MVP

Gene Summary

Gene:MVP; major vault protein
Aliases: LRP, VAULT1
Location:16p11.2
Summary:This gene encodes the major component of the vault complex. Vaults are multi-subunit ribonucleoprotein structures that may be involved in nucleo-cytoplasmic transport. The encoded protein may play a role in multiple cellular processes by regulating the MAP kinase, JAK/STAT and phosphoinositide 3-kinase/Akt signaling pathways. The encoded protein also plays a role in multidrug resistance, and expression of this gene may be a prognostic marker for several types of cancer. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:major vault protein
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 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.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: MVP (cancer-related)

Jiang YQ, Xu XP, Guo QM, et al.
Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P < 0.05). The growth of stem and H460 cells treated with a combination of T. chinensis var. and cisplatin was also significantly inhibited (P < 0.05). Rh-123 was significantly accumulated in the intracellular region and showed delayed efflux in stem cells treated with T. chinensis var. (P < 0.05), compared to those treated with verapamil. T. chinensis var.-treated stem cells showed significant downregulation of the ABCC1, ABCB1, and LRP mRNA and MRP1, MDR1, and LRP (P < 0.05) compared to H460 cells. Thus, T. chinensis var.-mediated downregulation of MRP1, MDR1, and LRP might contribute to the reversal of drug resistance in non-small cell lung cancer stem cells.

Moiseeva NI, Susova OY, Mitrofanov AA, et al.
Connection between Proliferation Rate and Temozolomide Sensitivity of Primary Glioblastoma Cell Culture and Expression of YB-1 and LRP/MVP.
Biochemistry (Mosc). 2016; 81(6):628-35 [PubMed] Related Publications
Glioblastomas (GBL) are the most common and aggressive brain tumors. They are distinguished by high resistance to radiation and chemotherapy. To find novel approaches for GBL classification, we obtained 16 primary GBL cell cultures and tested them with real-time PCR for mRNA expression of several genes (YB-1, MGMT, MELK, MVP, MDR1, BCRP) involved in controlling cell proliferation and drug resistance. The primary GBL cultures differed in terms of proliferation rate, wherein a group of GBL cell cultures with low proliferation rate demonstrated higher resistance to temozolomide. We found that GBL primary cell cultures characterized by high proliferation rate and lower resistance to temozolomide expressed higher mRNA level of the YB-1 and MDR1 genes, whereas upregulated expression of MVP/LRP mRNA was a marker in the group of GBL with low proliferation rate and high resistance. A moderate correlation between expression of YB-1 and MELK as well as YB-1 and MDR1 was found. In the case of YB-1 and MGMT expression, no correlation was found. A significant negative correlation was revealed between mRNA expression of MVP/LRP and MELK, MDR1, and BCRP. No correlation in expression of YB-1 and MVP/LRP genes was observed. It seems that mRNA expression of YB-1 and MVP/LRP may serve as a marker for GBL cell cultures belonging to distinct groups, each of which is characterized by a unique pattern of gene activity.

Stavrovskaya AA, Shushanov SS, Rybalkina EY
Problems of Glioblastoma Multiforme Drug Resistance.
Biochemistry (Mosc). 2016; 81(2):91-100 [PubMed] Related Publications
Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed.

Qin L, Qiu H, Zhang M, et al.
Soluble CD40 ligands sensitize the epithelial ovarian cancer cells to cisplatin treatment.
Biomed Pharmacother. 2016; 79:166-75 [PubMed] Related Publications
OBJECTIVE: CD154 (CD40L) is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects depending on the target cell type. Being an activator of immune cells, CD40L has also been shown to directly induce apoptosis in tumor cells by multiple mechanisms. To understand the role of sCD40L in regulating the proliferation of epithelial ovarian cancer cells treated or untreated with cisplatin.
METHODS: Epithelial ovarian cancer cells: SKOV3 and its cisplatin-resistant strain SKOV3/DDP cells were used to test the effect of sCD40L and cisplatin. The proliferation of SKOV3 and SKOV3/DDP cells were measured by MTT. Cell cycle was assessed by flow cytometry. The mRNA expressions of targeted genes were detected by qRT-PCR. The protein expressions were detected by Western blotting.
RESULTS: sCD40L showed a significant dose-dependence inhibitory effect on the proliferation of ovarian cancer cell lines. sCD40L in combination with cisplatin could sensitized SKOV3/DDP cells to cisplatin treatment and reversed the drug resistance of SKOV3/DDP cells. The reversal ratios of 1 μg/ml sCD40L combined with cisplatin in SKOV3 and SKOV3/DDP cells were 2.11, 2.71, while the reversal ratios of 2 μg/ml sCD40L combined with cisplatin in SKOV3 and SKOV3/DDP cells were 3.78, 5.20, respectively. sCD40L or sCD40L combined cisplatin increased tumor cells in G0/G1 phase. sCD40L in combination with cisplatin decreased the expression levels of GST-π, LRP, Survivin, p53 and Bcl-2 in both epithelial ovarian cancer cell lines. The protein expression level of GST-π, LRP and P53 protein was also decreased upon sCD40L in combination with cisplatin although the expression level of Bcl-2 and survivin protein had no significant difference.
CONCLUSION: sCD40L inhibits the proliferation of SKOV3 and SKOV3/DDP cells. The combined application of sCD40L and cisplatin can strength the inhibitory effect of cisplatin, and to a certain extent, reversing the resistance to cisplatin in SKOV3/DDP cells. sCD40L could lead a cell block in G0/G1 phase and make the cell growth restrained. sCD40L could induce SKOV3 and SKOV3/DDP cells apoptosis and reverse drug resistance through cutting GST-π mRNA, LRP mRNA, survivin mRNA, p53 mRNA and Bcl-2 mRNA and decreasing the expression of GST-π, LRP and P53 protein in SKOV3 and SKOV3/DDP cells, which provides in-vivo experiment basis to the application of sCD40L as a drug improving ovarian cancer cells sensitivity to cisplatin.

Barbone D, Van Dam L, Follo C, et al.
Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma.
PLoS One. 2016; 11(3):e0150044 [PubMed] Free Access to Full Article Related Publications
To investigate the underlying causes of chemoresistance in malignant pleural mesothelioma, we have studied mesothelioma cell lines as 3D spheroids, which acquire increased chemoresistance compared to 2D monolayers. We asked whether the gene expression of 3D spheroids would reveal mechanisms of resistance. To address this, we measured gene expression of three mesothelioma cell lines, M28, REN and VAMT, grown as 2D monolayers and 3D spheroids. A total of 209 genes were differentially expressed in common by the three cell lines in 3D (138 upregulated and 71 downregulated), although a clear resistance pathway was not apparent. We then compared the list of 3D genes with two publicly available datasets of gene expression of 56 pleural mesotheliomas compared to normal tissues. Interestingly, only three genes were increased in both 3D spheroids and human tumors: argininosuccinate synthase 1 (ASS1), annexin A4 (ANXA4) and major vault protein (MVP); of these, ASS1 was the only consistently upregulated of the three genes by qRT-PCR. To measure ASS1 protein expression, we stained 2 sets of tissue microarrays (TMA): one with 88 pleural mesothelioma samples and the other with additional 88 pleural mesotheliomas paired with matched normal tissues. Of the 176 tumors represented on the two TMAs, ASS1 was expressed in 87 (50%; staining greater than 1 up to 3+). For the paired samples, ASS1 expression in mesothelioma was significantly greater than in the normal tissues. Reduction of ASS1 expression by siRNA significantly sensitized mesothelioma spheroids to the pro-apoptotic effects of bortezomib and of cisplatin plus pemetrexed. Although mesothelioma is considered by many to be an ASS1-deficient tumor, our results show that ASS1 is elevated at the mRNA and protein levels in mesothelioma 3D spheroids and in human pleural mesotheliomas. We also have uncovered a survival role for ASS1, which may be amenable to targeting to undermine mesothelioma multicellular resistance.

Henríquez-Hernández LA, Valenciano A, Foro-Arnalot P, et al.
Association between single-nucleotide polymorphisms in DNA double-strand break repair genes and prostate cancer aggressiveness in the Spanish population.
Prostate Cancer Prostatic Dis. 2016; 19(1):28-34 [PubMed] Related Publications
BACKGROUND: Novel predictors of prognosis and treatment response for prostate cancer (PCa) are required to better individualize treatment. Single-nucleotide polymorphisms (SNPs) in four genes directly (XRCC5 (X-ray repair complementing defective repair in Chinese hamster cells 5) and XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6)) or indirectly (PARP1 and major vault protein (MVP)) involved in non-homologous end joining were examined in 494 Spanish PCa patients.
METHODS: A total of 22 SNPs were genotyped in a Biotrove OpenArray NT Cycler. Clinical tumor stage, diagnostic PSA serum levels and Gleason score at diagnosis were obtained for all participants. Genotypic and allelic frequencies were determined using the web-based environment SNPator.
RESULTS: (XRCC6) rs2267437 appeared as a risk factor for developing more aggressive PCa tumors. Those patients carrying the GG genotype were at higher risk of developing bigger tumors (odds ratio (OR)=2.04, 95% confidence interval (CI) 1.26-3.29, P=0.004), present higher diagnostic PSA levels (OR=2.12, 95% CI 1.19-3.78, P=0.011), higher Gleason score (OR=1.65, 95% CI 1.01-2.68, P=0.044) and D'Amico higher risk tumors (OR=2.38, 95% CI 1.24-4.58, P=0.009) than those patients carrying the CC/CG genotypes. Those patients carrying the (MVP) rs3815824 TT genotype were at higher risk of presenting higher diagnostic PSA levels (OR=4.74, 95% CI 1.40-16.07, P=0.013) than those patients carrying the CC genotype. When both SNPs were analyzed in combination, those patients carrying the risk genotypes were at higher risk of developing D'Amico higher risk tumors (OR=3.33, 95% CI 1.56-7.17, P=0.002).
CONCLUSIONS: We believe that for the first time, genetic variants at XRCC6 and MVP genes are associated with risk of more aggressive disease, and would be taken into account when assessing the malignancy of PCa.

Wu S, Wen F, Li Y, et al.
PIK3CA and PIK3CB silencing by RNAi reverse MDR and inhibit tumorigenic properties in human colorectal carcinoma.
Tumour Biol. 2016; 37(7):8799-809 [PubMed] Related Publications
Colorectal carcinoma (CRC) is the second most common and frequent cause of cancer-related deaths for men and women in the world. PIK3CA and PIK3CB that reverse multidrug resistance (MDR) can serve as predictive and prognostic markers as well as therapeutic targets for CRC treatment. In the present study, we showed that PIK3CA and PIK3CB are upregulated in CRCs and positively correlated with MDR-1, LRP, and GST-π. Long-term monitoring of 316 CRC patients showed that PIK3CA and PIK3CB were associated with poor survival time as shown by Kaplan-Meier analysis. Furthermore, we found that the downregulation of PIK3CA and PIK3CB reversed MDR; inhibited the capability of proliferation, migration, and invasion of CRC cells; and slowed down the CRC tumor growth in nude mice. Consistent with clinical observations, PIK3CA and PIK3CB significantly increase multidrug resistance of CRC cells in vivo. Together, these results suggest that PIK3CA and PIK3CB may be used as potential therapeutic drug targets for colorectal cancer.

Zhang D, Jia J, Zhao G, et al.
NDRG1 promotes the multidrug resistance of neuroblastoma cells with upregulated expression of drug resistant proteins.
Biomed Pharmacother. 2015; 76:46-51 [PubMed] Related Publications
BACKGROUND: Resistance to chemotherapeutic drugs and recurrence are two major causes of poor prognosis in many tumors including neuroblastoma. This study aimed to investigate the effect of the elevated intracellular NDRG1 expression on drug resistance of human neuroblastoma cells to chemotherapy, for exploring novel approaches for biotherapy of neuroblastoma.
METHODS: Human neuroblastoma KP-N-Ns cell lines were transfected with the lentivirus vector containing human NDRG1 cDNA, with empty vector-transfected or blank cells as controls. Transfection status was confirmed under fluorescence microscope, while PCR assay and western blot analysis were performed to determine the expression changes. MTT and TUNEL assays were used to detect the resistance of the cells to anticancer drugs, including vincristine, cyclophosphamide and so on. Additionally, the expression of drug resistant proteins was detected.
RESULTS: Stable lentiviral transfection cell line was successfully established with significantly upregulated NDRG1 expression. MTT assay revealed greater cell growth under NDRG1 overexpression with drugs stimulation, as compared to controls. TUNEL assay also showed less apoptosis of NDRG1 overexpressing cells than those of controls when exposed to these drugs, suggesting the increasing drug resistance through NDRG1 overexpression. Besides, the expression of MDR, LRP-1 and MRP-1 was also increased in NDRG1 overexpressing cells, implying NDRG1-mediated pathways in multidrug resistance of neuroblastoma.
CONCLUSION: NDRG1 could increase the resistance of neuroblastoma cells to chemotherapeutic drugs, with its positive regulation on drug resistant proteins. This study provided new insights for exploring the mechanism of the resistance to chemotherapeutic drugs and also novel approach for biotherapy in neuroblastoma.

Wei H, Lu W, Li M, et al.
Concomitance of P-gp/LRP Expression with EGFR Mutations in Exons 19 and 21 in Non-Small Cell Lung Cancers.
Yonsei Med J. 2016; 57(1):50-7 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Traditional chemotherapy is the main adjuvant therapy for the treatment of non-small cell lung cancer (NSCLC). However, the emergence of multi-drug resistance (MDR) has greatly restricted the curative effect of chemotherapy. Therefore, it is necessary to find a method to treat MDR NSCLC clinically. It is worth investigating whether NSCLCs that are resistant to traditional chemotherapy can be effectively treated with tyrosine kinase inhibitors targeting epidermal growth factor receptor (EGFR).
MATERIALS AND METHODS: The expression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) was detected by immunohistochemistry, and mutations in EGFR (exons 19 and 21) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (exon 2) were detected by high-resolution melting analysis (HRMA) of surgical NSCLC specimens from 127 patients who did not undergo traditional chemotherapy or radiotherapy. A Pearson chi-square test was performed to analyze the correlations between the expression of P-gp and LRP and mutations in EGFR and KRAS.
RESULTS: The expression frequencies of P-gp and LRP were significantly higher in adenocarcinomas from non-smoking patients; the expression frequency of LRP was significantly higher in cancer tissue from female patients. The frequency of EGFR mutations was significantly higher in well to moderately differentiated adenocarcinomas from non-smoking female patients. The frequency of EGFR mutations in the cancers that expressed P-gp, LRP, or both P-gp and LRP was significantly higher than that in cancers that did not express P-gp or LRP.
CONCLUSION: NSCLCs expressing P-gp/LRP bear the EGFR mutation in exon 19 or 21 easily.

Na Y, Choi JW, Kasala D, et al.
Potent antitumor effect of neurotensin receptor-targeted oncolytic adenovirus co-expressing decorin and Wnt antagonist in an orthotopic pancreatic tumor model.
J Control Release. 2015; 220(Pt B):766-82 [PubMed] Related Publications
Pancreatic cancer is highly aggressive, malignant, and notoriously difficult to cure using conventional cancer therapies. These conventional therapies have significant limitations due to excessive extracellular matrix (ECM) of pancreatic cancer and poor cancer specificity. The excess ECM prevents infiltration of drugs into the inner layer of the solid tumor. Therefore, novel treatment modalities that can specifically target the tumor and degrade the ECM are required for effective therapy. In the present study, we used ECM-degrading and Wnt signal-disrupting oncolytic adenovirus (oAd/DCN/LRP) to achieve a desirable therapeutic outcome against pancreatic cancer. In addition, to overcome the limitations in systemic delivery of oncolytic Ad (oAd) and to specifically target pancreatic cancer, neurotensin peptide (NT)-conjugated polyethylene glycol (PEG) was chemically crosslinked to the surface of Ad, generating a systemically injectable hybrid system, oAd/DCN/LRP-PEG-NT. We tested the targeting and therapeutic efficacy of oAd/DCN/LRP-PEG-NT toward neurotensin receptor 1 (NTR)-overexpressing pancreatic cancer cells, both in vitro and in vivo. The oAd/DCN/LRP-PEG-NT elicited increased NTR-selective cancer cell killing and transduction efficiency when compared with a cognate control lacking NT (oAd/DCN/LRP-PEG). Furthermore, systemic administration of oAd/DCN/LRP-PEG-NT significantly decreased induction of innate and adaptive immune responses against Ad, and blood retention time was markedly prolonged by PEGylation. Moreover, NTR-targeting oAd elicited greater in vivo tumor growth suppression when compared with naked oAd and 9.5 × 10(6)-fold increased tumor-to-liver ratio. This significantly enhanced antitumor effect of oAd/DCN/LRP-PEG-NT was mediated by active viral replication and viral spreading, which was facilitated by ECM degradation and inhibition of Wnt signaling-related factors (Wnt, β-catenin, and/or vimentin) in the tumor tissues. Taken together, these results demonstrate that oAd/DCN/LRP-PEG-NT has strong therapeutic potential for systemic treatment of NTR-overexpressing pancreatic cancer due to its NTR-targeting ability, enhanced therapeutic efficacy, and safety.

Pereira MS, de Almeida GC, Pinto F, et al.
SPINT2 Deregulation in Prostate Carcinoma.
J Histochem Cytochem. 2016; 64(1):32-41 [PubMed] Free Access to Full Article Related Publications
SPINT2 is a tumor suppressor gene that inhibits proteases implicated in cancer progression, like HGFA, hepsin and matriptase. Loss of SPINT2 expression in tumors has been associated with gene promoter hypermethylation; however, little is known about the mechanisms of SPINT2 deregulation in prostate cancer (PCa). We aimed to analyze SPINT2 expression levels and understand the possible regulation by SPINT2 promoter hypermethylation in PCa. In a cohort of 57 cases including non-neoplastic and PCa tissues, SPINT2 expression and promoter methylation was analyzed by immunohistochemistry and methylation-specific PCR, respectively. Methylation status of the SPINT2 promoter was also evaluated by bisulfite sequencing and 5-aza-2'-deoxycytidine treatment. Oncomine and TCGA databases were used to perform in silico PCa analysis of SPINT2 mRNA and methylation levels. A reduction in SPINT2 expression levels from non-neoplastic to PCa tissues was observed; however, none of the cases exhibited SPINT2 promoter methylation. Both bisulfite sequencing and 5-aza demonstrated that SPINT2 promoter is not methylated in PCa cells. Bioinformatics approaches did not show downregulation of SPINT2 at the mRNA level and, in corroboration with our results, SPINT2 promoter region is reported to be unmethylated. Our study suggests an involvement of SPINT2 in PCa tumorigenesis, probably in association with a post-translational regulation of SPINT2.

Bhatia P, Masih S, Varma N, et al.
High Expression of Lung Resistance Protein mRNA at Diagnosis Predicts Poor Early Response to Induction Chemotherapy in Childhood Acute Lymphoblastic Leukemia.
Asian Pac J Cancer Prev. 2015; 16(15):6663-8 [PubMed] Related Publications
BACKGROUND: Treatment failure in leukemia is due to either pharmacokinetic resistance or cell resistance to drugs.
MATERIALS AND METHODS: Gene expression of multiple drug resistance protein (MDR-1), multidrug resistance-related protein (MRP) and low resistance protein (LRP) was assessed in 45 pediatric ALL cases and 7 healthy controls by real time PCR. The expression was scored as negative, weak, moderate and strong.
RESULTS: The male female ratio of cases was 2.75:1 and the mean age was 5.2 years. Some 26/45 (58%) were in standard risk, 17/45(38%) intermediate and 2/45 (4%) in high risk categorie, 42/45 (93%) being B-ALL and recurrent translocations being noted in 5/45 (11.0%). Rapid early response (RER) at day 14 was seen in 37/45 (82.3%) and slow early response (SER) in 8/45 (17.7%) cases. Positive expression of MDR-1, LRP and MRP was noted in 14/45 (31%), 15/45 (33%) and 27/45 (60%) cases and strong expression in 3/14 (21%), 11/27 (40.7%) and 8/15 (53.3%) cases respectively. Dual or more gene positivity was noted in 17/45 (38%) cases. 46.5 % (7/15) of LRP positive cases at day 14 were in RER as compared to 100% (30/30) of LRP negative cases (p<0.05). All 8 (100%) LRP positive cases in SER had strong LRP expression (p=<0.05). Moreover, only 53.3% of LRP positive cases were in haematological remission at day 30 as compared to 100% of LRP negative cases (p=<0.05).
CONCLUSIONS: Our study indicated that increased LRP expression at diagnosis in pediatric ALL predicts poor response to early treatment and hence can be used as a prognostic marker. However, larger prospective studies with longer follow up are needed, to understand the clinical relevance of drug resistance proteins.

Khumalo T, Ferreira E, Jovanovic K, et al.
Knockdown of LRP/LR Induces Apoptosis in Breast and Oesophageal Cancer Cells.
PLoS One. 2015; 10(10):e0139584 [PubMed] Free Access to Full Article Related Publications
Cancer is a global burden due to high incidence and mortality rates and is ranked the second most diagnosed disease amongst non-communicable diseases in South Africa. A high expression level of the 37kDa/67kDa laminin receptor (LRP/LR) is one characteristic of cancer cells. This receptor is implicated in the pathogenesis of cancer cells by supporting tumor angiogenesis, metastasis and especially for this study, the evasion of apoptosis. In the current study, the role of LRP/LR on cellular viability of breast MCF-7, MDA-MB 231 and WHCO1 oesophageal cancer cells was investigated. Western blot analysis revealed that total LRP expression levels of MCF-7, MDA-MB 231 and WHCO1 were significantly downregulated by targeting LRP mRNA using siRNA-LAMR1. This knockdown of LRP/LR resulted in a significant decrease of viability in the breast and oesophageal cancer cells as determined by an MTT assay. Transfection of MDA-MB 231 cells with esiRNA-RPSA directed against a different region of the LRP mRNA had similar effects on LRP/LR expression and cell viability compared to siRNA-LAMR1, excluding an off-target effect of siRNA-LAMR1. This reduction in cellular viability is as a consequence of apoptosis induction as indicated by the exposure of the phosphatidylserine protein on the surface of breast MCF-7, MDA-MB 231 and oesophageal WHCO1 cancer cells, respectively, detected by an Annexin-V/FITC assay as well as nuclear morphological changes observed post-staining with Hoechst. These observations indicate that LRP/LR is crucial for the maintenance of cellular viability of breast and oesophageal cancer cells and recommend siRNA technology targeting LRP expression as a possible novel alternative technique for breast and oesophageal cancer treatment.

Bizzarro V, Belvedere R, Milone MR, et al.
Annexin A1 is involved in the acquisition and maintenance of a stem cell-like/aggressive phenotype in prostate cancer cells with acquired resistance to zoledronic acid.
Oncotarget. 2015; 6(28):25076-92 [PubMed] Related Publications
In this study, we have characterized the role of annexin A1 (ANXA1) in the acquisition and maintenance of stem-like/aggressive features in prostate cancer (PCa) cells comparing zoledronic acid (ZA)-resistant DU145R80 with their parental DU145 cells. ANXA1 is over-expressed in DU145R80 cells and its down-regulation abolishes their resistance to ZA. Moreover, ANXA1 induces DU145 and DU145R80 invasiveness acting through formyl peptide receptors (FPRs). Also, ANXA1 knockdown is able to inhibit epithelial to mesenchymal transition (EMT) and to reduce focal adhesion kinase (FAK) and metalloproteases (MMP)-2/9 expression in PCa cells. DU145R80 show a cancer stem cell (CSC)-like signature with a high expression of CSC markers including CD44, CD133, NANOG, Snail, Oct4 and ALDH7A1 and CSC-related genes as STAT3. Interestingly, ANXA1 knockdown induces these cells to revert from a putative prostate CSC to a more differentiated phenotype resembling DU145 PCa cell signature. Similar results are obtained concerning some drug resistance-related genes such as ATP Binding Cassette G2 (ABCG2) and Lung Resistant Protein (LRP). Our study provides new insights on the role of ANXA1 protein in PCa onset and progression.

Zhao Q, Li Y, Tan BB, et al.
HIF-1α Induces Multidrug Resistance in Gastric Cancer Cells by Inducing MiR-27a.
PLoS One. 2015; 10(8):e0132746 [PubMed] Free Access to Full Article Related Publications
This study aimed to determine the correlation between HIF-1α and miR-27a expression and to evaluate the effect of inhibition of HIF-1α expression on miR-27a expression and drug resistance in gastric cancer (GC). In the present study, real time-PCR and Western blot were performed to detect the expression of HIF-1α in GC tissues and cell lines. Then, OCUM-2MD3/L-OHP cells were transfected with HIF-1α-siRNA, a miR-27a mimic or pcDNA-HIF-1α, and cell survival was determined via the MTT assay. The expression of HIF-1α, miR-27a, and MDR-related genes was measured via real time-PCR and Western blot. ChIP and dual luciferase activity assays were performed to assess the transcriptional regulation of HIF-1α and miR-27a. The results revealed that transfection with HIF-1α-siRNA markedly decreased the levels of miR-27a, resulting in dramatically enhanced inhibition of the proliferation rate of OCUM-2MD3/L-OHP cells. Compared to non-transfected cells, the survival rate was significantly reduced in the cells transfected with HIF-1α-siRNA after treatment with L-OHP. The cell survival rate was significantly increased in OCUM-2MD3/L-OHP cells transfected with the miR-27a mimic, whereas HIF-1α overexpression did not result in any clear change in cell survival. The results of the dual luciferase activity assay demonstrated that HIF-1α enhances the transcriptional activity of the miR27a promoter in cells transfected with a reporter plasmid containing the upstream promoter region of miR27a together with pcDNA-HIF-1α. ChIP analysis suggested that HIF-1α directly binds to the promoter region of miR27a. Inhibition of HIF-1α or miR27a expression decreased MDR1/P-gp, LRP, and Bcl-2 expression in OCUM-2MD3/L-OHP cells. Thus, we found that HIF-1α is closely associated with MDR in GC and that HIF-1α may suppress MDR1/P-gp, LRP and Bcl-2 expression by inhibiting miR-27a expression.

Shah K, Mirza S, Desai U, et al.
Synergism of Curcumin and Cytarabine in the Down Regulation of Multi-Drug Resistance Genes in Acute Myeloid Leukemia.
Anticancer Agents Med Chem. 2016; 16(1):128-35 [PubMed] Related Publications
BACKGROUND: The aim of the study was to find a role of Curcumin from natural source to overcome drug resistance as well as to reduce cytotoxicity profile of the drug in Acute Myeloid Leukemia patients.
MATERIAL AND METHODS: Primary leukemic cells were obtained from AML patient's bone marrow. These cells were then exposed to different concentration of cytarabine and curcumin to find out IC50 values and also its effect on MDR genes like MDR1, BCRP, LRP and FLT3 by RT-PCR method.
RESULT & CONCLUSION: Our results suggested that curcumin down regulates MDR genes. Gene expression was decreased by 35.75, 31.30, 27.97 % for MDR1, LRP, BCRP respectively. In FLT3, it was 65.86 % for wild type and 31.79 % for FLT3-ITD. In addition to this, curcumin has also shown anti-proliferative effect as well as synergistic effect in combination with Cytarabine on primary leukemic cells. Thus, we can conclude that curcumin can be used as MDR modulator as well as chemosensitizer in combination with cytarabine, standard chemotherapeutic drug, to reduce the cytotoxicity profile as IC50 value decreases when treated in combination.

Sen A, Nelson TJ, Alkon DL
ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation.
J Neurosci. 2015; 35(19):7538-51 [PubMed] Related Publications
Apolipoprotein E4 (ApoE4) is a major genetic risk factor for several neurodegenerative disorders, including Alzheimer's disease (AD). Epigenetic dysregulation, including aberrations in histone acetylation, is also associated with AD. We show here for the first time that ApoE4 increases nuclear translocation of histone deacetylases (HDACs) in human neurons, thereby reducing BDNF expression, whereas ApoE3 increases histone 3 acetylation and upregulates BDNF expression. Amyloid-β (Aβ) oligomers, which have been implicated in AD, caused effects similar to ApoE4. Blocking low-density lipoprotein receptor-related protein 1 (LRP-1) receptor with receptor-associated protein (RAP) or LRP-1 siRNA abolished the ApoE effects. ApoE3 also induced expression of protein kinase C ε (PKCε) and PKCε retained HDACs in the cytosol. PKCε activation and ApoE3 supplementation prevented ApoE4-mediated BDNF downregulation. PKCε activation also reversed Aβ oligomer- and ApoE4-induced nuclear import of HDACs, preventing the loss in BDNF. ApoE4 induced HDAC6-BDNF promoter IV binding, which reduced BDNF exon IV expression. Nuclear HDAC4 and HDAC6 were more abundant in the hippocampus of ApoE4 transgenic mice than in ApoE3 transgenic mice or wild-type controls. Nuclear translocation of HDA6 was also elevated in the hippocampus of AD patients compared with age-matched controls. These results provide new insight into the cause of synaptic loss that is the most important pathologic correlate of cognitive deficits in AD.

Minn I, Bar-Shir A, Yarlagadda K, et al.
Tumor-specific expression and detection of a CEST reporter gene.
Magn Reson Med. 2015; 74(2):544-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To develop an imaging tool that enables the detection of malignant tissue with enhanced specificity using the exquisite spatial resolution of MRI.
METHODS: Two mammalian gene expression vectors were created for the expression of the lysine-rich protein (LRP) under the control of the cytomegalovirus (CMV) promoter and the progression elevated gene-3 promoter (PEG-3 promoter) for constitutive and tumor-specific expression of LRP, respectively. Using those vectors, stable cell lines of rat 9L glioma, 9L(CMV-LRP) and 9L(PEG-LRP) , were established and tested for CEST contrast in vitro and in vivo.
RESULTS: 9L(PEG-LRP) cells showed increased CEST contrast compared with 9L cells in vitro. Both 9L(CMV-LRP) and 9L(PEG-LRP) cells were capable of generating tumors in the brains of mice, with a similar growth rate to tumors derived from wild-type 9L cells. An increase in CEST contrast was clearly visible in tumors derived from both 9L(CMV-LRP) and 9L(PEG-LRP) cells at 3.4 ppm.
CONCLUSION: The PEG-3 promoter:LRP system can be used as a cancer-specific, molecular-genetic imaging reporter system in vivo. Because of the ubiquity of MR imaging in clinical practice, sensors of this class can be used to translate molecular-genetic imaging rapidly.

Navarro L, Gil-Benso R, Megías J, et al.
Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.
Neuroscience. 2015; 297:243-51 [PubMed] Related Publications
Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches.

Stefansson IM, Raeder M, Wik E, et al.
Increased angiogenesis is associated with a 32-gene expression signature and 6p21 amplification in aggressive endometrial cancer.
Oncotarget. 2015; 6(12):10634-45 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Angiogenesis is a hallmark of cancer. The aim of this study was to explore whether microvessel proliferation is associated with gene expression profiles or copy number alterations in endometrial cancer.
METHODS: A prospective series of endometrial carcinomas was studied for angiogenesis markers, gene expression profiles, and gene copy number data. For validation, an independent series of endometrial carcinomas as well as an external cohort of endometrial cancer patients were examined by gene expression microarrays.
RESULTS: Increased microvessel proliferation (MVP) was associated with aggressive tumor features and reduced survival, and a 32-gene expression signature was found to separate tumors with high versus low MVP. An increased 32-gene signature score was confirmed to associate with high-grade tumor features and reduced survival by independent cohorts. Copy number studies revealed that amplification of the 6p21 region was significantly associated with MVP, a high 32-gene score, as well as reduced survival.
CONCLUSION: Increased MVP was significantly associated with aggressive endometrial cancer and reduced survival. Integrated analyses demonstrated significant associations between increased vascular proliferation, amplification of the 6p21 region, VEGF-A mRNA expression, and the 32-gene angiogenesis signature. Our findings indicate amplification of 6p21 as a possible driver of tumor vascular proliferation in endometrial cancer.

Zhang W, Shen C, Li C, et al.
miR-577 inhibits glioblastoma tumor growth via the Wnt signaling pathway.
Mol Carcinog. 2016; 55(5):575-85 [PubMed] Related Publications
microRNAs (miRNAs) are commonly altered in glioblastoma. Publicly available algorithms suggest the Wnt pathway is a potential target of miR-577 and the Wnt pathway is commonly altered in glioblastoma. Glioblastoma has not been previously evaluated for miR-577 expression. Glioblastoma tumors and cell lines were evaluated for their expression of miR-577. Cell lines were transfected with miR-577, miR-577-mutant, or control mimics to evaluate the effect of miR-577 expression on cell proliferation in vitro and in an animal model. Wnt pathway markers were also evaluated for their association with miR-577 expression. miR-577 expression was decreased in 33 of 40 (82.5%) glioblastoma tumors and 5 of 6 glioblastoma cell lines. miR-577 expression correlated negatively with cell growth and cell viability. miR-577 down-regulation was associated with increased expression of the Wnt signaling pathway genes lipoprotein receptor-related protein (LRP) 6 (LRP6) and β-catenin. Western blot analysis confirmed decreased expression of the Wnt signaling pathway genes Axin2, c-myc, and cyclin D1 in miR-577 transfected cells. miR-577 expression is down-regulated in glioblastoma. miR-577 directly targets Wnt signaling pathway components LRP6 and β-catenin. miR-577 suppresses glioblastoma multiforme (GBM) growth by regulating the Wnt signaling pathway.

Yu T, Yang Y, Zhang J, et al.
Circumvention of cisplatin resistance in ovarian cancer by combination of cyclosporin A and low-intensity ultrasound.
Eur J Pharm Biopharm. 2015; 91:103-10 [PubMed] Related Publications
Cisplatin resistance is a challenge in the treatment of ovarian cancer. The aim of this study was to explore if ultrasound can overcome chemoresistance and enhance chemosensitization due to cyclosporin A. Ultrasound and/or cyclosporin A were employed to overcome cisplatin resistance in human ovarian cancer cell line COC1/DDP. Mechanisms were explored from the perspective of: DNA damage, intracellular platinum level, detoxification, and genes related to drug efflux and DNA repair. In vivo therapeutic efficacy was validated in a short-term model (subrenal cell-clot transplantation) in mice and the survival benefit was investigated in an orthotopic cancer model in mice using HO-8910PM cells. The findings were: (i) ultrasound enhanced the effect of cisplatin leading to a lower cell-survival rate (IC50 decreased from 3.19 to 0.35 μg/ml); (ii) ultrasound enhanced cisplatin via direct (increasing the intercellular level of active platinum) and indirect (decreasing the glutathione level, and expression of LRP and ERCC1 genes) mechanisms that intensified cisplatin-induced DNA damage, thus enhancing cell apoptosis and necrosis; (iii) cisplatin followed by ultrasound led to small tumor sizes in the short-term model without exacerbation of the systemic toxicity, and prolonged the survival times in the orthotopic model; and (iv) ultrasound synergized the sensitization due to cyclosporin A in vitro and in vivo. These data demonstrated that ultrasound combined with cyclosporin A overcame cisplatin resistance in ovarian cancer.

Celestino AT, Levy D, Maria Ruiz JL, Bydlowski SP
ABCB1, ABCC1, and LRP gene expressions are altered by LDL, HDL, and serum deprivation in a human doxorubicin-resistant uterine sarcoma cell line.
Biochem Biophys Res Commun. 2015; 457(4):664-8 [PubMed] Related Publications
Multidrug resistance (MDR) is the major cause of cancer treatment failure. The ATP-binding cassette-B1 (ABCB1) transporter, also known as MDR1 or P-glycoprotein, is thought to promote the efflux of drugs from cells. MDR is also associated with the multidrug resistance-associated protein 1 (ABCC1) and the lung resistance-related protein (LRP), a human major vault protein. Moreover, MDR has a complex relationship with lipids. The ABCB1 has been reported to modulate cellular cholesterol homeostasis. Conversely, cholesterol has been reported to modulate multidrug transporters. However, results reported to date are contradictory and confusing. The aim of this study was to investigate whether LDL, HDL, and serum deprivation could influence ABCB1, ABCC1, and LRP expression in a human doxorubicin-resistant uterine sarcoma cell line. ABCB1 and ABCC1 expression increased after 24 h of serum deprivation, and expression returned to basal levels after 72 h. LDL, depending on concentration, increased ABCB1, ABCC1, and LRP expression. ABCB1 expression increased at low HDL, and decreased at high HDL concentrations. We demonstrated that serum deprivation and lipoproteins, particularly LDL, modulated ABCB1 expression and, to a lesser extent, ABCC1 expression. This finding may link the phenomena of drug transport, cholesterol metabolism and cancer.

Wen F, He S, Sun C, et al.
PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma.
Int J Clin Exp Pathol. 2014; 7(11):8295-303 [PubMed] Free Access to Full Article Related Publications
The phosphoinositide 3-kinases (PI3Ks) are a critical family of signaling enzymes that participate in many cellular processes that promote the transformation of a normal cell into a cancer cell. These processes include cancer cell proliferation, migration, and invasion. However, the correlation between PI3Ks and multidrug resistance (MDR) remains unclear. The prognostic value of PI3Ks has not been previously evaluated. Thus, this study aims to evaluate the association between PIK3CA and PIK3CB expression and the MDR gene in colorectal cancer (CRC) patients. Immunohistochemistry was employed to detect the expressions of PIK3CA, PIK3CB, MDR-1, LRP, GST-π, and Topo II in 316 CRC specimens. Patients were followed-up annually by telephone or at an outpatient clinic. Results revealed that PIK3CA and PIK3CB expression was correlated with the degree of tumor differentiation and lymph node metastasis (P < 0.05). The overexpression of MDR-1, LRP, Topo II, and GST-π was found to be 72.78%, 70.89%, 77.53%, and 76.58% of CRC, respectively. Correlation analysis showed that PIK3CA and PIK3CB expression exhibits a positive correlation with MDR-1, LRP, and GST-π with correlation coefficients of 0.288, 0.128, and 0.197, respectively (P < 0.05). Kaplan-Meier analysis revealed that the five-year survival rate of patients without lymph node metastasis, positive expression of PIK3CA and PIK3CB, and negative expression of GST-π and MDR-1 was higher than those with these characteristics. Multivariate analysis revealed that GST-π, MDR-1 expression, and lymph node metastasis could serve as independent predictive factors of overall survival. The expression of both PIK3CA and PIK3CB is increased and related to the development and progress of colorectal carcinoma and MDR. The combined detection of PIK3CA andPIK3CB is important for patients with colorectal carcinoma in prognosis and optimal therapy.

Feber A, Arya M, de Winter P, et al.
Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer.
Clin Cancer Res. 2015; 21(5):1196-206 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer.
EXPERIMENTAL DESIGN: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations.
RESULTS: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature-negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021-0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13-0.78], HPV epi-signature is a better predictor of survival than HPV status alone.
CONCLUSIONS: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies.

Wu C, Wang Y, Xia Y, et al.
Wilms' tumor 1 enhances Cisplatin-resistance of advanced NSCLC.
FEBS Lett. 2014; 588(24):4566-72 [PubMed] Related Publications
Wilms' tumor 1 (WT1) is an oncogene that has been correlated with tumor progression, bad prognosis and chemo-resistance in Non-Small-Cell lung cancer (NSCLC). Here, we found that WT1 expression is significantly higher in NSCLCs than in benign controls, and that Cisplatin-resistant patients display a notable increase in WT1 expression following relapse. In vitro, WT1 levels were associated with the IC50 of NSCLC cells and increased along with treatment time and dose of Cisplatin. Furthermore, WT1 enhanced Major Vault Protein (MVP) transcription via binding to its promoter. Therefore, WT1 may be a potential therapeutic target for solving resistance.

Fukushima H, Abe T, Sakamoto K, et al.
3'-ethynylcytidine, an RNA polymerase inhibitor, combined with cisplatin exhibits a potent synergistic growth-inhibitory effect via Vaults dysfunction.
BMC Cancer. 2014; 14:562 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We previously reported that 3'-ethynylcytidine (ECyd, TAS-106), an RNA polymerases inhibitor, enhances the anti-tumor efficacy of platinum in several tumor types in both in vitro and in vivo tumor models. However, the molecular mechanisms underlying the ECyd-induced enhancement remain elusive.
METHODS: Cisplatin (CDDP)-resistant head and neck cancer KB cells were established by stepwise dose escalation with CDDP. The combination effect of ECyd and CDDP were assessed using isobologram analysis. The transcriptional and post-translational statuses of several molecules were detected using real-time PCR, immunoblot analysis and immunocytochemistry. Xenograft assays were used to confirm the mechanisms underlying the ECyd induced enhancement of CDDP anti-tumor efficacy in vivo.
RESULTS: ECyd sensitized KB to CDDP by inhibiting the drug transporter Vault complex (Vaults). First, we showed that Vaults were overexpressed in CDDP-resistant KB cells. The suppression of major vault protein (MVP) by RNA interference restored the sensitivity to CDDP. Next, we showed that ECyd significantly sensitized the resistant cells to CDDP, compared with the parental paired cell line. A molecular analysis revealed that ECyd inhibited the synthesis of vRNAs as well as the induction of MVP, both of which are critical components of Vaults as a drug transporter. Furthermore, we found that the synergistic effect of ECyd and CDDP was correlated with the MVP expression level when the effect was analyzed in additional cancer cell lines. Finally, we demonstrated that ECyd decreased the vRNAs expression level in xenograft tumor.
CONCLUSIONS: Our data indicated the ability of ECyd to cancel the resistance of cancer cells to CDDP by inhibiting the Vaults function and the decrease of Vaults expression itself, and the ability of the combination therapy with CDDP and ECyd to offer a new strategy for overcoming platinum resistance. Moreover, the study results suggest that Vaults could be a biomarker for stratifying patients who may benefit from the combination therapy with ECyd and platinum.

Yang Z, Xiang B, Dong D, et al.
Dual receptor-specific peptides modified liposomes as VEGF siRNA vector for tumor-targeting therapy.
Curr Gene Ther. 2014; 14(4):289-99 [PubMed] Related Publications
Tumor angiogenesis involves multiple signaling pathways that provide potential therapeutic targets to inhibit tumor growth and metastasis. Regarding the significant role of vascular endothelial growth factor (VEGF) in angiogenesis and tumor progression, VEGF sequence-specific small interfering RNA (siRNA) for anti-angiogenic tumor therapy are under development. In the present study, dual-modified liposomes (At-Lp) was designed by attaching two receptorspecific peptides, Angiopep and tLyP-1, which specifically targeting low-density lipoprotein receptor (LRP) for brain tumor targeting and neuropilin-1 receptor (NRP-1) for tumor penetration, respectively. Gene transfection and silencing, and antitumor effect of the At-Lp loaded with VEGF siRNA were evaluated in vitro and in orthotopic xenograft models of U87 MG tumor. The At-Lp significantly enhanced cellular uptake (2-fold) and down-regulated expression of VEGF in U87 MG glioblastoma cells compared with non-modified and single-modified liposomes. The internalization of the At-Lp into tumor cells was taken via the enhanced permeability and retention effect and receptor-mediated endocytosis, followed by an effective endosomal escape of loaded siRNA into the cytoplasm. The At-Lp showed great superiority in inhibition of tumor growth, anti-angiogenesis, expression of VEGF and apoptosis effect after in vivo application against nude mice bearing U87 MG glioblastoma without activation of system-associated toxicity and the innate immune response. These results demonstrated that the combination of two receptor-specific peptides-mediated liposomes presented a promising platform for effective targeting delivery of siRNA for cancer anti-angiogenic therapy.

Han T, Zhu X, Wang J, et al.
Establishment and characterization of a cisplatin‑resistant human osteosarcoma cell line.
Oncol Rep. 2014; 32(3):1133-9 [PubMed] Related Publications
The aim of the present study was to establish a new cisplatin-resistant human osteosarcoma cell line and investigate its biological characteristics. The human osteosarcoma cell line SOSP-9607 was exposed to cisplatin by stepwisely increasing the concentrations in the medium to select for the drug-resistant subline, SOSP-9607/CDDP cells. The morphological features were observed using inverted microscopy. The growth curves of SOSP-9607 and SOSP-9607/CDDP cells were drawn to calculate the doubling time. FCM was also used to determine the distribution of the cell cycle. The MTT assay was performed to test the drug resistance of SOSP-9607 and SOSP-9607/CDDP cells. Transwell assay was used to examine the invasive capability of the SOSP-9607/CDDP and SOSP-9607 cells. RT-PCR was performed to determine the mRNA expression levels of drug resistance-related and apoptosis-related genes, MDR1, MRP1, MRP2, LRP, ABCG2, GST-π, Bcl-2 and Bax, in both cell lines. SOSP-9607/CDDP cells exhibited changes in morphology, proliferation rate, doubling time, cell cycle distribution and invasive capability as compared with the SOSP-9607 cells. SOSP-9607/CDDP cells were 6.24-fold resistant to cisplatin in comparison with the SOSP‑9607 cells and also exhibited cross-resistance to methotrexate and adriamycin. SOSP-9607/CDDP cells overexpressed MRP1, MRP2 and GST-π. In conclusion, SOSP-9607/CDDP cells are invaluable tools with which to study the resistance of anticancer drugs and to identify the methods to overcome resistance.

Huang SY, Lin CW, Lin HH, et al.
Expression of cereblon protein assessed by immunohistochemicalstaining in myeloma cells is associated with superior response of thalidomide- and lenalidomide-based treatment, but not bortezomib-based treatment, in patients with multiple myeloma.
Ann Hematol. 2014; 93(8):1371-80 [PubMed] Free Access to Full Article Related Publications
Cereblon (CRBN) is essential for the anti-myeloma (MM) activity of immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide. However, the clinical implications of CRBN in MM patients are unclear. Using immunohistochemical (IHC) staining on paraffin-embedded bone marrow sections, the expression of CRBN protein in myeloma cells (MCs) was assessed in 40 relapsed/refractory MM (RRMM) patients who received lenalidomide/dexamethasone (LD) and 45 and 22 newly diagnosed MM (NDMM) patients who received thalidomide/dexamethasone (TD) and melphalan/bortezomib/prednisolone (MVP), respectively. IHC staining were scored on a scale representing the diffuseness and intensity of positive-staining MCs (range, 0-8) and a score ≥4.5 was used for CRBN positivity (CRBN(+)) on a cut-point analysis of all possible scores and response of TD and LD. Compared to CRBN(+) NDMM patients, CRBN(-) NDMM patients had more international staging system (ISS) III (26 vs. 61 %, respectively; P = 0.006). In the LD and TD cohorts, the response rate (RR) was higher in CRBN(+) patients than CRBN(-) patients (LD 79 vs. 33 %, respectively; P = 0.005) (TD 75 vs. 29 %, respectively; P = 0.005); however, this trend was not observed in the MVP cohort. In the LD and TD cohorts, the positive and negative prediction value of CRBN(+) for treatment response was 79 and 67 % and 75 and 71 %, respectively. Multivariate analysis showed that CRBN(+) was a significant factor associated with superior RR for LD and TD. The data suggest that expression of CRBN protein in MCs assessed using the IHC is a feasible approach to predict the response of IMiDs in MM patients.

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