Swadesh K Das

Virginia Commonwealth University, Ричмонд, Virginia, United States

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Publications (87)463.17 Total impact

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    ABSTRACT: Melanoma differentiation associated gene-7/Interleukin-24 (MDA-7/IL-24) is a novel member of the IL-10 gene family that selectively induces apoptosis and toxic autophagy in a broad spectrum of human cancers, including breast cancer, without harming normal cells or tissues. The ability to investigate the critical events underlying cancer initiation and progression, as well as the capacity to test the efficacy of novel therapeutics, has been significantly advanced by the development of genetically engineered mice (GEMs) that accurately recapitulate specific human cancers. We utilized three transgenic mouse models to better comprehend the in vivo role of MDA-7/IL-24 in breast cancer. Using the MMTV-PyMT spontaneous mammary tumor model, we confirmed that exogenously introducing MDA-7/IL-24 using a Cancer Terminator Virus caused a reduction in tumor burden and also produced an antitumor "bystander" effect. Next we performed xenograft studies in a newly created MMTV-MDA-7 transgenic model that over-expresses MDA-7/IL-24 in the mammary glands during pregnancy and lactation, and found that MDA-7/IL-24 overexpression delayed tumor growth following orthotopic injection of a murine PDX tumor cell line (mPDX) derived from a tumor formed in an MMTV-PyMT mouse. We also crossed the MMTV-MDA-7 line to MMTV-Erbb2 transgenic mice and found that MDA-7/IL-24 overexpression delayed the onset of mammary tumor development in this model of spontaneous mammary tumorigenesis as well. Finally, we assessed the role of MDA-7/IL-24 in immune regulation, which can potentially contribute to tumor suppression in vivo. Our findings provide further direct in vivo evidence for the role of MDA-7/IL-24 in tumor suppression in breast cancer in immune-competent transgenic mice.
    Preview · Article · Oct 2015 · Oncotarget
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    ABSTRACT: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) encodes a tumor suppressor gene implicated in the growth of various tumor types including breast cancer. We previously demonstrated that recombinant adenovirus-mediated mda-7/IL-24 expression in the mammary glands of carcinogen-treated (methylnitrosourea, MNU) rats suppressed mammary tumor development. Since most MNU-induced tumors in rats contain activating mutations in Ha-ras, which arenot frequently detected in humans, we presently examined the effect of MDA-7/IL-24 on Her2/Neu-induced mammary tumors, in which the RAS pathway is induced. We generated tet-inducible MDA-7/IL-24 transgenic mice and crossed them with Her2/Neu transgenic mice. Triple compound transgenic mice treated with doxycycline exhibited a strong inhibition of tumor development, demonstrating tumor suppressor activity by MDA-7/IL-24 in immune-competent mice. MDA-7/IL-24 induction also inhibited growth of tumors generated following injection of Her2/Neu tumor cells isolated from triple compound transgenic mice that had not been treated with doxycycline, into the mammary fat pads of isogenic FVB mice. Despite initial growth suppression, tumors in triple compound transgenic mice lost mda-7/IL-24 expression and grew, albeit after longer latency, indicating that continuous presence of this cytokine within tumor microenvironment is crucial to sustain tumor inhibitory activity. Mechanistically, MDA-7/IL-24 exerted its tumor suppression effect on HER2+ breast cancer cells, at least in part, through PERP, a member of PMP-22 family with growth arrest and apoptosis-inducing capacity. Overall, our results establish mda-7/IL-24 as a suppressor of mammary tumor development and provide a rationale for using this cytokine in the prevention/treatment of human breast cancer.
    Preview · Article · Oct 2015 · Oncotarget

  • No preview · Article · Sep 2015 · OncoImmunology
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    ABSTRACT: Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues.
    Full-text · Article · Jul 2015 · Scientific Reports

  • No preview · Article · Jul 2015 · Future Neurology
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    ABSTRACT: mda-9/Syntenin (melanoma differentiation-associated gene 9) is a PDZ domain containing, cancer invasion-related protein. In this study, we employed multiple integrated bioinformatic approaches to identify the probable epigenetic factors, molecular pathways, and functionalities associated with mda-9 dysregulation during cancer progression. Analyses of publicly available genomic data (e.g., expression, copy number, methylation) from TCGA, GEO, ENCODE, and Human Protein Atlas projects led to the following observations: (a) mda-9 expression correlates with both copy number and methylation level of an intronic CpG site (cg1719774) located downstream of the CpG island, (b) cg1719774 methylation is a likely prognostic marker in glioma, (c) among 22 cancer types, melanoma exhibits the highest mda-9 level, and lowest level of methylation at cg1719774, (d) cg1719774 hypomethylation is also associated with histone modifications (at the mda-9 locus) indicative of more active transcription, (e) using Gene Set Enrichment Analysis (GSEA), and the Virtual Gene Overexpression or Repression (VIGOR) analytical scheme, we were able to predict mda-9's association with extracellular matrix organization (e.g., MMPs, collagen, integrins), IGFBP2 and NF-κB signaling pathways, phospholipid metabolism, cytokines (e.g., interleukins), CTLA-4, and components of complement cascade pathways. Indeed, previous publications have shown that many of the aforementioned genes and pathways are associated with mda-9's functionality. © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Advances in Cancer Research
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    ABSTRACT: With therapies that date back to the 1950s, and few newly approved treatments in the last 20 years, pancreatic cancer remains a significant challenge for the development of novel therapeutics. Current regimens have successfully extended patient survival, although they still lead to prognoses measured in months rather than years. The genetic diversity inherent in pancreatic tumors forms the roadblocks that must be overcome in future therapeutics. Recent insight into the genetic patterns found in tumor cells may provide clues leading to better understanding of the challenges hindering the development of treatments. Here, we review currently used drugs and established combination therapies that comprise the standard of care for a highly recalcitrant disease. Novel approaches can improve upon current therapies in a variety of ways. Enhancing specificity, such that growth inhibition and cytotoxic effects act preferentially on tumor cells, is one approach to advance treatments. This can be accomplished through the targeting of extracellular markers specific to cancer cells. Additionally, enlisting natural defenses and overcoming tumor-driven immune suppression could prove to be a useful tactic. Recent studies utilizing these approaches have yielded promising results and could contribute to an ongoing effort battling a particularly difficult cancer. © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jun 2015 · Advances in Cancer Research
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    ABSTRACT: Improved treatments for pancreatic cancer remain a clinical imperative. Sabutoclax, a small-molecule BH3 mimetic, inhibits the function of antiapoptotic Bcl-2 proteins. Minocycline, a synthetic tetracycline, displays antitumor activity. Here, we offer evidence of the combinatorial antitumor potency of these agents in several preclinical models of pancreatic cancer. Sabutoclax induced growth arrest and apoptosis in pancreatic cancer cells and synergized with minocycline to yield a robust mitochondria-mediated caspase-dependent cytotoxicity. This combinatorial property relied upon loss of phosphorylated Stat3 insofar as reintroduction of activated Stat3-rescued cells from toxicity. Tumor growth was inhibited potently in both immune-deficient and immune-competent models with evidence of extended survival. Overall, our results showed that the combination of sabutoclax and minocycline was highly cytotoxic to pancreatic cancer cells and safely efficacious in vivo. Cancer Res; 75(11); 2305-15. ©2015 AACR. ©2015 American Association for Cancer Research.
    No preview · Article · Jun 2015 · Cancer Research
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    ABSTRACT: Oral and oropharyngeal cancers are the sixth most common cancers worldwide. Despite intensive investigation, oral squamous cell carcinomas (OSCC) represent a clinical challenge resulting in significant morbidity and mortality. Resistance to cell death is common in OSCC and is often mediated by the Bcl-2 family proteins. Among all anti-apoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers. Despite the confirmed importance of Mcl-1 in several neoplasms, the role of Mcl-1 in OSCC survival has yet to be explored. In this study, we found that knocking down Mcl-1 sensitized OSCC cells to ABT-737, which binds to Bcl-2/Bcl-xL but not Mcl-1. We report for the first time that a BH3 mimetic, Sabutoclax, which functions as an inhibitor of all anti-apoptotic Bcl-2 proteins, induced cancer-specific cell death in an Mcl-1-dependent manner through both apoptosis and toxic mitophagy. In vivo studies demonstrated that Sabutoclax alone decreased tumor growth in a carcinogen-induced tongue OSCC mouse model. In a combination regimen, Sabutoclax and COX-2 inhibitor, Celecoxib, synergistically inhibited the growth of OSCC in vitro and also significantly reduced OSCC tumor growth in vivo. Overall, these results identify Mcl-1 as a therapeutic prospective target in OSCC.
    Full-text · Article · May 2015 · Oncotarget
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    ABSTRACT: Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell deathcorrelated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.
    Preview · Article · Mar 2015 · Oncotarget
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    ABSTRACT: Gene therapy, which involves replacement of a defective gene with a functional, healthy copy of that gene, is a potentially beneficial cancer treatment approach particularly over chemotherapy, which often lacks selectivity and can cause non-specific toxicity. Despite significant progress pre-clinically with respect to both enhanced targeting and expression in a tumor-selective manner several hurdles still prevent success in the clinic, including non-specific expression, low-efficiency delivery and biosafety. Various innovative genetic approaches are under development to reconstruct vectors/transgenes to make them safer and more effective. Utilizing cutting-edge delivery technologies, gene expression can now be targeted in a tissue- and organ-specific manner. With these advances, gene therapy is poised to become amenable for routine cancer therapy with potential to elevate this methodology as a first line therapy for neoplastic diseases. This review discusses recent advances in gene therapy and their impact on a pre-clinical and clinical level. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Feb 2015 · Journal of Cellular Physiology
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    Luni Emdad · Bin Hu · Swadesh K. Das · Devanand Sarkar · Paul B. Fisher
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    ABSTRACT: AEG-1/MTDH/LYRIC expression is elevated in many cancers, including GBM, where it functions as an oncogene. AEG-1 activates AKT signaling and physically interacts with AKT2 in GBM. Disruption of this interaction reduces glioma cell survival and invasion uncovering a novel potential target for developing an effective therapy for GBM.
    Preview · Article · Jan 2015
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    ABSTRACT: Pancreatic cancer is an aggressive disease with limited therapeutic options. mda-7/IL-24, a potent anti-tumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing ER stress and apoptosis, toxic autophagy, an anti-tumor immune response, an anti-angiogenic effect and a significant 'bystander' anti-cancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, its applications in pancreatic cancer have been restricted due to a 'translational block' occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 as compared to Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that D-Limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the 'translational block' when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the pre-initiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24-mediated toxicity. The American Society for Pharmacology and Experimental Therapeutics.
    No preview · Article · Dec 2014 · Molecular pharmacology
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    ABSTRACT: As a strategy to identify gene expression changes affected by human polynucleotide phosphorylase (hPNPaseold-35), we performed gene expression analysis of HeLa cells in which hPNPaseold-35 was overexpressed. The observed changes were then compared to those of HO-1 melanoma cells in which hPNPaseold-35 was stably knocked down. Through this analysis, 90 transcripts, which positively or negatively correlated with hPNPaseold-35 expression, were identified. The majority of these genes were associated with cell communication, cell cycle, and chromosomal organization gene ontology categories. For a number of these genes, the positive or negative correlations with hPNPaseold-35 expression were consistent with transcriptional data extracted from the TCGA (The Cancer Genome Atlas) expression datasets for colon adenocarcinoma (COAD), skin cutaneous melanoma (SKCM), ovarian serous cyst adenocarcinoma (OV), and prostate adenocarcinoma (PRAD). Further analysis comparing the gene expression changes between Ad.hPNPaseold-35 infected HO-1 melanoma cells and HeLa cells overexpressing hPNPaseold-35 under the control of a doxycycline-inducible promoter, revealed global changes in genes involved in cell cycle and mitosis. Overall, this study provides further evidence that hPNPaseold-35 is associated with global changes in cell cycle-associated genes and identifies potential gene targets for future investigation. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2014 · Journal of Cellular Physiology
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    ABSTRACT: Bladder cancer is the second most common cancer of the urinary tract. Despite existing multiapproach treatment strategies, including radical cystectomy, bladder-sparing therapy with transurethral resection, chemotherapy and radiotherapy, patients with deeply invasive bladder cancers display poor prognosis, with a survival rate of only 30–50%. This can be avoided through proper surveillance and monitoring. Several genetic factors contribute to the progression of bladder cancer, and these molecules serve as cancer biomarkers. Blood, plasma, serum and urine are commonly analyzed for the presence of biomarkers, which can be both nuclear as well as mitochondrial in nature. This review discusses the efficacy of such biomarkers as well as highlights some potential prognostic markers in the field of noninvasive bladder cancer detection.
    Full-text · Article · Oct 2014 · Expert Review of Anti-infective Therapy
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    ABSTRACT: The oncogene AEG-1 (MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades which enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment.
    Full-text · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Molecular-genetic imaging of cancer using nonviral delivery systems has great potential for clinical application as a safe, efficient, noninvasive tool for visualization of various cellular processes including detection of cancer, and its attendant metastases. In recent years, significant effort has been expended in overcoming technical hurdles to enable clinical adoption of molecular-genetic imaging. This chapter will provide an introduction to the components of molecular-genetic imaging and recent advances on each component leading to safe, efficient clinical applications for detecting cancer. Combination with therapy, namely, generating molecular-genetic theranostic constructs, will provide further impetus for clinical translation of this promising technology.
    No preview · Article · Oct 2014 · Advances in Cancer Research
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    ABSTRACT: Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of the different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrate nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in peripheral and subsequent inner layers of multilayered nanocarriers. Characterizations revealed the size, surface charge, entrapment and controlled release. In vitro and in vivo studies evaluated nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced cellular levels of Bcl2 and p53, while increasing Bim. This delivery system successfully embodies sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers.
    Full-text · Article · Oct 2014 · Journal of Materials Chemistry
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    ABSTRACT: Introduction: Melanoma differentiation-associated gene - 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory. Areas covered: Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin's role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule. Expert opinion: Multiple studies demonstrate the importance of MDA-9/Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.
    No preview · Article · Sep 2014 · Expert Opinion on Therapeutic Targets
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    ABSTRACT: Background Malignant glioma is an aggressive cancer requiring new therapeutic targets. MicroRNAs (miRNAs) regulate gene expression post transcriptionally and are implicated in cancer development and progression. Deregulated expressions of several miRNAs, specifically hsa-miR-184, correlate with glioma development. Methods Bioinformatic approaches were used to identify potential miR-184-regulated target genes involved in malignant glioma progression. This strategy identified a multifunctional nuclease, SND1, known to be overexpressed in multiple cancers, including breast, colon, and hepatocellular carcinoma, as a putative direct miR-184 target gene. SND1 levels were evaluated in patient tumor samples and human-derived cell lines. We analyzed invasion and signaling in vitro through SND1 gain-of-function and loss-of-function. An orthotopic xenograft model with primary glioma cells demonstrated a role of miR-184/SND1 in glioma pathogenesis in vivo. Results SND1 is highly expressed in human glioma tissue and inversely correlated with miR-184 expression. Transfection of glioma cells with a miR-184 mimic inhibited invasion, suppressed colony formation, and reduced anchorage-independent growth in soft agar. Similar phenotypes were evident when SND1 was knocked down with siRNA. Additionally, knockdown (KD) of SND1 induced senescence and improved the chemoresistant properties of malignant glioma cells. In an orthotopic xenograft model, KD of SND1 or transfection with a miR-184 mimic induced a less invasive tumor phenotype and significantly improved survival of tumor bearing mice. Conclusions Our study is the first to show a novel regulatory role of SND1, a direct target of miR-184, in glioma progression, suggesting that the miR-184/SND1 axis may be a useful diagnostic and therapeutic tool for malignant glioma.
    No preview · Article · Sep 2014 · Neuro-Oncology

Publication Stats

1k Citations
463.17 Total Impact Points

Institutions

  • 2010-2015
    • Virginia Commonwealth University
      • Department of Human and Molecular Genetics
      Ричмонд, Virginia, United States
  • 2012
    • Cedars-Sinai Medical Center
      • Department of Medicine
      Los Ángeles, California, United States
  • 2005-2009
    • Kobe University
      • Graduate School of Agricultural Science
      Kōbe-shi, Hyogo-ken, Japan