STIP1

Gene Summary

Gene:STIP1; stress induced phosphoprotein 1
Aliases: HOP, P60, STI1, STI1L, HEL-S-94n, IEF-SSP-3521
Location:11q13.1
Summary:STIP1 is an adaptor protein that coordinates the functions of HSP70 (see HSPA1A; MIM 140550) and HSP90 (see HSP90AA1; MIM 140571) in protein folding. It is thought to assist in the transfer of proteins from HSP70 to HSP90 by binding both HSP90 and substrate-bound HSP70. STIP1 also stimulates the ATPase activity of HSP70 and inhibits the ATPase activity of HSP90, suggesting that it regulates both the conformations and ATPase cycles of these chaperones (Song and Masison, 2005 [PubMed 16100115]).[supplied by OMIM, Jul 2009]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:stress-induced-phosphoprotein 1
Source:NCBIAccessed: 09 March, 2017

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 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.

  • Tumor Suppressor Proteins
  • CA-125 Antigen
  • Ovarian Cancer
  • Protein Binding
  • HSP90 Heat-Shock Proteins
  • DNA-Binding Proteins
  • Western Blotting
  • STIP1
  • Molecular Chaperones
  • Signal Transduction
  • Immunohistochemistry
  • Up-Regulation
  • HSP70 Heat-Shock Proteins
  • Thymidine
  • Proteome
  • siRNA
  • Ubiquitin-Protein Ligases
  • Tandem Mass Spectrometry
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Chromosome 11
  • Heat-Shock Proteins
  • Cancer Gene Expression Regulation
  • Apoptosis
  • Telomerase
  • Breast Cancer
  • Prostate Cancer
  • Cell Cycle Proteins
  • Neoplasm Invasiveness
  • Antineoplastic Agents
  • Inhibitor of Differentiation Proteins
  • Base Sequence
  • Cell Proliferation
  • Protein Folding
  • Down-Regulation
  • Electrophoresis, Gel, Two-Dimensional
  • Staurosporine
  • Hepatocellular Carcinoma
  • Biomarkers, Tumor
  • Smad5 Protein
  • Neoplasm Proteins
  • Proteomics
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: STIP1 (cancer-related)

Bertram S, Padden J, Kälsch J, et al.
Novel immunohistochemical markers differentiate intrahepatic cholangiocarcinoma from benign bile duct lesions.
J Clin Pathol. 2016; 69(7):619-26 [PubMed] Related Publications
AIMS: The distinction between intrahepatic cholangiocarcinoma (ICC) and benign bile duct lesions can be challenging. Using our previously identified potential biomarkers for ICC, we examined whether these are useful for the differential diagnosis of ICC, bile duct adenoma and reactive bile duct proliferations in an immunohistochemical approach and identified a diagnostic marker panel including known biomarkers.
METHODS: Subjects included samples from 77 patients with ICC, 33 patients with bile duct adenoma and 47 patients with ductular reactions in liver cirrhosis. Our previously identified biomarkers (stress-induced phosphoprotein 1 (STIP1), SerpinH1, 14-3-3Sigma) were tested immunohistochemically following comparison with candidates from the literature (cluster of differentiation 56, heat shock protein (HSP)27, HSP70, B-cell-lymphoma2, p53, ki67).
RESULTS: The expression of SerpinH1 and 14-3-3Sigma was significantly higher in ICC than in bile duct adenomas and ductular reactions (p<0.05), whereas STIP1 expression was significantly higher (p<0.05) in ICC than in ductular reactions, but the difference to the bile duct adenoma group was not significant. A panel of the biomarker SerpinH1, 14-3-3Sigma and ki67 (≥2 marker positive) showed a high diagnostic accuracy (sensitivity 87.8%, specificity 95.9%, accuracy 91.8%) in the differential diagnosis of ICC versus non-malignant bile duct lesions.
CONCLUSIONS: This suggests that 14-3-3Sigma and SerpinH1 may be useful in the differential diagnosis of malignant, benign and reactive bile duct lesions in addition to ki67 where a cut-off of >5% might be used for the distinction of malignant and non-malignant lesions.

Baindur-Hudson S, Edkins AL, Blatch GL
Hsp70/Hsp90 organising protein (hop): beyond interactions with chaperones and prion proteins.
Subcell Biochem. 2015; 78:69-90 [PubMed] Related Publications
The Hsp70/Hsp90 organising protein (Hop), also known as stress-inducible protein 1 (STI1), has received considerable attention for diverse cellular functions in both healthy and diseased states. There is extensive evidence that intracellular Hop is a co-chaperone of the major chaperones Hsp70 and Hsp90, playing an important role in the productive folding of Hsp90 client proteins. Consequently, Hop is implicated in a number of key signalling pathways, including aberrant pathways leading to cancer. However, Hop is also secreted and it is now well established that Hop also serves as a receptor for the prion protein, PrP(C). The intracellular and extracellular forms of Hop most likely represent two different isoforms, although the molecular determinants of these divergent functions are yet to be identified. There is also a growing body of research that reports the involvement of Hop in cellular activities that appear independent of either chaperones or PrP(C). While Hop has been shown to have various cellular functions, its biological function remains elusive. However, recent knockout studies in mammals suggest that Hop has an important role in embryonic development. This review provides a critical overview of the latest molecular, cellular and biological research on Hop, critically evaluating its function in healthy systems and how this function is adapted in diseases states.

Padden J, Megger DA, Bracht T, et al.
Identification of novel biomarker candidates for the immunohistochemical diagnosis of cholangiocellular carcinoma.
Mol Cell Proteomics. 2014; 13(10):2661-72 [PubMed] Free Access to Full Article Related Publications
The aim of this study was the identification of novel biomarker candidates for the diagnosis of cholangiocellular carcinoma (CCC) and its immunohistochemical differentiation from benign liver and bile duct cells. CCC is a primary cancer that arises from the epithelial cells of bile ducts and is characterized by high mortality rates due to its late clinical presentation and limited treatment options. Tumorous tissue and adjacent non-tumorous liver tissue from eight CCC patients were analyzed by means of two-dimensional differential in-gel electrophoresis and mass-spectrometry-based label-free proteomics. After data analysis and statistical evaluation of the proteins found to be differentially regulated between the two experimental groups (fold change ≥ 1.5; p value ≤ 0.05), 14 candidate proteins were chosen for determination of the cell-type-specific expression profile via immunohistochemistry in a cohort of 14 patients. This confirmed the significant up-regulation of serpin H1, 14-3-3 protein sigma, and stress-induced phosphoprotein 1 in tumorous cholangiocytes relative to normal hepatocytes and non-tumorous cholangiocytes, whereas some proteins were detectable specifically in hepatocytes. Because stress-induced phosphoprotein 1 exhibited both sensitivity and specificity of 100%, an immunohistochemical verification examining tissue sections of 60 CCC patients was performed. This resulted in a specificity of 98% and a sensitivity of 64%. We therefore conclude that this protein should be considered as a potential diagnostic biomarker for CCC in an immunohistochemical application, possibly in combination with other candidates from this study in the form of a biomarker panel. This could improve the differential diagnosis of CCC and benign bile duct diseases, as well as metastatic malignancies in the liver.

Van Simaeys D, Turek D, Champanhac C, et al.
Identification of cell membrane protein stress-induced phosphoprotein 1 as a potential ovarian cancer biomarker using aptamers selected by cell systematic evolution of ligands by exponential enrichment.
Anal Chem. 2014; 86(9):4521-7 [PubMed] Free Access to Full Article Related Publications
In this paper, we describe the elucidation of the target of an aptamer against ovarian cancer previously obtained by cell-SELEX (SELEX = systematic evolution of ligands by exponential enrichment). The target's identity, stress-induced phosphoprotein 1 (STIP1), was determined by mass spectrometry and validated by flow cytometry, using siRNA silencing and protein blotting. Initial oncologic studies show that the aptamer inhibits cell invasion, indicating that STIP1, which is currently under investigation as a potential biomarker for ovarian cancer, plays a critical role in this process. These results serve as an excellent example of how protein target identification of aptamers obtained by cell-SELEX can serve as a means to identify promising biomarker candidates and can promote the development of aptamers as a new drug class to block important oncological processes.

Buckley NE, D'Costa Z, Kaminska M, Mullan PB
S100A2 is a BRCA1/p63 coregulated tumour suppressor gene with roles in the regulation of mutant p53 stability.
Cell Death Dis. 2014; 5:e1070 [PubMed] Free Access to Full Article Related Publications
Here, we show for the first time that the familial breast/ovarian cancer susceptibility gene, BRCA1, along with interacting ΔNp63 proteins, transcriptionally upregulate the putative tumour suppressor protein, S100A2. Both BRCA1 and ΔNp63 proteins are required for S100A2 expression. BRCA1 requires ΔNp63 proteins for recruitment to the S100A2 proximal promoter region, while exogenous expression of individual ΔNp63 proteins cannot activate S100A2 transcription in the absence of a functional BRCA1. Consequently, mutation of the ΔNp63/p53 response element within the S100A2 promoter completely abrogates the ability of BRCA1 to upregulate S100A2. S100A2 shows growth control features in a range of cell models. Transient or stable exogenous S100A2 expression inhibits the growth of BRCA1 mutant and basal-like breast cancer cell lines, while short interfering RNA (siRNA) knockdown of S100A2 in non-tumorigenic cells results in enhanced proliferation. S100A2 modulates binding of mutant p53 to HSP90, which is required for efficient folding of mutant p53 proteins, by competing for binding to HSP70/HSP90 organising protein (HOP). HOP is a cochaperone that is required for the efficient transfer of proteins from HSP70 to HSP90. Loss of S100A2 leads to an HSP90-dependent stabilisation of mutant p53 with a concomitant loss of p63. Accordingly, S100A2-deficient cells are more sensitive to the HSP-90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, potentially representing a novel therapeutic strategy for S100A2- and BRCA1-deficient cancers. Taken together, these data demonstrate the importance of S100A2 downstream of the BRCA1/ΔNp63 signalling axis in modulating transcriptional responses and enforcing growth control mechanisms through destabilisation of mutant p53.

Cho H, Kim S, Shin HY, et al.
Expression of stress-induced phosphoprotein1 (STIP1) is associated with tumor progression and poor prognosis in epithelial ovarian cancer.
Genes Chromosomes Cancer. 2014; 53(4):277-88 [PubMed] Related Publications
Stress-induced phosphoprotein1 (STIP1) is a candidate biomarker in epithelial ovarian cancer (EOC). In this study, we investigated in detail the expression of STIP1, as well as its functions, in EOC. STIP1 expression was assessed by immunohistochemistry (IHC) and the results were compared with clinicopathologic factors, including survival data. The effects of STIP1 gene silencing via small interfering RNA (siRNA) were examined in EOC cells and a xenograft model. The expression of STIP1 protein in EOC was significantly higher than in the other study groups (P < 0.001), and this increase of expression was significantly associated with tumor stage (P = 0.005), tumor grade (P = 0.029), and lymph node metastasis (P = 0.020). In multivariate analysis, overall survival in EOC was significantly shorter in cases with high STIP1 expression (HR = 2.78 [1.01-7.63], P = 0.047). STIP1 silencing in EOC cells resulted in inhibition of cell proliferation and invasion. In addition, in vivo experiments using STIP1 siRNA clearly showed a strong inhibition of tumor growth and a modulation of expression of prosurvival and apoptotic genes, further suggesting that STIP1 silencing can prevent cell proliferation and invasion. In conclusion, increased STIP1 expression is associated with poor survival outcome in EOC, and STIP1 may represent a useful therapeutic target in EOC patients.

Zhang D, Wang S, Zhu L, et al.
Profiling of hepatocellular carcinoma cell cycle regulating genes targeted by calycosin.
Biomed Res Int. 2013; 2013:317926 [PubMed] Free Access to Full Article Related Publications
We cocultured calycosin with human hepatocellular carcinoma cell line (BEL-7402) to investigate the effect on cell proliferation. Calycosin can markedly block the cell growth in G1 phase (P < 0.01) on the IC50 concentration. There were seventeen genes involved in cell-cycle regulation showing differentially expressed in treated cells detected by gene chip. Eight genes were upregulated and nine genes were downregulated. Downregulated TFDP-1, CDKN2D, and SPK2 and upregulated CDC2 and CCNB1 might affect cell cycle of tumor cells. Furthermore, we checked the transcription pattern using 2D gel method to find different expression of proteins in human hepatocellular carcinoma cells after exposure to calycosin. Fourteen proteins were identified by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Twelve proteins expression were increased such as transgelin 2, pyridoxine 5'-phosphate, stress-induced-phosphoprotein 1, peroxiredoxin 1, endoplasmic reticulum protein 29, and phosphoglycerate mutase 1. Only thioredoxin peroxidase and high-mobility group box1 proteins' expression decreased. Both genes and proteins changes might be relate to the mechanism of antitumor effect under treatment of calycosin. In conclusion, calycosin has a potential effect to inhibit the BEL-7402 cell growth by inhibiting some oncogene expression and increasing anticancer genes expression, what is more, by blocking cell cycle.

Yuan MH, Zhou RS, She B, et al.
Expression and clinical significance of STIP1 in papillary thyroid carcinoma.
Tumour Biol. 2014; 35(3):2391-5 [PubMed] Related Publications
The aim of this study was to detect stress-induced phosphoprotein 1 (STIP1) expression in papillary thyroid carcinoma (PTC) and to analyze its association with prognosis of PTC patients. Immunohistochemistry was performed to detect the expression of STIP1 in 113 PTC tissues and paired adjacent noncancerous tissues. The χ2 test was used to analyze the relationship between STIP1 expression and clinicopathological characteristics. Survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test. Survival data was evaluated using univariate and multivariate Cox regression analysis. We identified abnormally elevated expression of STIP1 protein in PTC tissues compared to paired adjacent noncancerous tissues. Clinicopathological analysis showed that STIP1 expression was significantly correlated with tumor size (P = 0.017), lymph node metastasis (P = 0.007), and TNM stage (P = 0.026). Patients with higher STIP1 expression had shorter overall survival time, whereas those with lower STIP1 expression had longer survival time. Multivariate analysis suggested that STIP1 expression might be an independent prognostic indicator (P < 0.05) for the survival of patients with PTC. In conclusion, our findings provide evidences that positive expression of STIP1 in PTC may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with PTC.

Chao A, Lee LY, Hsueh C, et al.
Immunohistological analysis of stress-induced phosphoprotein 1 in ovarian cancer patients with low serum cancer antigen 125 levels.
Taiwan J Obstet Gynecol. 2013; 52(2):185-91 [PubMed] Related Publications
OBJECTIVE: Stress-induced phosphoprotein 1 (STIP1) was recently identified as a potential tumor marker for human ovarian cancer. This study further evaluates the usefulness of STIP1 in ovarian tumor patients with normal CA125 serum levels.
MATERIALS AND METHODS: STIP1 and CA125 were immunohistochemically analyzed in 84 primary ovarian cancer and 30 benign ovarian tumors in patients with serum CA125 levels < 35 U/mL before surgery. Histoscores (0-300) were calculated as staining intensities (0-3) multiplied by percentage of tumor tissue (0-100%).
RESULTS: The cell types of the 84 cancers included 11 serous, 10 clear-cell, 51 mucinous, and 12 endometrioid carcinomas. There were 55 patients with invasive cancer and 29 with borderline ovarian tumors. The histoscores of STIP1, but not of CA125, in invasive cancer (mean ± SD, 186.3 ± 82.5) were significantly (p < 0.0001) higher than those seen in borderline ovarian tumors (86.2 ± 85.5). When the STIP1 histoscore was set at 183.8, invasive cancers (n = 55) were identified from benign tumors (n = 30) with a sensitivity of 56.4%, a specificity of 93.3%, a positive predictive value of 93.9%, and a negative predictive value of 53.8%. Results of receiver operating characteristics analysis showed that the area under curve of the STIP1 histoscore was 0.755, which was superior to that of CA125 (0.599).
CONCLUSION: STIP1 histoscores may be useful in detecting invasive human ovarian cancer in patients with low serum CA125 levels.

Zhang Y, Owusu L, Duan W, et al.
Anti-metastatic and differential effects on protein expression of epigallocatechin-3-gallate in HCCLM6 hepatocellular carcinoma cells.
Int J Mol Med. 2013; 32(4):959-64 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third highest cause of cancer-related mortality in humans. Epigallocatechin-3-gallate (EGCG) has been shown to inhibit the metastatic activity of certain cancer cells. The aim of this study was to determine the effects and molecular mechanism(s) of action of EGCG in human HCC cells. A migration and invasion assay for the metastatic behavior of HCCLM6 cells was performed. The anti-metastatic effects of EGCG were investigated by RT-PCR and gelatin zymography. A total cellular protein profile was obtained using 2-dimensional gel electrophoresis (2-DE), followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) analyses of proteins with significant differences in expression following treatment with EGCG. The results revealed that EGCG induced apoptosis and inhibited the metastasis of HCCLM6 cells. The anti-metastatic effects of EGCG were associated with the inhibition of matrix metalloproteinase (MMP)-2 and MMP-9 activity. The expression levels of far upstream element (FUSE) binding protein 1 (FUBP1), heat shock protein beta 1 (HSPB1), heat shock 60 kDa protein 1 (chaperonin) (CH60) and nucleophosmin (NPM) proteins, which are associated with metastasis, were significantly altered in the EGCG-treated HCCLM6 cells. The data from the present study suggest that EGCG has potential as a therapeutic agent for the treatment of HCC.

Díaz-Chávez J, Fonseca-Sánchez MA, Arechaga-Ocampo E, et al.
Proteomic profiling reveals that resveratrol inhibits HSP27 expression and sensitizes breast cancer cells to doxorubicin therapy.
PLoS One. 2013; 8(5):e64378 [PubMed] Free Access to Full Article Related Publications
The use of chemopreventive natural compounds represents a promising strategy in the search for novel therapeutic agents in cancer. Resveratrol (3,4',5-trans-trihydroxystilbilene) is a dietary polyphenol found in fruits, vegetables and medicinal plants that exhibits chemopreventive and antitumor effects. In this study, we searched for modulated proteins with preventive or therapeutic potential in MCF-7 breast cancer cells exposed to resveratrol. Using two-dimensional electrophoresis we found significant changes (FC >2.0; p≤0.05) in the expression of 16 proteins in resveratrol-treated MCF-7 cells. Six down-regulated proteins were identified by tandem mass spectrometry (ESI-MS/MS) as heat shock protein 27 (HSP27), translationally-controlled tumor protein, peroxiredoxin-6, stress-induced-phosphoprotein-1, pyridoxine-5'-phosphate oxidase-1 and hypoxanthine-guanine phosphoribosyl transferase; whereas one up-regulated protein was identified as triosephosphate isomerase. Particularly, HSP27 overexpression has been associated to apoptosis inhibition and resistance of human cancer cells to therapy. Consistently, we demonstrated that resveratrol induces apoptosis in MCF-7 cells. Apoptosis was associated with a significant increase in mitochondrial permeability transition, cytochrome c release in cytoplasm, and caspases -3 and -9 independent cell death. Then, we evaluated the chemosensitization effect of increasing concentrations of resveratrol in combination with doxorubicin anti-neoplastic agent in vitro. We found that resveratrol effectively sensitize MCF-7 cells to cytotoxic therapy. Next, we evaluated the relevance of HSP27 targeted inhibition in therapy effectiveness. Results evidenced that HSP27 inhibition using RNA interference enhances the cytotoxicity of doxorubicin. In conclusion, our data indicate that resveratrol may improve the therapeutic effects of doxorubicin in part by cell death induction. We propose that potential modulation of HSP27 levels using natural alternative agents, as resveratrol, may be an effective adjuvant in breast cancer therapy.

Chao A, Lai CH, Tsai CL, et al.
Tumor stress-induced phosphoprotein1 (STIP1) as a prognostic biomarker in ovarian cancer.
PLoS One. 2013; 8(2):e57084 [PubMed] Free Access to Full Article Related Publications
Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. The quantification of immunoreactivity was accomplished by applying an immunohistochemical scoring system (histoscore). Patients with high-level STIP1 expression (histoscore ≥169) had a significantly worse survival (high STIP1, mean survival time = 76 months; low STIP1, mean survival time = 112 months; P<0.0001). Moreover, STIP1 histoscores were significantly higher in high-grade tumors (grade 3) than in low-grade (grade 1-2) malignancies (P<0.0001), suggesting that STIP1 may be a proxy for tumor aggressiveness. The results of multivariable analysis revealed that high STIP1 histoscores, advanced stages, histologic types, and the presence of residual disease (≥2 cm) were independent predictors of poor prognosis. The addition of STIP1 histoscores improved the prediction of overall and progression-free survival rates in the multivariable Cox proportional hazard model. The treatment of ovarian cancer cells with recombinant STIP1 stimulated cell proliferation and migration, but co-treatment with anti-STIP1 antibodies abrogated this effect. Our findings suggest that STIP1 expression may be related to prognosis and that the STIP1 pathway may represent a novel therapeutic target for human ovarian cancer.

Tsai CL, Tsai CN, Lin CY, et al.
Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells.
Cell Rep. 2012; 2(2):283-93 [PubMed] Related Publications
Stress-induced phosphoprotein 1 (STIP1), a cochaperone that organizes other chaperones, heat shock proteins (HSPs), was recently shown to be secreted by human ovarian cancer cells. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase) signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP) receptor, ALK2 (activin A receptor, type II-like kinase 2), was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3), promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.

Muller P, Ruckova E, Halada P, et al.
C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances.
Oncogene. 2013; 32(25):3101-10 [PubMed] Related Publications
Heat shock proteins Hsp90 and Hsp70 facilitate protein folding but can also direct proteins for ubiquitin-mediated degradation. The mechanisms regulating these opposite activities involve Hsp binding to co-chaperones including CHIP and HOP at their C-termini. We demonstrated that the extreme C-termini of Hsp70 and Hsp90 contain phosphorylation sites targeted by kinases including CK1, CK2 and GSK3-β in vitro. The phosphorylation of Hsp90 and Hsp70 prevents binding to CHIP and thus enhances binding to HOP. Highly proliferative cells contain phosphorylated chaperones in complex with HOP and phospho-mimetic and non-phosphorylable Hsp mutant proteins show that phosphorylation is directly associated with increased proliferation rate. We also demonstrate that primary human cancers contain high levels of phosphorylated chaperones and show increased levels of HOP protein and mRNA. These data identify C-terminal phosphorylation of Hsp70 and Hsp90 as a switch for regulating co-chaperone binding and indicate that cancer cells possess an elevated protein folding environment by the concerted action of co-chaperone expression and chaperone modifications. In addition to identifying the pathway responsible for regulating chaperone-mediated protein folding/degradation balances in normal cells, the data provide novel mechanisms to account for the aberrant chaperone activities observed in human cancer cells and have implications for the application of anti-chaperone therapies in cancer treatment.

Moghanibashi M, Jazii FR, Soheili ZS, et al.
Proteomics of a new esophageal cancer cell line established from Persian patient.
Gene. 2012; 500(1):124-33 [PubMed] Related Publications
Although the highest incidence of esophageal squamous cell carcinoma (ESCC) has repeatedly been reported from Persia (Iran), nevertheless the so far proteomic published reports were limited to one study on tissue specimens. Here we report the proteome of a newly established cell line from Persian ESCC patients and compare it with the normal primary cell proteome. Among polypeptides, whose expression was different in cell line sixteen polypeptides were identified by MALDI/TOF/TOF spectrometry. S100-A8 protein, annexin A1, annexin A2, regulatory subunit of calpain, subunit alpha type-3 of proteasome and glutamate dehydrogenase 1 were proteins down-regulated in cell line while peroxiredoxin-5, non-muscle myosin light polypeptide 6, keratin 1, annexin A4, keratin 8, tropomyosin 3, stress-induced-phosphoprotein 1 and albumin were found to be subject of up-regulation in cell line compared to the primary normal cells. The proteomic results were further verified by western blotting and RT-PCR on annexin A1 and keratin 8. In addition, among the aforementioned proteins, glutamate dehydrogenase 1, regulatory subunit of calpain, subunit alpha of type-3 proteasome and annexin A4 are proteins whose deregulation in ESCC is reported for the first time by this study.

Wang S, Lin L, Zhou J, et al.
Effects of yiqi chutan tang on the proteome in Lewis lung cancer in mice.
Asian Pac J Cancer Prev. 2011; 12(7):1665-9 [PubMed] Related Publications
In order to verify effects of yiqi chutan tang on lung cancer and assess molecular mechanisms involved we focused on size, tumor weight and the numbers of lung metastases and differential expression protein spot information acquired by two-way fluorescence with a tumor difference gel electrophoresis (2D-DIGE) system, and differentially expressed proteins were identified by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-TOF). Differences were finally verified by Western blot and fluorescence quantitative PCR. We found that tumor size, tumor weight in yiqi chutan tang treatment group were significantly less than that in model group (p<0.01), with a tumor growth inhibition rate of 57.2%. For gel diagram analysis of 2D-DIGE system, compared with model group, there were 44 expressed differentially protein spots, of which 6 were up-regulated and 38 were down-regulated. Among these proteins, 37 (30 down-regulated and 7 up-regulated) were successfully identified by MALDI-TOF-TOF. In conclusion, yiqi chutan tang effects on Lewis lung cancer appeared highly related to down-regulated expression of Hspd1, prolyl 4-hydroxylase, protein disulfide-isomerase A3 precursor, EG433182, heat shock protein 5 precursor, heat shock protein 9 and stress-induced phosphoprotein 1.

Walsh N, Larkin A, Swan N, et al.
RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation.
Cancer Lett. 2011; 306(2):180-9 [PubMed] Related Publications
We previously identified Hop as over expressed in invasive pancreatic cancer cell lines and malignant tissues of pancreatic cancer patients, suggesting an important role for Hop in the biology of invasive pancreatic cancer. Hop is a co-chaperone protein that binds to both Hsp70/Hsp90. We hypothesised that by targeting Hop, signalling pathways modulating invasion and client protein stabilisation involving Hsp90-dependent complexes may be altered. In this study, we show that Hop knockdown by small interfering (si)RNA reduces the invasion of pancreatic cancer cells, resulting in decreased expression of the downstream target gene, matrix metalloproteinases-2 (MMP-2). Hop in conditioned media co-immunoprecipitates with MMP-2, implicating a possible extracellular function for Hop. Knockdown of Hop expression also reduced expression levels of Hsp90 client proteins, HER2, Bcr-Abl, c-MET and v-Src. Furthermore, Hop is strongly expressed in high grade PanINs compared to lower PanIN grades, displaying differential localisation in invasive ductal pancreatic cancer, indicating that the localisation of Hop is an important factor in pancreatic tumours. Our data suggests that the attenuation of Hop expression inactivates key signal transduction proteins which may decrease the invasiveness of pancreatic cancer cells possibly through the modulation of Hsp90 activity. Therefore, targeting Hop in pancreatic cancer may constitute a viable strategy for targeted cancer therapy.

Tan SS, Ahmad I, Bennett HL, et al.
GRP78 up-regulation is associated with androgen receptor status, Hsp70-Hsp90 client proteins and castrate-resistant prostate cancer.
J Pathol. 2011; 223(1):81-7 [PubMed] Related Publications
GRP78/BiP is a key member of the molecular chaperone heat shock protein (Hsp) 70 family. It has a critical role in prostate cancer (PC) including Pten loss-driven carcinogenesis, but the molecular basis of this remains unclear. We investigated the effect of GRP78 and its putative client proteins, including androgen receptor (AR) in clinical PC. Expression of GRP78 and key Hsp70-hsp90 client proteins (HER2, HER3, AR and AKT) were studied in an incidence tissue microarray (TMA) of prostate cancer. The relationship of GRP78 and AR was further tested in in vitro cell models (LNCaP and its derived LNCaP-CR subclone) and a matched TMA of hormone-naïve (HNPC) and castrate-resistant prostate cancer (CRPC). In vitro and in vivo expression of GRP78 and client proteins were assessed by western blotting and immunohistochemistry, respectively, using the weighted histoscore method. Significant co-expression of GRP78, pAKT, HER2, HER3 and AR was observed in PC. Abnormal AR, GRP78 and pAKT expression have significant impact on patient survival. GRP78 expression in AR(+) tumours was significantly higher than in AR(-) tumours. In keeping with our clinical data, activation of AR by dihydrotestosterone (DHT) potently activated GRP78 expression in both LNCaP and LNCaP-CR cells. For the first time, using a matched HNPC and CRPC TMA, enhanced cytoplasmic and membranous GRP78 expression was observed in CRPC. Future prospective studies are therefore warranted to validate GRP78 as prognostic marker and therapeutic target, in the context of the AR and pAKT status. In summary, GRP78 is co-expressed with Hsp70-hsp90 client proteins. Up-regulated expression of AR and GRP78 expression in untreated prostate cancer predicts a less favourable outcome. This points to the importance of understanding in the molecular interaction among AR, GRP78 and AKT.

Kubota H, Yamamoto S, Itoh E, et al.
Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma.
Cell Stress Chaperones. 2010; 15(6):1003-11 [PubMed] Free Access to Full Article Related Publications
Co-chaperone HOP (also called stress-inducible protein 1) is a co-chaperone that interacts with the cytosolic 70-kDa heat shock protein (HSP70) and 90-kDa heat shock protein (HSP90) families using different tetratricopeptide repeat domains. HOP plays crucial roles in the productive folding of substrate proteins by controlling the chaperone activities of HSP70 and HSP90. Here, we examined the levels of HOP, HSC70 (cognate of HSP70, also called HSP73), and HSP90 in the tumor tissues from colon cancer patients, in comparison with the non-tumor tissues from the same patients. Expression level of HOP was significantly increased in the tumor tissues (68% of patients, n = 19). Levels of HSC70 and HSP90 were also increased in the tumor tissues (95% and 74% of patients, respectively), and the HOP level was highly correlated with those of HSP90 (r = 0.77, p < 0.001) and HSC70 (r = 0.68, p < 0.01). Immunoprecipitation experiments indicated that HOP complexes with HSC70 or HSP90 in the tumor tissues. These data are consistent with increased formation of co-chaperone complexes in colon tumor specimens compared to adjacent normal tissue and could reflect a role for HOP in this process.

Wang TH, Chao A, Tsai CL, et al.
Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation.
Mol Cell Proteomics. 2010; 9(9):1873-84 [PubMed] Free Access to Full Article Related Publications
Ovarian cancers are frequently not diagnosed until advanced stages, resulting in a high case fatality rate. Because of this, more tumor markers, in addition to CA125, for detecting and monitoring ovarian cancer are needed. During a systematic search for potential biomarkers of ovarian cancer, we compared the protein profiles between tumor interstitial fluid and normal interstitial fluid of ovaries, rationalizing that abnormal levels of proteins in tumor interstitial fluid may be detected in peripheral blood and thus serve as easily accessible tumor markers. Here, we show that stress-induced phosphoprotein 1 (STIP1) was secreted by ovarian cancer tissues into the peripheral blood of patients, resulting in a significant increase of serum levels of STIP1 in cancer patients compared with those in age-matched normal controls. Our results further indicated that combined use of CA125 and STIP1 may increase early detection of ovarian cancer. Functionally, recombinant STIP1 significantly induced ERK phosphorylation, promoted DNA synthesis, and increased Ki-67 immunoreactivity in ovarian cancer cells, suggesting that STIP1 in vitro promotes cell proliferation. Colocalization of STIP1 and phospho-ERK in human ovarian cancer tissues also supports an in vivo activation of ERK by STIP1. Further understanding of molecular roles of STIP1 in human ovarian cancer may shed light on its pathophysiology and development of novel therapeutic strategies.

Huang TT, Chen JY, Tseng CE, et al.
Decreased GRP78 protein expression is a potential prognostic marker of oral squamous cell carcinoma in Taiwan.
J Formos Med Assoc. 2010; 109(5):326-37 [PubMed] Related Publications
BACKGROUND/PURPOSE: Oral squamous cell carcinoma (OSCC) is an aggressive tumor and its occurrence in Taiwan is closely related to chronic smoking, alcohol consumption, and especially to betel quid chewing. It became the fourth most common malignant tumor of Taiwanese men in 2006. Unfortunately, there are few biomarkers for diagnosis and treatment of this disease.
METHODS: To find potential markers, two domestic cell lines (OC2 and OCSL) derived from different grades of OSCC were established and their proteins were compared by global proteomic analysis. The expression differences of GRP78 protein in these two cell lines and clinical samples from OSCC patients were verified.
RESULTS: Of the 11 candidate proteins expressed differentially in both cell lines, six [heat shock protein 90 kDa beta member 1 (94 kDa glucose-regulated protein; GRP94), protein disulfide-isomerase precursor, vimentin, tubulin beta-2C chain, 78 kDa glucose-regulated protein precursor (GRP78), and annexin A2] were increased in OC2 cells (low-grade OSCC), and five (heat shock protein 90-beta, annexin A1, stress-induced phosphoprotein 1, elongation factor-2, and integrin alpha-3 precursor) were increased in OCSL cells (high-grade OSCC). Some of these proteins have been previously associated with malignant tumors, but no previous association of GRP78 with OSCC has been reported. GRP78 protein expression in these two OSCC cell lines was confirmed by Western blotting. Immunohistochemical staining of clinical samples from OSCC patients revealed that decreased GRP78 protein expression was significantly correlated with advance tumor stage (p < 0.001) and neck lymph node metastasis (p = 0.001).
CONCLUSION: GRP78 protein is a possible biomarker of oral cancer in Taiwan.

Kim S, Cho H, Nam EJ, et al.
Autoantibodies against stress-induced phosphoprotein-1 as a novel biomarker candidate for ovarian cancer.
Genes Chromosomes Cancer. 2010; 49(7):585-95 [PubMed] Related Publications
Detection of autoantibodies against tumor-associated antigens (TAA) has recently been shown to be a powerful tool for early detection of various cancers. The aim of this study was to investigate the possibility of using autoantibodies against TAA as novel biomarkers by a proteomics-based approach in patients with ovarian cancer. We used two-dimensional differential gel electrophoresis analysis of immuno-precipitated tumor antigens (2D-DITA) to compare the levels of autoantibodies in pretreatment and posttreatment sera of patients with ovarian cancers. The identified autoantibodies were validated by SYBR Green real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC). We further evaluated the level of autoantibody in sera of 68 ovarian cancer patients by an enzyme-linked immunosorbent assay (ELISA). The autoantibody directed against stress-induced phosphoprotein-1 (STIP-1) emerged as a novel biomarker candidate for ovarian cancer. SYBR Green PCR and IHC confirmed that the STIP-1 mRNA and protein expression levels were significantly up-regulated in ovarian cancers compared with normal and benign tumors (P = 0.003 and P < 0.001, respectively). A preliminary ELISA study showed that the serum levels of anti-STIP-1 autoantibodies were significantly elevated in ovarian cancer patients compared with healthy controls (P = 0.03). The results suggest that 2D-DITA is a useful tool to detect autoantibodies and that STIP-1 is a potential biomarker candidate for ovarian cancers.

Chen J, Huang P, Kaku H, et al.
A comparison of proteomic profiles changes during 17beta-estradiol treatment in human prostate cancer PC-3 cell line.
Cancer Genomics Proteomics. 2009 Nov-Dec; 6(6):331-5 [PubMed] Related Publications
Human telomerase reverse transcriptase (hTERT) is overexpressed in prostate cancer. Estrogen plays a central role in the development of prostate cancer. hTERT activity has been shown to be increased after estrogen treatment. Although significant efforts have been made to understand the role of estrogen, the telomerase connection with estrogen is poorly understood. In this report, we describe a proteomics approach for investigating the global changes in protein expression in estrogen-treated human prostate cancer PC-3 cells. PC-3 cells were seeded in medium and then treated with estrogen; the protein extract from these cells was used for two-dimensional (2D) gel electrophoresis. The protein spots were subjected to comparative analysis by liquid chromatography/mass spectrometry (LC/MS). We observed that the expression of 17 proteins, including stress-induced phosphoprotein 1 and lamin-A/C was down-regulated, and that the expression of proteins such as subunit alpha of T-complex protein 1, tubulin alpha-1B, and other 13 proteins was up-regulated. These proteins may have been closely associated with estrogen-induced hTERT activity. The expression level of these proteins could be a useful parameter for evaluating the estrogen-induced hTERT activity in clinical specimens of human prostate cancer.

Erlich RB, Kahn SA, Lima FR, et al.
STI1 promotes glioma proliferation through MAPK and PI3K pathways.
Glia. 2007; 55(16):1690-8 [PubMed] Related Publications
Gliomas are tumors derived from glia or their precursors within the central nervous system. Clinically, gliomas are divided into four grades and the glioblastoma multiforme (GBM), also referred as grade IV astrocytoma, is the most aggressive and the most common glioma in humans. The prognosis for patients with GBM remains dismal, with a median survival of 9-12 months. Despite their striking heterogeneity, common alterations in specific cellular signal transduction pathways occur within most GBMs. Previous work from our group identified the co-chaperone stress-inducible protein 1 (STI1) as a cell surface ligand for cellular prion (PrP(C)), which leads to the activation of several signal transduction pathways, some of which modulate cell survival. In the present work, we used thymidine incorporation assays to investigate the effect of STI1 upon proliferation of the human glioblastoma-derived cell line A172. Here we report that STI1 is secreted by and induces proliferation in tumor cells, an effect that is modulated by the Erk and PI3K pathways, and that, in contrast to glioma cells, STI1 does not induce proliferation of normal glia. In addition, our data suggest the involvement of PrP(C) in STI1-induced proliferation of A172 cells. These results provide initial evidence of a new functional role for STI1 on the physiology of human gliomas, and may lead to the identification of new therapeutic targets in these tumors.

Short DM, Heron ID, Birse-Archbold JL, et al.
Apoptosis induced by staurosporine alters chaperone and endoplasmic reticulum proteins: Identification by quantitative proteomics.
Proteomics. 2007; 7(17):3085-96 [PubMed] Related Publications
Apoptosis contributes to cell death after cerebral ischaemia. A quantitative proteomics approach has been employed to define alterations in protein levels in apoptosis induced with staurosporine (STS). Human neuroblastoma derived SH-SY5Y cells were treated with STS (500 nM for 6 h) to induce apoptosis. Quantitative 2-DE was used to determine the changing protein levels with MALDI-TOF MS identification of proteins. Of the 154 proteins analysed, 13 proteins were significantly altered as a result of the apoptotic stimulus; ten of the proteins showed an increase in level with STS and were identified as heat shock cognate 71 (Hsc71), two isoforms of heat shock protein 70 (Hsp70), glucose regulated protein 78 (GRP78), F-actin capping protein, stress-induced phosphoprotein 1, chromatin assembly factor 1 (CAF-1), protein disulphide isomerase A3 (PDI A3) precursor, transitional ER ATPase and actin interacting protein 1 (AIP 1). Three proteins which displayed significant decrease in levels with STS were identified as tubulin, vimentin and glucose regulated protein 94 (GRP94). The functional roles and subcellular locations of these proteins collectively indicate that STS-induced apoptosis provokes induces an unfolded protein response involving molecular chaperones, cochaperones and structural proteins indicative of ER stress.

Sun W, Xing B, Sun Y, et al.
Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues.
Mol Cell Proteomics. 2007; 6(10):1798-808 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly malignant tumor, and chronic infection with hepatitis B virus is one of its major risk factors. To identify the proteins involved in HCC carcinogenesis, we used two-dimensional fluorescence DIGE to study the differentially expressed proteins in tumor and adjacent nontumor tissue samples. Samples from 12 hepatitis B virus-associated HCC patients were analyzed. A total of 61 spots were significantly up-regulated (ratio >/= 2, p

Ji H, Moritz RL, Kim YS, et al.
Analysis of Ras-induced oncogenic transformation of NIH-3T3 cells using differential-display 2-DE proteomics.
Electrophoresis. 2007; 28(12):1997-2008 [PubMed] Related Publications
Ras proteins control at least three crucial signalling networks responsible for several cellular processes including anchorage independence, survival, and proliferation. Point mutations in one of the three ras genes are frequent in human tumours. In these tumours, Ras oncoproteins contribute significantly to the malignant phenotype, including deregulation of tumour-cell growth, apoptosis and invasiveness, and the ability to induce angiogenesis. Although significant strides have been made in understanding Ras biology, the collaborative actions of Ras effectors are still poorly understood. Here, we describe a proteomics approach to study global changes in protein expression in Ras-transformed NIH3T3 cells. We exploited 2-D difference gel electrophoresis (DIGE) for pre-separation fluorescent protein labelling with three separate dyes to reduce gel-to-gel variability, to increase sensitivity and dynamic range of protein detection, and to enhance quantification of dysregulated proteins. Proteins dysregulated (> 1.5-fold) by oncogenic Ras transformation reported to be implicated in Ras-regulated pathways include S-methyl-5-thioadenosine phosphorylase, stress-induced-phosphoprotein 1, galectin-1, annexin A7 (synexin), 60S acidic ribosomal protein P0, serine/threonine protein phosphatase type 1 (PP1alpha) and prohibitin. Significantly, we report for the first time the expression of the newly discovered cytokine IL-25 (or IL-17E) in mouse embryonic fibroblast cells and its down-regulation (2.1-fold) upon Ras-induced oncogenic transformation.

Watras J, Fink CC, Loew LM
Endogenous inhibitors of InsP3-induced Ca2+ release in neuroblastoma cells.
Brain Res. 2005; 1055(1-2):60-72 [PubMed] Related Publications
Cerebellar Purkinje neurons and neuroblastoma N1E-115 cells require 10-50 times more InsP3 to induce Ca2+ release than do a variety of non-neuronal cells (including astrocytes, hepatocytes, endothelial cells, or smooth muscle cells). Given the importance of InsP3-induced Ca2+ release for the development of synaptic plasticity in Purkinje neurons, a low InsP3 sensitivity may facilitate the integration of numerous synaptic inputs before initiating a change in synaptic strength. In the present study, attention is directed at the mechanism underlying this low InsP3 sensitivity of Ca2+ release. We show that permeabilization of neuroblastoma cells with saponin increased InsP3 sensitivity of Ca2+ release, indicating the presence of a diffusible, cytosolic inhibitor(s) of Ca2+ release. Consistent with this hypothesis, gel filtration of the neuroblastoma cytosol yielded three peaks that inhibited InsP3-induced Ca2+ release from permeabilized cells. The prominent inhibitory peak decreased the InsP3 sensitivity of Ca2+ release from permeabilized cells, did not bind 3H-InsP3, and was present in sufficient levels to account for the low InsP3 sensitivity of Ca2+ release in intact neuroblastoma cells. Purification of this prominent inhibitory fraction yielded a protein band that was identified by mass spectrometry as stress-induced phosphoprotein 1 (mSTI1). Furthermore, immunoprecipitation of mSTI1 decreased the inhibitory activity of N1E-115 cytosol, indicating that mSTI1 contributes to the inhibition of InsP3-induced Ca2+ release. Thus, the low InsP3 sensitivity of Ca2+ release in neuroblastoma cells can be explained by the presence of cytosolic inhibitors of Ca2+ release and include stress-induced phosphoprotein 1.

Lee KA, Kang JW, Shim JH, et al.
Protein profiling and identification of modulators regulated by human papillomavirus 16 E7 oncogene in HaCaT keratinocytes by proteomics.
Gynecol Oncol. 2005; 99(1):142-52 [PubMed] Related Publications
OBJECTIVES: Viral oncogenes E6 and E7 are selectively retained and expressed in carcinoma cells infected with human papillomavirus type 16 and cooperated with each other in immortalization and transformation of primary keratinocytes. This study was performed to identify proteins to be bound or modulated by high risk HPV E7 oncogene by using a proteomics.
METHODS: HaCaT normal keratinocyte was prepared to establish a stable cell line expressing E7. The E7-affinity column was also prepared to obtain E7-interacting proteins. In order to search the target molecules modulated by E7 expression, we used 2-dimensional electrophoresis and matrix-assisted laser desorption/ionization time of flight (MALDI/TOF) mass spectrometry. Pull down assay was also performed in order to confirm the E7-interacting proteins.
RESULTS: We identified 28 spots that are modulated by E7 in HaCaT/E7 using 2-dimensional electrophoresis (2-DE) and MALDI/TOF mass spectrometry. Proteomics analyses showed that actin and leukocyte elastase inhibitor were down-regulated, whereas stress-induced phosphoprotein 1, CD2 binding protein 1, catalase, T-complex protein 1, Ku70-binding protein, heat shock 60 kDa protein 1, G1/S-specific cyclin E1 and peroxiredoxin 2 were up-regulated. Western blot revealed that heat shock 60 kDa protein, catalase and peroxiredoxin 2 were also up-regulated. Pull down assay also showed that leukocyte elastase inhibitor (LEI) and Ku70-binding protein were bound to the E7 oncoprotein. By using E7-affinity column and 2-DE/MALDI-TOF, 22 spots were found to interact with E7 recombinant protein. MG11-like proteins, livin inhibitor-of-apoptosis, protein serine kinase c17, CD2 binding protein 1, cyclin E1, TATA box binding protein-associated factor and uridine-cytidine kinase 2 were up-regulated by E7 oncogene and also bound to E7 oncoprotein.
CONCLUSIONS: It is presumed that E7 can influence cell status by modulating the factors related to cell signaling, apoptosis and cell cycle regulation.

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