The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells

Losert, Annemarie; Lötsch, Daniela; Lackner, Andreas; Koppensteiner, Herwig; Peter-Vörösmarty, Barbara; Steiner, Elisabeth; Holzmann, Klaus; Grunt, Thomas W.; Schmid, Katharina; Marian, Brigitte; Grasl‐Kraupp, Bettina; Schulte‐Hermann, Rolf; Krupitza, Georg; Berger, Walter; Grusch, Michael

doi:10.1016/j.canlet.2012.01.002

Cited by 25 publications

(28 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been associated with several signaling pathways, including PI3K/Akt, MAPK, and STAT suggesting regulatory roles in these signaling processes (83)(84)(85). More recently, MVP has been found to be involved in resistance to epidermal growth factor inhibition of several HCC-derived cell lines (86). In our current study, we observed a significant up-regulation of MVP in HCC tissue that was CLIC1: Immunohistochemistry against CLIC1 shows reactivity in sinusoidal lining cells but shows no signal in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Differences Between Hepatocellular Carcinoma and Nontumorous Liver Tissue Investigated by a Combined Gel-based and Label-free Quantitative Proteomics Study

Megger

Bracht

Köhl

et al. 2013

Molecular & Cellular Proteomics

107

109

View full text Add to dashboard Cite

Proteomics-based clinical studies have been shown to be promising strategies for the discovery of novel biomarkers of a particular disease. Here, we present a study of hepatocellular carcinoma (HCC) that combines complementary two-dimensional difference in gel electrophoresis (2D-DIGE) and liquid chromatography (LC-MS)-based approaches of quantitative proteomics. In our proteomic experiments, we analyzed a set of 14 samples (7 ؋ HCC versus 7 ؋ nontumorous liver tissue) with both techniques. Thereby we identified 573 proteins that were differentially expressed between the experimental groups. Among these, only 51 differentially expressed proteins were identified irrespective of the applied approach. Using Western blotting and immunohistochemical analysis the regulation patterns of six selected proteins from the study overlap (inorganic pyrophosphatase 1 (PPA1), tumor necrosis factor type 1 receptor-associated protein 1 (TRAP1), betaine-homocysteine S-methyltransferase 1 (BHMT)) were successfully verified within the same sample set. In addition, the up-regulations of selected proteins from the complements of both approaches (major vault protein (MVP), gelsolin (GSN), chloride intracellular channel protein 1 (CLIC1)) were also reproducible. Within a second independent verification set (n ‫؍‬ 33) the altered protein expression levels of major vault protein and betaine-homocysteine S-methyltransferase were further confirmed by Western blots quantitatively analyzed via densitometry. For the other candidates slight but nonsignificant trends were detectable in this independent cohort. Based on these results we assume that major vault protein and betaine-homocysteine S-methyltransferase have the potential to act as diagnostic HCC biomarker candidates that are worth to be followed in further validation studies. Hepatocellular carcinoma (HCC)1 currently is the fifth most common malignancy worldwide with an annual incidence up to 500 per 100,000 individuals depending on the geographic region investigated. Whereas 80% of new cases occur in developing countries, the incidence increases in industrialized nations including Western Europe, Japan, and the United States (1). To manage patients with HCC, tumor markers are very important tools for diagnosis, indicators of disease progression, outcome prediction, and evaluation of treatment efficacy. Several tumor markers have been reported for HCC, including ␣-fetoprotein (AFP) (2), Lens culinaris agglutininreactive fraction of AFP (AFP-L3) (3), and des-␥-carboxyl prothrombin (DCP) (4). However, none of these tumor markers show 100% sensitivity or specificity, which calls for new and better biomarkers.To identify novel biomarkers of HCC, many clinical studies using "omics"-based methods have been reported over the past decade (5-6). In particular, the proteomics-based approach has turned out to be a promising one, offering several quantification techniques to reveal differences in protein expression that are caused by a particular disease. In most studies, the well-established 2D-D...

show abstract

Section: Discussionmentioning

confidence: 99%

Proteomic Differences Between Hepatocellular Carcinoma and Nontumorous Liver Tissue Investigated by a Combined Gel-based and Label-free Quantitative Proteomics Study

Megger

Bracht

Köhl

et al. 2013

Molecular & Cellular Proteomics

107

109

View full text Add to dashboard Cite

show abstract

“…MVP is a multimeric vault particle (also known as lung resistance-related protein (LRP)) that consists of a telomeraseassociated protein, a vault-poly (ADP-ribose) polymerase, and a small un-translated RNA. MVP has been suggested to contribute to resistance toward chemotherapeutic agents in lung cancer, as the name suggests (44,45). MVP expression is significantly increased across malignant brain tumors when compared with nonmalignant brain tissues (46), and MVP expression correlates with EGFR inhibitor (gefitinib) resistance (45), suggesting that increased expression of MVP may contribute to therapeutic resistance in EGFRvIII expressing tumors.…”

Section: Discussionmentioning

confidence: 99%

“…MVP has been suggested to contribute to resistance toward chemotherapeutic agents in lung cancer, as the name suggests (44,45). MVP expression is significantly increased across malignant brain tumors when compared with nonmalignant brain tissues (46), and MVP expression correlates with EGFR inhibitor (gefitinib) resistance (45), suggesting that increased expression of MVP may contribute to therapeutic resistance in EGFRvIII expressing tumors. GBP1 is a large GTP-binding interferon-inducible protein belonging to the dynamin family (47).…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts

Johnson

Rosario

Bryson

et al. 2012

Molecular & Cellular Proteomics

107

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with a mean survival of 15 months with the current standard of care. Genetic profiling efforts have identified the amplification, overexpression, and mutation of the wild-type (wt) epidermal growth factor receptor tyrosine kinase (EGFR) in ϳ50% of GBM patients. The genetic aberration of wtEGFR is frequently accompanied by the overexpression of a mutant EGFR known as EGFR variant III (EGFRvIII, de2-7EGFR, ⌬EGFR), which is expressed in 30% of GBM tumors. The molecular mechanisms of tumorigenesis driven by EGFRvIII overexpression in human tumors have not been fully elucidated. To identify specific therapeutic targets for EGFRvIII driven tumors, it is important to gather a broad understanding of EGFRvIII specific signaling. Here, we have characterized signaling through the quantitative analysis of protein expression and tyrosine phosphorylation across a panel of glioblastoma tumor xenografts established from patient surgical specimens expressing wtEGFR or overexpressing wtEGFR (wtEGFR؉) or EGFRvIII (EGFRvIII؉). S100A10 (p11), major vault protein, guanylate-binding protein 1(GBP1), and carbonic anhydrase III (CAIII) were identified to have significantly increased expression in EGFRvIII expressing xenograft tumors relative to wtEGFR xenograft tumors. Increased expression of these four individual proteins was found to be correlated with poor survival in patients with GBM; the combination of these four proteins represents a prognostic signature for poor survival in gliomas. Integration of protein expression and phosphorylation data has uncovered significant heterogeneity among the various tumors and has highlighted several novel pathways, related to EGFR trafficking, activated in glioblastoma. The pathways and proteins identified in these tumor xenografts represent potential therapeutic targets for this disease. Molecular & Cellular Proteomics

show abstract

“…Similarly, Siva et al (51) demonstrated that the upregulation of MVP is not sufficient to confer an MDR phenotype. In addition, recent studies have correlated MVP with several signaling pathways (52)(53)(54)(55)(56) and immune responses (57)(58)(59)(60), which imply that the function of MVP may be more complex than expected. Thirdly, the inability to find an association between variants of the MVP gene and platinum resistance or survival in the present study may be due to the limited number of patients enrolled in the study, since the number of patients in the subgroup was below the statistical threshold.…”

Section: Discussionmentioning

confidence: 99%

Association of single nucleotide polymorphisms in the MVP gene with platinum resistance and survival in patients with epithelial ovarian cancer

Wang

2016

Oncology Letters

View full text Add to dashboard Cite

Abstract. The human major vault protein (MVP) has been linked to the development of multidrug resistance in cancer cells, and overexpression of MVP has been observed in ovarian cancer tissues. The aim of the present study was to investigate the association between single nucleotide polymorphisms (SNPs) in the MVP gene and the tumor response to platinum-based chemotherapy and survival of patients affected by epithelial ovarian cancer (EOC), in addition to confirm whether tetra-primer amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) is an accurate genotyping method. For this purpose, two polymorphisms in the MVP gene, namely reference SNP (rs)1057451 and rs4788186, were selected from the data obtained by the International haplotype map (HapMap) Project regarding Chinese Han population, and were evaluated by tetra-primer ARMS-PCR. Upon validation by DNA sequencing, the association of these polymorphisms with platinum resistance, progression-free survival (PFS) and overall survival (OS) in patients with EOC was assessed. The results of tetra-primer ARMS-PCR were in agreement with those derived from DNA sequencing. No significant differences were observed between platinum-sensitive and platinum-resistant cohorts in terms of allele and genotype distribution of these two polymorphisms in the MVP gene, which were not associated with PFS or OS. However, a trend toward prolonged PFS was observed in patients carrying the heterozygous AG allele at the rs4788186 locus. These results suggest that rs1057451 and rs4788186 variants in the MVP gene are not associated with favorable therapeutic response to platinum or longer survival in Chinese Han patients affected by EOC. In addition, the data of the present study confirm that tetra-primer ARMS-PCR is a trustworthy and economical genotyping method.

show abstract

The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells

Cited by 25 publications

References 58 publications

Proteomic Differences Between Hepatocellular Carcinoma and Nontumorous Liver Tissue Investigated by a Combined Gel-based and Label-free Quantitative Proteomics Study

Proteomic Differences Between Hepatocellular Carcinoma and Nontumorous Liver Tissue Investigated by a Combined Gel-based and Label-free Quantitative Proteomics Study

Molecular Characterization of EGFR and EGFRvIII Signaling Networks in Human Glioblastoma Tumor Xenografts

Association of single nucleotide polymorphisms in the MVP gene with platinum resistance and survival in patients with epithelial ovarian cancer

Contact Info

Product

Resources

About