-2, and HSP70-hom) genes were identified to be associated with cancer risk. However, the results are inconsistent. We perform a meta-analysis to evaluate the association between the three HSP70 polymorphisms and cancer risk. Relevant studies were identified using PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases up to March 29, 2014. The cancer risk associated with the HSP70 polymorphisms was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively. Twenty case-control studies from eighteen publications were included; a significant association was observed for HSP70-2 polymorphism (dominant model: OR = 1.53, 95% CI: 1.11-2.09; recessive model: OR = 1.91, 95% CI: 1.06-3.45; AG versus AA: OR = 1.38, 95% CI: 1.03-1.84; GG versus AA: OR = 2.34, 95% CI: 1.21-4.54), while there was no significant association for HSP70-1 and HSP70-hom polymorphisms. Besides, in stratification analyses by ethnicity, cancer type, and source of control, significant association was detected for HSP70-2 polymorphism, while for HSP70-hom polymorphism, we found a significant association in hospital-based population under homozygote comparison model. This meta-analysis suggests that the HSP70-2 polymorphism rather than HSP70-hom and HSP70-1 polymorphisms was associated with the risk of cancer.

Lin CC, Chao PY, Shen CY, et al.
Novel target genes responsive to apoptotic activity by Ocimum gratissimum in human osteosarcoma cells.
Am J Chin Med. 2014; 42(3):743-67 [PubMed] Related Publications
Osteosarcoma (OS) is a type of bone cancer. Eighty percent of this tumor will metastasize to the lungs or liver, and as a result, patients generally need chemotherapy to improve survival possibility. Recently, antitumor activity has been reported in Ocimum gratissimum aqueous extract (OGE), which has been the focus of recent extensive studies on therapeutic strategies due to its antioxidant properties. We performed pharmacogenomics analyses for the effect of OGE on human osteosarcoma U2-OS and HOS cell growth. Cell viability, Western blot and flow cytometry analysis were performed before performing pharmacogenomics analyses for the effect of OGE on human osteosarcoma U2-OS and HOS cell growth, including cDNA microarray and RT-PCR assays. Cell viability assays revealed that OGE significantly and dose-dependently decreased the viability of U2-OS and HOS cells. Increases in cell shrinkage, Sub-G1 fragments and the activation of caspase 3 indicated that OGE induced cell apoptosis in U2-OS and HOS cells. There was no change in human osteoblast hFOS cells. cDNA microarray assay demonstrated that the expression of cell cycle regulators, apoptosis-related factors and cell proliferation markers were all modified by OGE treatment. RT-PCR analysis also confirmed the down-regulation of SKA2 and BUB1B, and the up-regulation of PPP1R15A, SQSTM1, HSPA1B, and DDIT4 by OGE treatment. The finding of anticancer activity in OGE and the identification of some potential target genes raise the expectation that OGE may become a useful therapeutic drug for human OS.

Ferrer-Ferrer M, Malespín-Bendaña W, Ramírez V, et al.
Polymorphisms in genes coding for HSP-70 are associated with gastric cancer and duodenal ulcer in a population at high risk of gastric cancer in Costa Rica.
Arch Med Res. 2013; 44(6):467-74 [PubMed] Related Publications
BACKGROUND AND AIMS: Costa Rica has among the highest incidence and mortality rates for gastric cancer worldwide. The reasons for this are largely unknown. Polymorphisms of inflammatory response genes including genes encoding heat shock proteins (HSP) have been shown to be associated with the risk of gastric cancer in some populations. This study addresses the possible association between the HSP70-2 +1267 and HSP70-Hom +2437 polymorphisms and the risk of developing gastric cancer in a high-risk population in Costa Rica.
METHODS: DNA from 39 individuals diagnosed with gastric cancer, 79 healthy controls, 55 individuals with chronic gastritis and 52 individuals with duodenal ulcer was genotyped for the polymorphisms HSP70-2 +1267 and HSP70-Hom +2437 by RFLP. Logistic regression analysis was used to determine possible associations with the diagnoses and lineal regression analysis to determine associations with blood pepsinogen (PGs) levels as measured by serology.
RESULTS: The GA genotype of HSP70-2 was associated with increased risk of gastric cancer (OR = 3.42; 95% CI = 1.27-9.21; p = 0.015) and duodenal ulcer (OR = 2.57; 95% CI = 1.03-6.36; p = 0.042) as compared to the GG genotype. Persons with C carrier genotypes of HSP70-Hom were significantly less susceptible to gastric cancer than those with the TT genotype (OR = 0.29; 95% CI = 0.09-0.87; p = 0.027). The C carrier genotype was associated with lower PGI concentrations but none of the polymorphisms were associated with PGI/PGII.
CONCLUSIONS: Polymorphisms of HSP70 genes are associated with the development of gastric cancer and duodenal ulcers in a population at high risk for gastric cancer in Costa Rica.

Qi W, White MC, Choi W, et al.
Inhibition of inducible heat shock protein-70 (hsp72) enhances bortezomib-induced cell death in human bladder cancer cells.
PLoS One. 2013; 8(7):e69509 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
The proteasome inhibitor bortezomib (Velcade) is a promising new agent for bladder cancer therapy, but inducible cytoprotective mechanisms may limit its potential efficacy. We used whole genome mRNA expression profiling to study the effects of bortezomib on stress-induced gene expression in a panel of human bladder cancer cell lines. Bortezomib induced strong upregulation of the inducible HSP70 isoforms HSPA1A and HSPA1B isoforms of Hsp72 in 253J B-V and SW780 (HSPA1A(high)) cells, but only induced the HSPA1B isoform in UM-UC10 and UM-UC13 (HSPA1A(low)) cells. Bortezomib stimulated the binding of heat shock factor-1 (HSF1) to the HSPA1A promoter in 253JB-V but not in UM-UC13 cells. Methylation-specific PCR revealed that the HSPA1A promoter was methylated in the HSPA1A(low) cell lines (UM-UC10 and UM-UC13), and exposure to the chromatin demethylating agent 5-aza-2'-deoxycytidine restored HSPA1A expression. Overexpression of Hsp72 promoted bortezomib resistance in the UM-UC10 and UM-UC13 cells, whereas transient knockdown of HSPA1B further sensitized these cells to bortezomib, and exposure to the chemical HSF1 inhibitor KNK-437 promoted bortezomib sensitivity in the 253J B-V cells. Finally, shRNA-mediated stable knockdown of Hsp72 in 253J B-V promoted sensitivity to bortezomib in vitro and in tumor xenografts in vivo. Together, our results provide proof-of-concept for using Hsp72 inhibitors to promote bortezomib sensitivity in bladder cancers and suggest that selective targeting of HSPA1B could produce synthetic lethality in tumors that display HSPA1A promoter methylation.

Peng Z, Liu N, Huang D, et al.
N,N'-dinitrosopiperazine--mediated heat-shock protein 70-2 expression is involved in metastasis of nasopharyngeal carcinoma.
PLoS One. 2013; 8(5):e62908 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
N,N'-Dinitrosopiperazine (DNP) is invovled in nasopharyngeal carcinoma (NPC) development and metastasis, and it shows organ specificity to the nasopharyngeal epithelium. Herein, we demonstrate that DNP induces heat-shock protein (HSP) 70-2 expression in NPC cells (6-10B) at a non-cytotoxic concentration. DNP induced HSP70-2 expression in a dose- and time- dependent manner, but showed no effect on other HSP70 family members. Furthermore, DNP also increased HSP70-2 RNA transcription through directly binding to the hypoxia-responsive elements (HRE) and heat shock elements (HSE) located in the HSP70-2 promoter. DNP-mediated HSP70-2 expression might act through enhancing the transcription of HSP70-2 RNA. Importantly, DNP induced motility and invasion of 6-10B cells dose- and time-dependently, and DNP-mediated NPC metastasis was confirmed in nude mice, which showed high HSP70-2 expression in the metastatic tumor tissue. However, the motility and invasion of NPC cells that were stably transfected using short interfering RNA against HSP70-2 could not effectively induce DNP. These results indicate that DNP induces HSP70-2 expression through increasing HSP70-2 transcription, increases the motility and invasion of cells, and promotes NPC tumor metastasis. Therefore, DNP mediated HSP70-2 expression may be an important factor of NPC-high metastasis.

Medhi S, Sarma MP, Asim M, Kar P
Genetic variants of heat shock protein A1L2437 and A1B1267 as possible risk factors for hepatocellular carcinoma in India.
J Viral Hepat. 2013; 20(4):e141-7 [PubMed] Related Publications
To study the role of heat shock protein A1L (HSPA1L) and A1B (HSPA1B) polymorphisms and subsequent risk of hepatocellular carcinoma (HCC) in India. Subjects enrolled included 185 cases of HCC, 182 cases of chronic hepatitis (CH) and 200 healthy controls. Genomic DNA was typed for HSPA1L2437 and HSPA1B1267 SNP using polymerase chain reaction with restriction fragment length polymorphism. Other risk factors were also analysed. Hepatitis B virus (HBV) infection, older age >35 years and high aflatoxin level in urine increased the risk of HCC. The frequencies of HSPA1L BB genotype and B allele in HCC were more than in CH [odds ratio (OR): 9.83; P = 0.000], but also in HBV-related HCC than Chronic Hepatitis B (CHB) [OR: 3.44; P = 0.004] and HCV-related HCC compared to CHC [OR: 6.32; P = 0.010]. The frequency of HSPA1B genotype in the homozygous state was more in CH [OR: 6.01; P = 0.001] and is a good marker to predict the risk of HCV-related CH (CHC) compared to controls. HCV-related HCC has a higher frequency of the B allele of HSPA1B than healthy controls [OR: 3.95; P = 0.000] and CHC [OR: 2.35; P = 0.000], respectively. The frequencies increased further significantly in CHC compared to healthy controls [OR: 9.26; P = 0.000]. The risk for the development of CH and HCC compared to healthy controls irrespective of the aetiology was significant in terms of the HSPA1B marker than HSPA1L in the Indian population.

Hundt W, Schink C, Steinbach S, et al.
Imaging of firefly luciferase activity under antiangiogenic therapy in a heat shock protein 70-transfected melanoma tumor model.
Mol Imaging. 2013 Mar-Apr; 12(2):129-36 [PubMed] Related Publications
We investigated the effect of targeted gene therapy on heat shock protein 70 (Hsp70) expression in a melanoma tumor model (M21). M21 cells transfected with a plasmid containing the firefly luciferase reporter gene (ffluc), whose expression is driven by the hsp70 (hspa1b) or the cytomegalovirus (CMV) promoter, were grown to a size of 600 mm3. Five animals in each group were intravenously treated with an Arg-Gly-Asp peptide-nanoparticle/Raf-1 kinase inhibitor protein [RGD-NP/RAF(-)] complex. Bioluminescence imaging (BLI) (IVIS, Xenogen, Alameda, CA) was performed at set time intervals. Western blot analysis of the HSP70 protein was simultaneously performed. The size of the treated M21 tumors was nearly constant (637.8 ± 33.4 mm3 vs 674.8 ± 34.4 mm3). BLI showed that if transcription was controlled by the CMV promoter, firefly luciferase activity decreased to 51.1% ± 8.3%. When transcription was controlled by the hsp70 promoter, the highest firefly luciferase activity (4.4 ± 0.3-fold) was observed after 24 hours. In accordance with BLI, Western blot analysis showed an increase in the level of HSP70, with the maximum detection 24 hours after the injection of the RGD-NP/RAF(-) complex. Targeted antiangiogenic therapy can induce luciferase activity where transcription is controlled by an hsp70 promoter and HSP70 protein in melanoma tumors.

Karlisch C, Harati K, Chromik AM, et al.
Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma.
Int J Oncol. 2013; 42(3):945-56 [PubMed] Related Publications
Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.

Zagouri F, Sergentanis TN, Gazouli M, et al.
HSP90, HSPA8, HIF-1 alpha and HSP70-2 polymorphisms in breast cancer: a case-control study.
Mol Biol Rep. 2012; 39(12):10873-9 [PubMed] Related Publications
This case control study aims to investigate the role of HSP90 Gln488His (C > G), HSP70-2 P1/P2, HIF-1 alpha C1772T and HSPA8 intronic 1541-1542delGT polymorphisms as potential risk factors and/or prognostic markers for breast cancer. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy cases were recruited. The above mentioned polymorphisms were genotyped; multivariate logistic regression was performed. HSP90 GG (His/His) genotype was associated with elevated breast cancer risk. Similarly, the allele dose-response model pointed to increase in breast cancer risk per G allele. HSP70-2 P1/P2, HSPA8 intronic 1541-1542delGT and HIF-1 alpha polymorphisms were not associated with breast cancer risk, as evidenced by the dose-response allele models. The positive association between HSP90 G allele and breast cancer risk seemed to pertain to both premenopausal and postmenopausal women. With respect to survival analysis, none of the aforementioned polymorphisms was associated with either disease-free survival or overall survival. HSP90α Gln488His polymorphism seems to be a risk factor for breast cancer. On the other hand, our study did not point to excess risk conferred by HSPA8 1541-1542delGT, Hsp70-2 P1/P2 and HIF-1α C1772T.

Hundt W, Steinbach S, O'Connell-Rodwell CE, et al.
In vivo monitoring of antiangiogenic therapy by magnetic resonance and bioluminescence imaging in an M21 tumor model through activation of an hsp70 promoter-luciferase reporter construct.
Contrast Media Mol Imaging. 2012 Sep-Oct; 7(5):450-9 [PubMed] Related Publications
We have investigated the effect of targeted gene therapy on the melanoma cell line M21, using a combination of bioluminescence imaging (BLI) and magnetic resonance imaging (MRI). M21 cells transfected with a plasmid containing either an hsp70 (Hspa1b) or a CMV promoter fragment, along with the luciferase reporter gene, were grown to a tumor size of 900 mm(3) . Five mice in each group were intravenously treated every 72 h with a complex consisting of a nanoparticle, an Arg-Gly-Asp-peptide, and a dominant negative mutant protein kinase inhibitor gene. BLI and MRI were performed at specific time intervals. The MRI scan protocol included T(1) -weighted-spin-echo ± contrast medium, T(2) -weighted-fast-spin-echo, dynamic contrast-enhanced MRI (DCE-MRI), and diffusion-weighted-stimulated-echo-acquisition-mode-sequence. The T(2) times were obtained using a 1.5 T GE MRI scanner. The size of the treated M21 tumors remained almost constant during the treatment phase (837.8 ± 133.4 vs 914.8 ± 134.4 mm(3) ). BLI showed that, if transcription was controlled by the CMV promoter, the luciferase activity decreased to 51.1 ± 8.3%. After transcription was controlled by the hsp70 promoter, the highest luciferase activity (4.4 ± 0.3 fold) was seen after 24 h. The signal-to-noise ratio (SNR; T(2) -weighted images) of the tumors was 36.7 ± 0.6 and subsequently dropped to 31.2 ± 4.4 (p=0.004). DCE-MRI showed a reduction of the slope and the Ak(ep) of 67.8% ± 4.3 and 64.8% ± 3.3%, respectively, compared with the baseline. The SNR value (T(1) -weighted images) of the tumors was 42.3 ± 1.9 immediately following contrast medium application and subsequently dropped to 28.5 ± 3.0 (p<0.001). In the treatment group, the diffusion coefficient increased significantly under therapy (0.66 ± 0.05 vs the pretreatment value of 0.54 ± 0.009 p<0.01). Thus, we observed that targeted antiangiogenic therapy can induce activation of the hsp70 promoter through a heat shock/luciferase reporter system. Moreover, MRI showed a significant reduction of the contrast medium uptake parameters and an increase in the diffusion coefficient of the tumors.

Srivastava P, Shafiq N, Bhasin DK, et al.
Differential expression of heat shock protein (HSP) 70-2 gene polymorphism in benign and malignant pancreatic disorders and its relationship with disease severity and complications.
JOP. 2012; 13(4):414-9 [PubMed] Related Publications
CONTEXT: The role of heat shock protein (HSP) 70-2 gene polymorphism (at position 1267, A to G transition) in patients with pancreatic disorders is not clear.
OBJECTIVE: To evaluate HSP 70-2 gene polymorphism (at position 1267, A to G transition) in patients with acute and chronic pancreatitis as well as pancreatic carcinoma, and to find any association of this polymorphism with disease complications and severity.
METHODS: One-hundred and fifty patients (50 each of acute, chronic pancreatitis, and pancreatic carcinoma) and 50 healthy blood donors as controls were prospectively studied. Three alleles (AA, AG and GG) of HSP 70-2 gene determined by PstI restriction fragment length polymorphism.
RESULTS: There was a statistically significant difference in the distribution pattern of HSP 70-2 gene polymorphism in patients with acute pancreatitis (P=0.001) and pancreatic carcinoma (P<0.001) as compared to controls. The frequency of mutant allele (G allele) was significantly higher in diseased group as compared to control group (19% in control group, 40% in acute pancreatitis, 33% in chronic pancreatitis and 45% in pancreatic carcinoma). No association of this polymorphism was found with disease severity in patients with acute and chronic pancreatitis or pancreatic carcinoma.
CONCLUSIONS: In our patient sample the frequency of mutant allele (G allele) of HSP 70-2 gene is significantly higher in patients with acute pancreatitis and pancreatic carcinoma compared to controls (50 healthy blood donors). However, this polymorphism was not associated with disease severity and complications.

Szondy K, Rusai K, Szabó AJ, et al.
Tumor cell expression of heat shock protein (HSP) 72 is influenced by HSP72 [HSPA1B A(1267)G] polymorphism and predicts survival in small Cell lung cancer (SCLC) patients.
Cancer Invest. 2012; 30(4):317-22 [PubMed] Related Publications
The inducible heat shock protein (HSP)72 plays a central role in antitumor immunomodulation. HSP72 expression was assessed on tumor samples of 43 patients with advanced and metastatic small cell lung cancer (SCLC) by immunohistochemistry and HSP72 [HSPA1B A(1267)G] polymorphism was determined. HSP72 expression of SCLC cells was significantly decreased in GG as compared to cells of AA or AG genotype patients, and was associated with significantly shorter survival in GG patients as compared to carriers of the A allele. Decreased HSP72 expression of SCLC cells associated with HSP72 GG genotype is a negative prognostic factor for survival in SCLC patients.

Tabuchi Y, Wada S, Furusawa Y, et al.
Gene networks related to the cell death elicited by hyperthermia in human oral squamous cell carcinoma HSC-3 cells.
Int J Mol Med. 2012; 29(3):380-6 [PubMed] Related Publications
Local hyperthermia (HT) for various types of malignant tumors has shown promising antitumor effects. To confirm the detailed molecular mechanism underlying cell death induced by HT, gene expression patterns and gene networks in human oral squamous cell carcinoma (OSCC) cells were examined using a combination of DNA microarray and bioinformatics tools. OSCC HSC-3 cells were treated with HT at 44˚C for 90 min or mild hyperthermia (MHT) at 42˚C for 90 min, followed by culturing at 37˚C for 0-24 h. Treatment of cells with HT prevented cell proliferation (62%) and induced cell death (17%), whereas these alterations were not observed in cells treated with MHT. Microarray analysis revealed substantial differences with respect to gene expression patterns and biological function for the two different hyperthermic treatments. Moreover, we identified the temperature-specific gene networks D and H that were obtained from significantly up-regulated genes in the HT and MHT conditions, respectively, using Ingenuity pathway analysis tools. Gene network D, which contains 14 genes such as ATF3, DUSP1 and JUN, was associated with relevant biological functions including cell death and cellular movement. Gene network H, which contains 13 genes such as BAG3, DNAJB1 and HSPA1B, was associated with cellular function and maintenance and cellular assembly and organization. These findings provide a basis for understanding the detailed molecular mechanisms of cell death elicited by HT in human OSCC cells.

Guo H, Deng Q, Wu C, et al.
Variations in HSPA1B at 6p21.3 are associated with lung cancer risk and prognosis in Chinese populations.
Cancer Res. 2011; 71(24):7576-86 [PubMed] Related Publications
The heat shock protein Hsp70 is crucial for regulating cellular homeostasis in stressed cells. Although the tumorigenic potential and prognostic applications of Hsp70 have been widely investigated, it remains unclear whether genetic variations of the human isoforms HSPA1L, HSPA1A, and HSPA1B are associated with cancer risk and prognosis. In this study, we genotyped six tagSNPs in these genes in 1,152 paired patients with lung cancer and controls, and then validated the results in additional cohorts of 1,781 patients with lung cancer and 1,038 controls. In addition, we evaluated the associations of these tagSNPs with survival in 330 patients with advanced non-small cell lung cancer (NSCLC) with additional validation in another 331 patients with advanced NSCLC. Functions of the risk variants identified were investigated using cell-based reporter assays. We found that the HSPA1B rs6457452T allele was associated with increased lung cancer risk compared with the rs6457452C allele in both data sets and also pooled analysis (adjusted OR = 1.41; P = 2.8 × 10(-5)). The HSPA1B rs2763979TT genotype conferred poor survival outcomes for patients with advanced NSCLC in two independent cohorts and pooled analysis [adjusted hazard ratio (HR) = 1.80, 1.61, and 1.66; P = 0.013, 0.036, and 0.002, respectively]. Lastly, we also found that the rs2763979T and rs6457452T alleles were each sufficient to reduce expression of transcriptional reporter constructs, when compared with the rs2763979C and rs6457452C alleles, respectively. Taken together, our findings define that functional HSPA1B variants are associated with lung cancer risk and survival. These Hsp70 genetic variants may offer useful biomarkers to predict lung cancer risk and prognosis.

Zhang C, Elkahloun AG, Liao H, et al.
Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells.
Mol Cancer Ther. 2011; 10(7):1137-48 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non-small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity.

Daigeler A, Chromik AM, Haendschke K, et al.
Synergistic effects of sonoporation and taurolidin/TRAIL on apoptosis in human fibrosarcoma.
Ultrasound Med Biol. 2010; 36(11):1893-906 [PubMed] Related Publications
Sonodynamic therapy, in combination with ultrasound contrast agents, proved to enhance the uptake of chemotherapeutics in malignant cells. HT1080 fibrosarcoma cells were treated in vitro with a combination of ultrasound SonoVue™-microbubbles and taurolidine (TRD) plus tumor necrosis factor related apoptosis inducing ligand (TRAIL). Apoptosis was measured by TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and fluorescence activated cell sorting (FACS) analysis. Gene expression was analysed by RNA-microarray. The apoptotic effects of TRD and TRAIL on human fibrosarcoma are enhanced by sonodynamic therapy and additional application of contrast agents, such as SonoVue™ by 25%. A broad change in the expression of genes related to apoptotic pathways is observed when ultrasound and microbubbles act synchronously in combination with the chemotherapeutics (e.g. BIRC3, NFKBIA and TNFAIP3). Some of these genes have already been proven to play a role in programmed cell death in human fibrosarcoma (HSPA1A/HSPA1B, APAF1, PAWR, SOCS2) or were associated with sonication induced apoptosis (CD44). Further studies are needed to explore the options of sonodynamic therapy on soft tissue sarcoma and its molecular mechanisms.

Wang Y, Zhou F, Wu Y, et al.
The relationship between three heat shock protein 70 gene polymorphisms and susceptibility to lung cancer.
Clin Chem Lab Med. 2010; 48(11):1657-63 [PubMed] Related Publications
BACKGROUND: Heat shock protein 70 (Hsp70) has been shown to act as a chaperone and be associated with a variety of tumors. We investigated HSP70-1 G+190C, HSP70-2 A+1267G, and HSP70-hom T+2437C polymorphisms to assess whether genetic variation in HSP70 plays a role in the occurrence and development of lung cancer.
METHODS: A case-control study was conducted using 159 patients with lung cancer and 202 control subjects. Genomic DNA was typed for HSP70 polymorphisms using polymerase chain reactions with restriction fragment length polymorphism (PCR-RFLP). Unconditional logistic regression was used to estimate the relative risks of lung cancer.
RESULTS: There were significant differences in genotype and allele distributions between patients and controls for the HSP70-1 G+190C polymorphisms with and without adjustment for age, gender, smoking history, drinking history and family history of cancer (p<0.05). No significant differences were found in the polymorphisms of HSP70-2 A+1267G and HSP70-hom T+2437C. The haplotype analysis showed that the G/A/C and C/G/T haplotypes were associated with a significantly increased risk of lung cancer compared to the G/G/T haplotype. After adjustments for other risk factors, such as age, gender, drinking history and family history of cancer, the interactions between the HSP70-1 and HSP70-hom genotypes and smoking were confirmed [I(AB), 2.56 and 5.12, respectively].
CONCLUSIONS: HSP70-1 G+190C may be a functional polymorphism and affect susceptibility to lung cancer, and homozygous C/C genotype may enhance the risk of lung cancer. In addition, smoking along with HSP70-1 G+190C and HSP70-hom T+2437C, may increase the risk of lung cancer.

Garg M, Kanojia D, Saini S, et al.
Germ cell-specific heat shock protein 70-2 is expressed in cervical carcinoma and is involved in the growth, migration, and invasion of cervical cells.
Cancer. 2010; 116(16):3785-96 [PubMed] Related Publications
BACKGROUND: Cervical cancer is a major cause of death among women worldwide, and the most cases are reported in the least developed countries. Recently, a study on DNA microarray gene expression analysis demonstrated the overexpression of heat shock protein 70-2 (HSP70-2) in cervical carcinoma cells (HeLa). The objective of the current study was to evaluate the association between HSP70-2 expression in cervical carcinogenesis and its potential role in various malignant properties that result in disease progression.
METHODS: HSP70-2 expression was examined in various cervical cancer cell lines with different origins and in clinical cervical cancer specimens by reverse transcriptase-polymerase chain reaction (RT-PCR), flow cytometry, and immunohistochemistry (IHC) analyses. A plasmid-based, short-hairpin RNA approach was used specifically to knock down the expression of HSP70-2 in cervical tumor cells in vitro and in vivo to examine the role of HSP70-2 on various malignant properties.
RESULTS: RT-PCR and IHC analyses revealed HSP70-2 expression in 86% of cervical cancer specimens. Furthermore, knockdown of HSP70-2 expression significantly reduced cellular growth, colony formation, migration, and invasion in vitro and reduced tumor growth in vivo. A significant association of HSP70-2 gene and protein expression was observed among the various tumor stages (P=.046) and different grades (P=.006), suggesting that HSP70-2 expression may be an indicator of disease progression.
CONCLUSIONS: The current findings suggested that HSP70-2 may play an important role in disease progression in cervical carcinogenesis. Patients who had early stage disease and low-grade tumors had HSP70-2 expression, supporting its potential role in early detection and aggressive treatment modalities for cervical cancer management.

Lu S, Tan Z, Wortman M, et al.
Regulation of heat shock protein 70-1 expression by androgen receptor and its signaling in human prostate cancer cells.
Int J Oncol. 2010; 36(2):459-67 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Heat shock protein (hsp) 70-1 (hsp70-1) is overexpressed in human prostate cancer cells and may play important roles in prostate cancer resistance to conventional therapies. The purpose of this study was to investigate whether androgen receptor (AR) and its signaling regulate hsp70-1 expression. Several lines of AR-positive (LNCaP, LAPC-4, and 22Rv1) and -negative (PC-3, DU145, WPE1-NB14 and WPE1-NB-26) human prostatic cells were used in the study. Dihydrotestosterone (DHT) enhanced hsp70-1 expression in LNCaP cells. Expression of hsp70-1 in LNCaP cells was downregulated by the anti-androgens bicalutamide (Bic), and flutamide (Flut), and a newly identified AR signaling antagonist DL3. The downregulation of hsp70-1 by DL3 was also observed in LAPC-4 and 22Rv1 cells, but not in the four lines of AR-negative cells examined. Expression of hsp70-1 was also reduced by DL3 in PC-3 cells engineered with AR. On the other hand, knocking down AR in LNCaP cells by siRNA moderately reduced hsp70-1 level and abolished effects of DL3 on hsp70-1 expression. DL3 reduced hsp70-1 mRNA synthesis in cells and its in vitro gene transcription but did not significantly alter the stabilities of hsp70-1 mRNA and protein. Chromatin-immunoprecipitation (ChIP) assay showed that AR bound to the promoter region of HSPA1B gene, which was reduced in cells treated with DL3 or Bic. These data suggest that AR and its signaling regulate hsp70-1 expression in prostate cancer cells and that HSPA1B could be an AR target gene.

Ucisik-Akkaya E, Davis CF, Gorodezky C, et al.
HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility.
Cell Stress Chaperones. 2010; 15(5):475-85 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5'UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction-restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.16-0.78; P = 0.007) with gene-dosage effect (additive model) reaching significance (P = 0.0001) in the Welsh case-control group. This association was replicated in the second case-control group from Mexico (OR (recessive model) = 0.49, 95% CI = 0.24-0.96; P = 0.03), and the pooled analysis yielded a strong association (Mantel-Haenszel OR = 0.43, 95% CI = 0.27-0.69, P = 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P = 0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case-control group from Wales (adjusted P = 0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

Garg M, Kanojia D, Seth A, et al.
Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion.
Eur J Cancer. 2010; 46(1):207-15 [PubMed] Related Publications
PURPOSE: Testis specific heat-shock protein 70-2 (HSP70-2), a member of HSP70 chaperone family, is essential for the growth of spermatocytes and cancer cells. We investigated the association of HSP70-2 expression with clinical behaviour and progression of urothelial carcinoma of bladder.
EXPERIMENTAL DESIGN: We assessed the HSP70-2 expression by RT-PCR and HSP70-2 protein expression by immunofluorescence, flow cytometry, immunohistochemistry and Western blotting in urothelial carcinoma patient specimens and HTB-1, UMUC-3, HTB-9, HTB-2 and normal human urothelial cell lines. Further, to investigate the role of HSP70-2 in bladder tumour development, HSP70-2 was silenced in the high-grade invasive HTB-1 and UMUC-3 cells. The malignant properties of urothelial carcinoma cells were examined using colony formation, migration assay, invasion assay in vitro and tumour growth in vivo.
RESULTS: Our RT-PCR analysis and immunohistochemistry analysis revealed that HSP70-2 was expressed in both moderate to well-differentiated and high-grade invasive urothelial carcinoma cell lines studied and not in normal human urothelial cells. In consistence with these results, HSP70-2 expression was also observed in superficially invasive (70%) and muscle-invasive (90%) patient's tumours. Furthermore, HSP70-2 knockdown significantly suppressed cellular motility and invasion ability. An in vivo xenograft study showed that inhibition of HSP70-2 significantly suppressed tumour growth.
CONCLUSIONS: In conclusion, our data suggest that the HSP70-2 expression is associated with early spread and progression of urothelial carcinoma of bladder cancer and that HSP70-2 can be the potential therapeutic target for bladder urothelial carcinoma.

Furusawa Y, Tabuchi Y, Takasaki I, et al.
Gene networks involved in apoptosis induced by hyperthermia in human lymphoma U937 cells.
Cell Biol Int. 2009; 33(12):1253-62 [PubMed] Related Publications
To define the molecular mechanisms that mediate hyperthermia-induced apoptosis, we performed microarray and computational gene expression analyses. U937 cells, a human myelomonocytic lymphoma cell line, were treated with hyperthermia at 42 degrees C for 90 min and cultured at 37 degrees C. Apoptotic cells ( approximately 15%) were seen 6 h after hyperthermic treatment, and elevated expression of heat shock proteins (HSPs) including Hsp27, Hsp40, and Hsp70 was detected, following the activation of heat shock factor-1. Of the 54,675 probe sets analyzed, 1334 were upregulated and 4214 were downregulated by >2.0-fold in the cells treated with hyperthermia. A non-hierarchical gene clustering algorithm, K-means clustering, demonstrated 10 gene clusters. The gene network U1 or U2 that was obtained from up-regulated genes in cluster I or IX contained HSPA1B, DNAJB1, HSPH1, and TXN or PML, LYN, and DUSP1, and were mainly associated with cellular compromise, and cellular function and maintenance or death, and cancer, respectively. In the decreased gene cluster II, the gene network D1 including CCNE1 and CEBPE was associated with the cell cycle and cellular growth and proliferation. These findings will provide a basis for understanding the detailed molecular mechanisms of apoptosis induced by hyperthermia at 42 degrees C in cells.

Tahara T, Shibata T, Arisawa T, et al.
The BB genotype of heat-shock protein (HSP) 70-2 gene is associated with gastric pre-malignant condition in H. pylori-infected older patients.
Anticancer Res. 2009; 29(8):3453-8 [PubMed] Related Publications
BACKGROUND: Heat-shock protein (HSP) 70 plays essential roles in cellular response to a variety of environmental stresses or unfavorable conditions. A to G transition at the 1267 position of the HSP70-2 gene confers different levels of HSP70 mRNA expression. We aimed to clarify the effect of HSP70-2 polymorphism on the risk of premalignant condition, on the degree of acute or chronic inflammation in the stomach.
PATIENTS AND METHODS: A total of 378 individuals participated in this study. Restriction fragment length polymorphism analysis was performed for polymorphisms at 1267 of HSP70-2 gene. Prevalence of intestinal metaplasia was investigated histologically and the degree of histological gastritis in the antrum was classified according to the updated Sydney System.
RESULTS: Although a direct association was not observed between HSP70-2 polymorphism and prevalence of intestinal metaplasia, a significant association was found between the BB genotype and lower metaplasia score in individuals who were Helicobacter pylori (H. pylori) positive and aged 60 years or older (BB vs. A carriers; 0.84+/-0.95 vs. 1.23+/-1.01, p=0.0197). When individuals were divided into 3 groups according to the severity of gastric mucosal atrophy: non-atrophic gastritis (NA) group (atrophy score=0 and metaplasia score=0), severe atrophic gastritis (SA) group (atrophy score > or =2 or metaplasia score > or =2), and mild atrophic gastritis (MA) group (all others), the BB genotype was associated with a lower risk of severe atrophy in the SA sub-group (adjusted odds ratio=0.37, 95% confidence interval =0.16-0.84, p=0.0172).
CONCLUSION: The BB genotype of HSP70-2 gene is associated with a reduced risk of gastric pre-malignant condition in H. pylori-infected older individuals.

Partida-Rodríguez O, Torres J, Flores-Luna L, et al.
Polymorphisms in TNF and HSP-70 show a significant association with gastric cancer and duodenal ulcer.
Int J Cancer. 2010; 126(8):1861-8 [PubMed] Related Publications
Tumour Necrosis Factor (TNF) and Heat Shock Protein 70 (HSP70) are important molecules in inflammatory, infectious and tumoral processes. The genes codifying these molecules are polymorphic and certain alleles have been associated with susceptibility to disease. Gastric cancer is associated with an Helicobacter pylori-induced chronic inflammatory response. The aim of this work was to analyze whether polymorphisms in inflammation-related genes are associated with the development of gastric cancer. We studied 447 Mexican adult patients including 228 with non-atrophic gastritis, 98 with intestinal metaplasia, 63 with gastric cancer and 58 with duodenal ulcer, and 132 asymptomatic individuals as well. DNA from peripheral white blood cells was typed for the Single Nucleotide Polymorphisms (SNPs) -308 of TNF-alpha, +252 of TNF-beta, +190 of HSP70-1, +1267 of HSP70-2 and +2437 of HSP70-HOM. Compared with the asymptomatic group, we found a significant association of TNF-beta*A and HSP70-1*C alleles with gastric cancer (OR 5.69 and 3.76, respectively) and HSP70-1*C with duodenal ulcer (OR 3.08). Genotype TNF-beta G/G showed a significant gene-dose effect with gastric cancer (OR 0.09); whereas HSP70-1 C/G showed significant association with both, gastric cancer (OR 13.31) and duodenal ulcer (OR 16.19). Polymorphisms in TNF and HSP70 showed a significant severity-dose-response as risk markers from preneoplastic lesions to gastric cancer in Mexican population, probably because of their association with an intense and sustained inflammatory response.

Halatsch ME, Löw S, Mursch K, et al.
Candidate genes for sensitivity and resistance of human glioblastoma multiforme cell lines to erlotinib. Laboratory investigation.
J Neurosurg. 2009; 111(2):211-8 [PubMed] Related Publications
OBJECT: The authors have previously reported that erlotinib, an EGFR tyrosine kinase inhibitor, exerts widely variable antiproliferative effects on 9 human glioblastoma multiforme (GBM) cell lines in vitro and in vivo. These effects were independent of EGFR baseline expression levels, raising the possibility that more complex genetic properties form the molecular basis of the erlotinib-sensitive and erlotinib-resistant GBM phenotypes. The aim of the present study was to determine candidate genes for mediating the cellular response of human GBMs to erlotinib.
METHODS: Complementary RNA obtained in cell lines selected to represent the sensitive, somewhat responsive, and resistant phenotypes were hybridized to CodeLink Human Whole Genome Bioarrays.
RESULTS: Expression analysis of 814 prospectively selected genes involved in major proliferation and apoptosis signaling pathways identified 19 genes whose expression significantly correlated with phenotype. Functional annotation analysis revealed that 2 genes (DUSP4 and STAT1) were significantly associated with sensitivity to erlotinib, and 10 genes (CACNG4, FGFR4, HSPA1B, HSPB1, NFATC1, NTRK1, RAC1, SMO, TCF7L1, and TGFB3) were associated with resistance to erlotinib. Moreover, 5 genes (BDNF, CARD6, FOSL1, HSPA9B, and MYC) involved in antiapoptotic pathways were unexpectedly found to be associated with sensitivity. Gene expressions were confirmed by quantitative polymerase chain reaction.
CONCLUSIONS: Based on an analysis of gene expressions in cell lines with sensitive, somewhat responsive, and resistant phenotypes, the authors propose candidate genes for GBM response to erlotinib. The 10 gene candidates for conferring GBM resistance to erlotinib may represent therapeutic targets for enhancing the efficacy of erlotinib against GBMs. Five additional genes warrant further investigation into their role as putative cotargets of erlotinib.

Song D, Chaerkady R, Tan AC, et al.
Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer.
Mol Cancer Ther. 2008; 7(10):3275-84 [PubMed] Related Publications
Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

Tabuchi Y, Takasaki I, Wada S, et al.
Genes and genetic networks responsive to mild hyperthermia in human lymphoma U937 cells.
Int J Hyperthermia. 2008; 24(8):613-22 [PubMed] Related Publications
In this study, to better understand the molecular mechanism underlying cellular responses to mild hyperthermia, we investigated gene expression patterns and genetic networks in human myelomonocytic lymphoma U937 cells using high-density oligonucleotide microarrays and computational gene expression analysis tools. The cells were incubated at 41 degrees C for 30 min (mild hyperthermia treatment) and then at 37 degrees C for 0-6 h. Although the mild hyperthermia treatment of the cells did not induce apoptosis, significant increases in the protein expression levels of heat shock proteins (HSPs), namely, Hsp27, Hsp40 and Hsp70, were observed following the activation of heat shock factor-1. Of the 22,283 probe sets analyzed, 423 probe sets were up-regulated and 515 probe sets were down-regulated by >1.5-fold in the cells 3 h post-treatment. Computational gene network analysis demonstrated that the significant genetic network A that contained many HSPs such as DNAJB1, HSPA1A, and HSPA1B was associated with cellular function and maintenance, post-transcriptional modification, or protein folding. Moreover, the significant genetic network B whose core contained v-myc myelocytomatosis viral oncogene homolog (MYC) was associated with cell morphology, cell cycle, and cellular development. The expression levels of nine selected genes were comparable to those determined by microarray analysis with real-time quantitative PCR assay. The present results indicate that mild hyperthermia affects the expression of a large number of genes and provides additional novel insights into the molecular basis of mild hyperthermia in cells.

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