TNFRSF25

Gene Summary

Gene:TNFRSF25; tumor necrosis factor receptor superfamily, member 25
Aliases: DR3, TR3, DDR3, LARD, APO-3, TRAMP, WSL-1, WSL-LR, TNFRSF12
Location:1p36.2
Summary:The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed preferentially in the tissues enriched in lymphocytes, and it may play a role in regulating lymphocyte homeostasis. This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Knockout studies in mice suggested the role of this gene in the removal of self-reactive T cells in the thymus. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules. The alternative splicing of this gene in B and T cells encounters a programmed change upon T-cell activation, which predominantly produces full-length, membrane bound isoforms, and is thought to be involved in controlling lymphocyte proliferation induced by T-cell activation. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor receptor superfamily member 25
HPRD
Source:NCBIAccessed: 25 June, 2015

Ontology:

What does this gene/protein do?
Show (12)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 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 25 June, 2015 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: TNFRSF25 (cancer-related)

Escara-Wilke J, Keller JM, Ignatoski KM, et al.
Raf kinase inhibitor protein (RKIP) deficiency decreases latency of tumorigenesis and increases metastasis in a murine genetic model of prostate cancer.
Prostate. 2015; 75(3):292-302 [PubMed] Related Publications
BACKGROUND: Raf kinase inhibitor protein (RKIP) has been shown to act as a metastasis suppressor gene in multiple models of cancer. Loss of RKIP expression promotes invasion and metastasis in cell transplantation animal models. However, it is unknown if RKIP expression can impact the progression of cancer in an autochthonous model of cancer. The goal of this study was to determine if loss of RKIP expression in a genetic mouse model of prostate cancer (PCa) impacts metastasis.
METHODS: Endogenous RKIP expression was measured in the primary tumors and metastases of transgenic adenocarcinoma of the mouse prostate (TRAMP(+) ) mice. RKIP knockout mice (RKIP(-/-) ) were crossbred with (TRAMP(+) ) mice to create RKIP(-/-) TRAMP(+) mice. Mice were euthanized at 10, 20, and 30 weeks for evaluation of primary and metastatic tumor development. To determine if loss of RKIP alone promotes metastasis, RKIP was knocked down in the low metastatic LNCaP prostate cancer cell line.
RESULTS: Endogenous RKIP expression decreased in TRAMP(+) mice as tumors progressed. Primary tumors developed earlier in RKIP(-/-) TRAMP(+) compared to TRAMP(+) mice. At 30 weeks of age, distant metastases were identified only the RKIP(-/-) TRAMP(+) mice. While prostate epithelial cell proliferation rates were higher at 10 and 20 weeks in RKIP(-/-) TRAMP(+) compared to TRAMP(+) mice, by 30 weeks there was no difference. Apoptosis rates in both groups were similar at all timepoints. Decreased RKIP expression did not impact the metastatic rate of LNCaP in an orthotopic PCa model.
CONCLUSIONS: These results demonstrate that loss of RKIP decreases latency of tumor development and promotes distant metastasis in the TRAMP mouse model in the context of a pro-metastatic background; but loss of RKIP alone is insufficient to promote metastasis. These findings suggest that in addition to its known metastasis suppressor activity, RKIP may promote tumor progression through enhancing tumor initiation. Prostate 75:292-302, 2015. © 2014 Wiley Periodicals, Inc.

Ammirante M, Shalapour S, Kang Y, et al.
Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts.
Proc Natl Acad Sci U S A. 2014; 111(41):14776-81 [PubMed] Free Access to Full Article Related Publications
Prostate cancer (PC) is a slowly progressing malignancy that often responds to androgen ablation or chemotherapy by becoming more aggressive, acquiring a neuroendocrine phenotype, and undergoing metastatic spread. We found that B lymphocytes recruited into regressing androgen-deprived tumors by C-X-C motif chemokine 13 (CXCL13), a chemokine whose expression correlates with clinical severity, play an important role in malignant progression and metastatic dissemination of PC. We now describe how androgen ablation induces CXCL13 expression. In both allografted and spontaneous mouse PC, CXCL13 is expressed by tumor-associated myofibroblasts that are activated on androgen ablation through a hypoxia-dependent mechanism. The same cells produce CXCL13 after chemotherapy. Myofibroblast activation and CXCL13 expression also occur in the normal prostate after androgen deprivation, and CXCL13 is expressed by myofibroblasts in human PC. Hypoxia activates hypoxia-inducible factor 1 (HIF-1) and induces autocrine TGF-β signaling that promotes myofibroblast activation and CXCL13 induction. In addition to TGF-β receptor kinase inhibitors, myofibroblast activation and CXCL13 induction are blocked by phosphodiesterase 5 (PDE5) inhibitors. Both inhibitor types and myofibroblast immunodepletion block the emergence of castration-resistant PC in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of spontaneous metastatic PC with neuroendocrine differentiation.

Pu H, Horbinski C, Hensley PJ, et al.
PARP-1 regulates epithelial-mesenchymal transition (EMT) in prostate tumorigenesis.
Carcinogenesis. 2014; 35(11):2592-601 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Poly (ADP-ribose) polymerase (PARP) is involved in key cellular processes such as DNA replication and repair, gene transcription, cell proliferation and apoptosis. The role of PARP-1 in prostate cancer development and progression is not fully understood. The present study investigated the function of PARP-1 in prostate growth and tumorigenesis in vivo. Functional inactivation of PARP-1 by gene-targeted deletion led to a significant reduction in the prostate gland size in young PARP-1-/- mice (6 weeks) compared with wild-type (WT) littermates. To determine the effect of PARP-1 functional loss on prostate cancer onset, PARP-1-/- mice were crossed with the transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Pathological assessment of prostate tumors revealed that TRAMP+/-, PARP-1-/- mice exhibited higher grade prostate tumors compared with TRAMP+/- PARP-1+/+ (16-28 weeks) that was associated with a significantly increased proliferative index and decreased apoptosis among the epithelial cells in TRAMP+/- PARP-1-/- prostate tumors. Furthermore tumors harboring PARP-1 loss, exhibited a downregulation of nuclear androgen receptor. Impairing PARP-1 led to increased levels of transforming growth factor-β (TGF-β) and Smads that correlated with induction of epithelial-mesenchymal transition (EMT), as established by loss of E-cadherin and β-catenin and upregulation of N-cadherin and ZEB-1. Our findings suggest that impaired PARP-1 function promotes prostate tumorigenesis in vivo via TGF-β-induced EMT. Defining the EMT control by PARP-1 during prostate cancer progression is of translational significance for optimizing PARP-1 therapeutic targeting and predicting response in metastatic castration-resistant prostate cancer.

Thapa D, Meng P, Bedolla RG, et al.
NQO1 suppresses NF-κB-p300 interaction to regulate inflammatory mediators associated with prostate tumorigenesis.
Cancer Res. 2014; 74(19):5644-55 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
UNLABELLED: NADPH reductase
NAD(P)H: quinone oxidoreductase 1 (NQO1) is needed to maintain a cellular pool of antioxidants, and this enzyme may contribute to tumorigenesis on the basis of studies in NQO1-deficient mice. In this work, we sought deeper insights into how NQO1 contributes to prostate carcinogenesis, a setting in which oxidative stress and inflammation are established contributors to disease development and progression. In the TRAMP mouse model of prostate cancer, NQO1 was highly expressed in tumor cells. NQO1 silencing in prostate cancer cells increased levels of nuclear IKKα and NF-κB while decreasing the levels of p53, leading to interactions between NF-κB and p300 that reinforce survival signaling. Gene expression analysis revealed upregulation of a set of immune-associated transcripts associated with inflammation and tumorigenesis in cells in which NQO1 was attenuated, with IL8 confirmed functionally in cell culture as one key NQO1-supported cytokine. Notably, NQO1-silenced prostate cancer cells were more resistant to androgen deprivation. Furthermore, NQO1 inhibition increased migration, including under conditions of androgen deprivation. These results reveal a molecular link between NQO1 expression and proinflammatory cytokine signaling in prostate cancer. Furthermore, our results suggest that altering redox homeostasis through NQO1 inhibition might promote androgen-independent cell survival via opposing effects on NF-κB and p53 function.

Abrate A, Buono R, Canu T, et al.
Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression.
Eur J Cancer. 2014; 50(14):2478-88 [PubMed] Related Publications
Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.

Chen X, Corbin JM, Tipton GJ, et al.
The TMEFF2 tumor suppressor modulates integrin expression, RhoA activation and migration of prostate cancer cells.
Biochim Biophys Acta. 2014; 1843(6):1216-24 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Cell adhesion and migration play important roles in physiological and pathological states, including embryonic development and cancer invasion and metastasis. The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed mainly in brain and prostate and its expression is deregulated in prostate cancer. We have previously shown that TMEFF2 can function as a tumor suppressor by inhibiting cell migration and invasion of prostate cells. However, the molecular mechanisms involved in this inhibition are not clear. In this study we demonstrate that TMEFF2 affects cell adhesion and migration of prostate cancer cells and that this effect correlates with changes in integrin expression and RhoA activation. Deletion of a 13 basic-rich amino acid region in the cytoplasmic domain of TMEFF2 prevented these effects. Overexpression of TMEFF2 reduced cell attachment and migration on vitronectin and caused a concomitant decrease in RhoA activation, stress fiber formation and expression of αv, β1 and β3 integrin subunits. Conversely, TMEFF2 interference in 22Rv1 prostate cancer cells resulted in an increased integrin expression. Results obtained with a double TRAMP/TMEFF2 transgenic mouse also indicated that TMEFF2 expression reduced integrin expression in the mouse prostate. In summary, the data presented here indicate an important role of TMEFF2 in regulating cell adhesion and migration that involves integrin signaling and is mediated by its cytoplasmic domain.

Morris JC, Ramlogan-Steel CA, Yu P, et al.
Vaccination with tumor cells expressing IL-15 and IL-15Rα inhibits murine breast and prostate cancer.
Gene Ther. 2014; 21(4):393-401 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
A number of antitumor vaccines have recently shown promise in upregulating immune responses against tumor antigens and improving patient survival. In this study, we examine the effectiveness of vaccination using interleukin (IL)-15-expressing tumor cells and also examine their ability to upregulate immune responses to tumor antigens. We demonstrated that the coexpression of IL-15 with its receptor, IL-15Rα, increased the cell-surface expression and secretion of IL-15. We show that a gene transfer approach using recombinant adenovirus to express IL-15 and IL-15Rα in murine TRAMP-C2 prostate or TS/A breast tumors induced antitumor immune responses. From this, we developed a vaccine platform, consisting of TRAMP-C2 prostate cancer cells or TS/A breast cancer cells coexpressing IL-15 and IL-15Rα that inhibited tumor formation when mice were challenged with tumor. Inhibition of tumor growth led to improved survival when compared with animals receiving cells expressing IL-15 alone or unmodified tumor cells. Animals vaccinated with tumor cells coexpressing IL-15 and IL-15Rα showed greater tumor infiltration with CD8(+) T and natural killer (NK) cells, as well as increased antitumor CD8(+) T-cell responses. Vaccination with IL-15/IL-15Rα-modified TS/A breast cancer cells provided a survival advantage to mice challenged with unrelated murine TUBO breast cancer cells, indicating the potential for allogeneic IL-15/IL-15Rα-expressing vaccines.

Shimada K, Anai S, Fujii T, et al.
Syndecan-1 (CD138) contributes to prostate cancer progression by stabilizing tumour-initiating cells.
J Pathol. 2013; 231(4):495-504 [PubMed] Related Publications
Increasing evidence suggests that tumour-initiating cells (TICs) contribute to the development of prostate cancer. Here, we identified syndecan-1 as a key molecule maintaining the stability of prostate cancer TICs. Holoclones harbouring the biological properties of stemness were derived from single-cell cultures of the PC3 human prostate cancer cell line. These holoclones over-expressed syndecan-1, but showed reduced expression of NADPH oxidase (NOX) and synthesis of hydrogen peroxide and oxygen radicals. Stable RNA-mediated silencing of syndecan-1 gene expression up-regulated NOX-dependent generation of reactive oxygen species and reduced the survival of holoclones in vitro. Syndecan-1 down-regulation also strongly reduced the number of CD133(+)/CD44(+) primitive cancer cells and tumour growth in vivo. Interestingly, syndecan-1 gene knockdown significantly enhanced the tumour-suppressive effects of docetaxel by inhibiting the docetaxel-induced increase in CD133(+)/CD44(+) cells in vivo. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model of prostate cancer, early intervention with a syndecan-1 inhibitor (OGT2115) or syndecan-1 RNAi reduced the incidence of adenocarcinoma and the number of c-kit(+)/CD44(+) cells in cancer foci. Finally, we found that syndecan-1 immunopositivity in prostate cancer cells was significantly associated with biochemical recurrence after radical prostatectomy. Taken together, our results show that syndecan-1 contributes to prostatic carcinogenesis by maintaining TICs and may be a target molecule for therapy.

Lee SO, Jin UH, Kang JH, et al.
The orphan nuclear receptor NR4A1 (Nur77) regulates oxidative and endoplasmic reticulum stress in pancreatic cancer cells.
Mol Cancer Res. 2014; 12(4):527-38 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
UNLABELLED: NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNA interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum stress, including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and endoplasmic reticulum stress by these agents was attenuated after cotreatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and endoplasmic reticulum stress; thus, demonstrating that NR4A1 regulates levels of endoplasmic reticulum stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.
IMPLICATIONS: The NR4A1 receptor is pro-oncogenic, regulates the ROS/endoplasmic reticulum stress pathways, and inactivation of the receptor represents a novel pathway for inducing cell death in pancreatic cancer.

Cho Y, Turner ND, Davidson LA, et al.
Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation.
Exp Biol Med (Maywood). 2014; 239(3):302-10 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
DNA methylation and histone acetylation contribute to the transcriptional regulation of genes involved in apoptosis. We have demonstrated that docosahexaenoic acid (DHA, 22:6 n-3) and butyrate enhance colonocyte apoptosis. To determine if DHA and/or butyrate elevate apoptosis through epigenetic mechanisms thereby restoring the transcription of apoptosis-related genes, we examined global methylation; gene-specific promoter methylation of 24 apoptosis-related genes; transcription levels of Cideb, Dapk1, and Tnfrsf25; and global histone acetylation in the HCT-116 colon cancer cell line. Cells were treated with combinations of (50 µM) DHA or linoleic acid (18:2 n-6), (5 mM) butyrate or an inhibitor of DNA methyltransferases, and 5-aza-2'-deoxycytidine (5-Aza-dC, 2 µM). Among highly methylated genes, the combination of DHA and butyrate significantly reduced methylation of the proapoptotic Bcl2l11, Cideb, Dapk1, Ltbr, and Tnfrsf25 genes compared to untreated control cells. DHA treatment reduced the methylation of Cideb, Dapk1, and Tnfrsf25. These data suggest that the induction of apoptosis by DHA and butyrate is mediated, in part, through changes in the methylation state of apoptosis-related genes.

Hahm ER, Karlsson AI, Bonner MY, et al.
Honokiol inhibits androgen receptor activity in prostate cancer cells.
Prostate. 2014; 74(4):408-20 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling has not been studied.
METHODS: LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear level of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining.
RESULTS: HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment.
CONCLUSIONS: The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status.

Seuter S, Pehkonen P, Heikkinen S, Carlberg C
Dynamics of 1α,25-dihydroxyvitamin D3-dependent chromatin accessibility of early vitamin D receptor target genes.
Biochim Biophys Acta. 2013; 1829(12):1266-75 [PubMed] Related Publications
The signaling cascade of the transcription factor vitamin D receptor (VDR) is triggered by its specific ligand 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3). In this study we demonstrate that in THP-1 human monocytic leukemia cells 87.4% of the 1034 most prominent genome-wide VDR binding sites co-localize with loci of open chromatin. At 165 of them 1α,25(OH)2D3 strongly increases chromatin accessibility and has at further 217 sites weaker effects. Interestingly, VDR binding sites in 1α,25(OH)2D3-responsive chromatin regions are far more often composed of direct repeats with 3 intervening nucleotides (DR3s) than those in ligand insensitive regions. DR3-containing VDR sites are enriched in the neighborhood of genes that are involved in controling cellular growth, while non-DR3 VDR binding is often found close to genes related to immunity. At the example of six early VDR target genes we show that the slope of their 1α,25(OH)2D3-induced transcription correlates with the basal chromatin accessibility of their major VDR binding regions. However, the chromatin loci controlling these genes are indistinguishable in their VDR association kinetics. Taken together, ligand responsive chromatin loci represent dynamically regulated contact points of VDR with the genome, from where it controls early 1α,25(OH)2D3 target genes.

Valdez CD, Kunju L, Daignault S, et al.
The E2F1/DNMT1 axis is associated with the development of AR negative castration resistant prostate cancer.
Prostate. 2013; 73(16):1776-85 [PubMed] Related Publications
BACKGROUND: Research on castration resistant prostate cancer (CRPC) has focused primarily on functional alterations of the androgen receptor (AR). However, little is known about the loss of AR gene expression itself and the possible contribution of AR negative cells to CRPC.
METHODS: Human and murine prostate cancer tissue microarrays (TMAs) were evaluated with antibodies specific for E2F1, DNA methyltransferase 1 or AR. The human prostate cancer TMA consisted of clinical samples ranging from normal tissue to samples of metastatic disease. The murine TMA was comprised of benign, localized or metastatic prostate cancer acquired from TRAMP mice treated with castration and/or 5'-Aza-2'-deoxycytidine (5Aza).
RESULTS: Immunohistochemical analysis revealed increased nuclear DNMT1 staining in localized PCa (P < 0.0001) and metastatic PCa (P < 0.0001) compared to normal tissue. Examination of specific diagnoses revealed that Gleason seven tumors exhibited greater nuclear DNMT1 staining than Gleason six tumors (P < 0.05) and that metastatic tissue exhibited greater levels of nuclear DNMT1 than Gleason seven tumors (P < 0.01). Evaluation of the murine tissue cores revealed that 8.2% and 8.1% of benign tissue cores stained positive for E2F1 and DNMT1 respectively, while 97.0% were AR positive. Conversely, 81% and 100% of tumors were positive for E2F1 and DNMT1 respectively. This was in stark contrast to only 18% of tumors positive for AR. Treatment of mice with 5Aza reduced DNMT1 staining by 30%, while AR increased by 27%.
CONCLUSIONS: These findings demonstrate that the E2F1/DNMT1 inhibitory axis of AR transcription is activated during the emergence of CRPC.

Jia W, Sander AJ, Jia G, et al.
Vascular endothelial growth inhibitor (VEGI) is an independent indicator for invasion in human pituitary adenomas.
Anticancer Res. 2013; 33(9):3815-22 [PubMed] Related Publications
Pituitary ademonas are benign tumours from the pituitary gland but may have an invasive and destructive growth pattern. There is little understanding of the growth and progression control of pituitary tumours. In the present study, we investigated the expression of vascular endothelial growth inhibitor (VEGI), a vascular endothelial growth and apoptosis regulator and VEGI receptor Death Receptor-3 (DR3), in clinical pituitary tumours. Pituitary tumours from 95 patients were included in the study. Fresh pituitary tumours were obtained immediately after surgery and processed for histological and molecular-based analyses. Histopathological and clinical information including tumour size, tumour invasion and endocrine status were analyzed against the gene transcript expression of VEGI, DR3 and VEGF. VEGI and VEGF family and VEGF receptors were quantitatively determined for their gene transcript expression. The expression levels of VEGI were significantly lower in pituitary tumours which invaded the sella floor, and with suprasellar extension than in non-invasive tumours (p=0.0073). VEGI levels were also negatively correlated with cavernous sinus invasion stage (p<0.0001), in that a high level of VEGI was associated with low tumour grade. Multivariate analysis indicated that VEGI is an independent factor predictive of invasion (p=0.05). It was further demonstrated that the relationship between VEGI and pituitary tumour invasion were independent of the expression of VEGF and its receptors. Low levels of VEGI transcripts were associated with the intratumoural haemorrhage (p=0.05). Out of all the pituitary tumours, 59 were non-functional. Out of the functional tumours, it was found that follicle stimulating hormone (FSH)-expressing and gonadotrophic tumours tended to have markedly low levels of VEGI transcripts, compared with non-functional tumours (p=0.0026 and p=0.003, respectively). The opposite was seen with thyroid-stimulating hormone (TSH)-secreting tumours. Levels of DR3 in tumours with sella destruction were also lower than in those without destruction. VEGI, possibly via DR3, suppresses the aggressive nature of pituitary tumours and its expression level is closely linked to the invasion and destruction of the suprasellar and sella regions. It also has implications for the endocrine nature of these tumours. VEGI thus has an important predictive and prognostic value in patients with pituitary tumours.

Han DJ, Kim JB, Park SY, et al.
Growth inhibition of hepatocellular carcinoma Huh7 cells by Lactobacillus casei extract.
Yonsei Med J. 2013; 54(5):1186-93 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
PURPOSE: Lactobacillus casei (L. casei) is known to exert anti-proliferation effects on many types of cancer cells. However, the effect of L. casei on liver cancer has not been reported. Accordingly, the aim of this study was to determine the anti-cancer effect of L. casei extract on Huh7 cells.
MATERIALS AND METHODS: L. casei ATCC393 extract was prepared and purified. After the treatment of L. casei extract on Huh7 cells, cell viability, cell cycle arrest and cell death were analyzed by flow cytometry. The expression levels of tumor necrosis factor-α receptor 1 (TNFR1) and death receptor 3 (DR3) mRNA related with extrinsic apoptosis were assessed by reverse transcription polymerase chain reaction. Additionally, P21 and P27 cell cycle proteins as well as Caspase-3, -8, -9, phospho-Bad and Bcl-2 apoptosis proteins were analyzed by western blot analysis. To determine the effect of L. casei extract on cancer stem-like cells, we analyzed changes in side population fraction through flow cytometry.
RESULTS: The cell viability of Huh7 cells treated with L. casei extract was decreased by 77%, potentially owing to increases in the rates of Huh7 cells arrested in the G2/M phase (3% increase) and that underwent apoptosis (6% increase). The expression levels of TNFR1 and DR3 mRNA, as well as P21 and P27 cell cycle proteins, were increased. Meanwhile, the expressions of caspase-8, -9, phospho-Bad and Bcl-2 proteins decreased. However, in the case of side population cells, no remarkable changes were observed.
CONCLUSION: L. casei extract exerts a potent anti-tumor effect on the viability of liver cancer cells, although not on cancer stem-like cells.

Mazzoleni S, Jachetti E, Morosini S, et al.
Gene signatures distinguish stage-specific prostate cancer stem cells isolated from transgenic adenocarcinoma of the mouse prostate lesions and predict the malignancy of human tumors.
Stem Cells Transl Med. 2013; 2(9):678-89 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The relevant social and economic impact of prostate adenocarcinoma, one of the leading causes of death in men, urges critical improvements in knowledge of the pathogenesis and cure of this disease. These can also be achieved by implementing in vitro and in vivo preclinical models by taking advantage of prostate cancer stem cells (PCSCs). The best-characterized mouse model of prostate cancer is the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice develop a progressive lesion called prostatic intraepithelial neoplasia that evolves into adenocarcinoma (AD) between 24 and 30 weeks of age. ADs often metastasize to lymph nodes, lung, bones, and kidneys. Eventually, approximately 5% of the mice develop an androgen-independent neuroendocrine adenocarcinoma. Here we report the establishment of long-term self-renewing PCSC lines from the different stages of TRAMP progression by application of the neurosphere assay. Stage-specific prostate cell lines were endowed with the critical features expected from malignant bona fide cancer stem cells, namely, self-renewal, multipotency, and tumorigenicity. Notably, transcriptome analysis of stage-specific PCSCs resulted in the generation of well-defined, meaningful gene signatures, which identify distinct stages of human tumor progression. As such, TRAMP-derived PCSCs represent a novel and valuable preclinical model for elucidating the pathogenetic mechanisms leading to prostate adenocarcinoma and for the identification of molecular mediators to be pursued as therapeutic targets.

Freytag SO, Barton KN, Zhang Y
Efficacy of oncolytic adenovirus expressing suicide genes and interleukin-12 in preclinical model of prostate cancer.
Gene Ther. 2013; 20(12):1131-9 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Oncolytic adenovirus-mediated suicide gene therapy has been shown to improve local tumor control in preclinical tumor models and in the clinic. Although local tumor control is important, for most human cancers, new therapies must also target metastatic disease if they are to have an impact on survival. Here, we test the hypothesis that adding cytokine gene therapy to our multimodal platform improves both local and metastatic tumor control in a preclinical model of prostate cancer. An oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse interleukin-12 (IL-12) was generated. Relative to an adenovirus lacking IL-12 (Ad5-yCD/mutTKSR39rep), Ad5-yCD/mutTKSR39rep-mIL12 improved local and metastatic tumor control in the TRAMP-C2 prostate adenocarcinoma model, resulting in a significant increase in survival. Ad5-yCD/mutTKSR39rep-mIL12 resulted in high levels of IL-12 and interferon gamma in serum and tumor, increased natural killer (NK) and cytotoxic T-lymphocyte lytic activities, and the development of tumor-specific antitumor immunity. Immune cell depletion studies indicated that both the innate and adaptive arms of immunity were required for maximal Ad5-yCD/mutTKSR39rep-mIL12 activity. The results demonstrate that the addition of IL-12 significantly improves the efficacy of oncolytic adenovirus-mediated suicide gene therapy and provide the scientific basis for future trials targeting locally aggressive cancers.

Han JH, Park SY, Kim JB, et al.
TLR7 expression is decreased during tumour progression in transgenic adenocarcinoma of mouse prostate mice and its activation inhibits growth of prostate cancer cells.
Am J Reprod Immunol. 2013; 70(4):317-26 [PubMed] Related Publications
PROBLEM: Although various Toll-like receptors (TLRs) have been associated with immune response and tumorigenesis in the prostate cells, little is known about the role of TLR7. Accordingly, we examined the expression of TLR7 during tumour progression of TRMAP (transgenic mouse model for prostate cancer) mice and its role on cell growth.
METHOD OF STUDY: Toll-like receptor7 expression was examined by RT-polymerase chain reaction (PCR), Western blot, and immunohistochemistry. Cell growth was examined by MTT assay. Colony formation was investigated by crystal violet staining.
RESULTS: Strong expression of TLR7 was detected in the normal prostate epithelia of Wild-type (WT) mice, but not in TLR7-deficient mice. In contrast, TLR7 expression was weak in transgenic adenocarcinoma of mouse prostate (TRAMP)-C2 cells, as compared with murine bone marrow-derived macrophages (BMDMs). Moreover, TLR7 mRNA was markedly expressed in RWPE-1 cells (non-cancerous prostate epithelial cells), but not in PC3 and DU145 (prostate cancer cells). Immunohistochemically, TLR7 expression gradually decreased in TRAMP mice depending on the pathologic grade of the prostate cells. TLR7 agonists increased both the gene and protein expression of TLR7 and promoted production of proinflammatory cytokines/chemokines and IFN-β gene expression in prostate cancer cell lines. Moreover, loxoribine inhibited the growth and colony formation of TRAMP-C2 cells dependent of TLR7.
CONCLUSION: These findings suggest that TLR7 may participate in tumour suppression in the prostate cells.

Cai Y, Balli D, Ustiyan V, et al.
Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis.
J Biol Chem. 2013; 288(31):22527-41 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11β-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for prostate cancer chemotherapy.

Wilson AJ, Liu AY, Roland J, et al.
TR3 modulates platinum resistance in ovarian cancer.
Cancer Res. 2013; 73(15):4758-69 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
In metastatic ovarian cancer, resistance to platinum chemotherapy is common. Although the orphan nuclear receptor TR3 (nur77/NR4A1) is implicated in mediating chemotherapy-induced apoptosis in cancer cells, its role in ovarian cancer has not been determined. In an ovarian cancer tissue microarray, TR3 protein expression was elevated in stage I tumors, but downregulated in a significant subset of metastatic tumors. Moreover, TR3 expression was significantly lower in platinum-resistant tumors in patients with metastatic disease, and low TR3 staining was associated with poorer overall and progression-free survival. We have identified a direct role for TR3 in cisplatin-induced apoptosis in ovarian cancer cells. Nucleus-to-cytoplasm translocation of TR3 was observed in cisplatin-sensitive (OVCAR8, OVCAR3, and A2780PAR) but not cisplatin-resistant (NCI/ADR-RES and A2780CP20) ovarian cancer cells. Immunofluorescent analyses showed clear overlap between TR3 and mitochondrial Hsp60 in cisplatin-treated cells, which was associated with cytochrome c release. Ovarian cancer cells with stable shRNA- or transient siRNA-mediated TR3 downregulation displayed substantial reduction in cisplatin effects on apoptotic markers and cell growth in vitro and in vivo. Mechanistic studies showed that the cisplatin-induced cytoplasmic TR3 translocation required for apoptosis induction was regulated by JNK activation and inhibition of Akt. Finally, cisplatin resistance was partially overcome by ectopic TR3 overexpression and by treatment with the JNK activator anisomycin and Akt pathway inhibitor, wortmannin. Our results suggest that disruption of TR3 activity, via downregulation or nuclear sequestration, likely contributes to platinum resistance in ovarian cancer. Moreover, we have described a treatment strategy aimed at overcoming platinum resistance by targeting TR3.

Galli R, Paone A, Fabbri M, et al.
Toll-like receptor 3 (TLR3) activation induces microRNA-dependent reexpression of functional RARβ and tumor regression.
Proc Natl Acad Sci U S A. 2013; 110(24):9812-7 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Toll-like receptor 3 (TLR3) is a key effector of the innate immune system against viruses. Activation of TLR3 exerts an antitumoral effect through a mechanism of action still poorly understood. Here we show that TLR3 activation by polyinosinic:polycytidylic acid induces up-regulation of microRNA-29b, -29c, -148b, and -152 in tumor-derived cell lines and primary tumors. In turn, these microRNAs induce reexpression of epigenetically silenced genes by targeting DNA methyltransferases. In DU145 and TRAMP-C1 prostate and MDA-MB-231 breast cancer cells, we demonstrated that polyinosinic:polycytidylic acid-mediated activation of TLR3 induces microRNAs targeting DNA methyltransferases, leading to demethylation and reexpression of the oncosuppressor retinoic acid receptor beta (RARβ). As a result, cancer cells become sensitive to retinoic acid and undergo apoptosis both in vitro and in vivo. This study provides evidence of an antitumoral mechanism of action upon TLR3 activation and the biological rationale for a combined TLR3 agonist/retinoic acid treatment of prostate and breast cancer.

Lee GT, Jung YS, Ha YS, et al.
Bone morphogenetic protein-6 induces castration resistance in prostate cancer cells through tumor infiltrating macrophages.
Cancer Sci. 2013; 104(8):1027-32 [PubMed] Related Publications
Bone morphogenetic protein (BMP) is a pleiotropic growth factor that has been implicated in inflammation and prostate cancer (CaP) progression. We investigated the potential role of BMP-6 in the context of macrophages and castration-resistant prostate cancer. When the androgen-responsive murine (Tramp-C1 and PTENCaP8) and human (LNCaP) CaP cell lines were cocultured with macrophages in the presence of dihydrotestosterone, BMP-6 increased androgen-responsive promoter activity and cell count significantly. Subsequent studies revealed that BMP-6 increased the expression level of androgen receptor (AR) mRNA and protein in CaP cell lines only in the presence of macrophages. Simultaneously, the AR antagonists bicalutamide and MDV3100 partially or completely blocked BMP-6-induced macrophage-mediated androgen hypersensitivity in CaP cells. Abolishing interleukin-6 signaling with neutralizing antibody in CaP/macrophage cocultures inhibited the BMP-6-mediated AR upregulation in CaP cells. Using Tramp-C1 and PTENCaP8 cells with a tetracycline-inducible expression of BMP-6, the induction of BMP-6 in vivo resulted in a significant resistance to castration. However, this resistance was blocked after the removal of macrophages with clodronate liposomes. Taken together, these results show that BMP-6 induces castration resistance by increasing the expression of AR through macrophage-derived interleukin-6.

Keith ME, LaPorta E, Welsh J
Stable expression of human VDR in murine VDR-null cells recapitulates vitamin D mediated anti-cancer signaling.
Mol Carcinog. 2014; 53(4):286-99 [PubMed] Related Publications
Mammary tumor cells derived from vitamin D receptor (VDR) knock-out (KO) mice were engineered to stably express wild-type (WT) or mutated VDR for characterization of the mechanisms by which 1,25-dihydroxyvitamin D (1,25D), the VDR ligand, mediates growth regulation. Although KO cells were completely resistant to 1,25D, introduction of WT human VDR restored gene expression and growth inhibition in response to 1,25D and a variety of structural analogs. Pdgfb, Vegfa, and Nfkbi were identified as genomic targets of both human and murine VDR signaling in this cell model. KO cells expressing hVDRs containing point mutations (W286R, R274L) that reduce or abolish ligand binding did not exhibit changes in gene expression or growth in response to physiological doses of 1,25D but did respond to higher doses and more potent analogs. KO cells expressing hVDR with the G46D point mutation, which abrogates VDR binding to DR3 response elements, exhibited partial growth inhibition in response to 1,25D and synthetic vitamin D analogs, providing proof of principle that VDR signaling through alternative genomic or non-genomic mechanisms contributes to vitamin D mediated growth effects in transformed cells. We conclude that the 1,25D-VDR signaling axis that triggers anti-cancer effects is highly conserved between the murine and human systems despite differences in VDR protein, cofactors, and target genes and that these actions are not solely mediated via canonical VDRE signaling.

Patel SJ, Molinolo AA, Gutkind S, Crawford NP
Germline genetic variation modulates tumor progression and metastasis in a mouse model of neuroendocrine prostate carcinoma.
PLoS One. 2013; 8(4):e61848 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
Neuroendocrine (NE) differentiation has gained increased attention as a prostate cancer (PC) prognostic marker. The aim of this study is to determine whether host germline genetic variation influences tumor progression and metastasis in C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive NEPC. TRAMP mice were crossed to the eight progenitor strains of the Collaborative Cross recombinant inbred panel to address this. Tumor growth and metastasis burden were quantified in heterozygous transgene positive F1 male mice at 30 weeks of age. Compared to wild-type C57BL/6J-Tg(TRAMP)824Ng/J males, TRAMP x CAST/EiJ, TRAMP x NOD/ShiLtJ and TRAMP x NZO/HlLtJ F1 males displayed significant increases in tumor growth. Conversely, TRAMP x WSB/EiJ and TRAMP x PWK/PhJ F1 males displayed significant reductions in tumor growth. Interestingly, despite reduced tumor burden, TRAMP x WSB/EiJ males had an increased nodal metastasis burden. Patterns of distant pulmonary metastasis tended to follow the same patterns as that of local dissemination in each of the strains. All tumors and metastases displayed positive staining for NE markers, synaptophysin, and FOXA2. These experiments conclusively demonstrate that the introduction of germline variation by breeding modulates tumor growth, local metastasis burden, and distant metastasis frequency in this model of NEPC. These strains will be useful as model systems to facilitate the identification of germline modifier genes that promote the development of aggressive forms of PC.

Ge Z, Sanders AJ, Ye L, et al.
Expression of death receptor-3 in human breast cancer and its functional effects on breast cancer cells in vitro.
Oncol Rep. 2013; 29(4):1356-64 [PubMed] Related Publications
Death receptor-3 (DR3) plays controversial roles in cancer. Currently, DR3 is known to be a functional receptor of vascular endothelial growth inhibitor (VEGI). The role of DR3 in breast cancer remains unclear. The present study investigated DR3 expression in a clinical cohort of breast cancer patients and its role in breast cancer cells in vitro. The expression of DR3 was examined in a breast cancer cohort using quantitative PCR (Q-PCR) and immunohistochemistry (IHC) in comparison to the patients' data. In vitro function of DR3 was examined through the targeting of this molecule in MCF7 and MDA-MB-231 breast cancer cells using ribozyme transgene technology. Decreased DR3 expression was noted in breast cancer tissues compared to normal tissues and decreased expression of DR3 was generally associated with a poorer prognosis as well as a significantly shorter long-term survival (p=0.038). Targeting of DR3 in vitro in breast cancer cell lines resulted in impaired migratory rates compared to respective control cells. Collectively, these data suggest a complex role for DR3 in breast cancer development and progression.

Yu CF, Hong JH, Chiang CS
The roles of macrophages and nitric oxide in interleukin-3-enhanced HSV-Sr39tk-mediated prodrug therapy.
PLoS One. 2013; 8(2):e56508 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
The herpes simplex virus thymidine kinase/ganciclovir (HSV-sr39tk/GCV) system is a well-established prodrug system used in cancer gene therapy. However, this system is currently not effective enough to eradicate malignant tumors completely. This study aimed to evaluate whether co-expression of interleukin-3 (IL-3) could enhance the anti-tumor activity of HSV-sr39tk/GCV prodrug gene therapy using a murine TRAMP-C1 prostate tumor model. In vitro results demonstrated that HSV-sr39tk-transfected cells exhibited enhanced sensitivity to the GCV prodrug, which was not affected by co-expression of the mIL-3 gene. However, in vivo studies showed that co-expression of the mIL-3 gene significantly increased the HSV-sr39tk/GCV-induced tumor growth delay and even cured the tumor. The TRAMP-C1-specific immune response of spleen lymphocytes from mice bearing HSV-sr39tk- and IL-3-expressing TRAMP-C1 tumors was measured by ELISA. Results showed that IL-3-activated IL-4-dominant lymphocytes became IFN-γ- dominant lymphocytes after combined HSV-sr39tk/GCV therapy. The efficacy of combined therapies on tumor regression was reduced when macrophages populations were depleted by carrageenan or NO production was inhibited by administration of the iNOS inhibitor, L-NAME. These results suggest that utilizing a bicistronic vector to express HSV-sr39tk and the IL-3 gene induced an enhanced macrophage- or NO-dependent anti-tumor effect.

Witt D, Burfeind P, von Hardenberg S, et al.
Valproic acid inhibits the proliferation of cancer cells by re-expressing cyclin D2.
Carcinogenesis. 2013; 34(5):1115-24 [PubMed] Related Publications
In this study, primary murine prostate cancer (PCa) cells were derived using the well-established TRAMP model. These PCa cells were treated with the histone deacetylase inhibitor, valproic acid (VPA), and we demonstrated that VPA treatment has an antimigrative, antiinvasive and antiproliferative effect on PCa cells. Using microarray analyses, we discovered several candidate genes that could contribute to the cellular effects we observed. In this study, we could demonstrate that VPA treatment of PCa cells causes the re-expression of cyclin D2, a known regulator that is frequently lost in PCa as we could show using immunohistochemical analyses on PCa specimens. We demonstrate that VPA specifically induces the re-expression of cyclin D2, one of the highly conserved D-type cyclin family members, in several cancer cell lines with weak or no cyclin D2 expression. Interestingly, VPA treatment had no effect in fibroblasts, which typically have high basal levels of cyclin D2 expression. The re-expression of cyclin D2 observed in PCa cells is activated by increased histone acetylation in the promoter region of the Ccnd2 gene and represents one underlying molecular mechanism of VPA treatment that inhibits the proliferation of cancer cells. Altogether, our results confirm that VPA is an anticancer therapeutic drug for the treatment of tumors with epigenetically repressed cyclin D2 expression.

Tao YF, Lu J, Du XJ, et al.
Survivin selective inhibitor YM155 induce apoptosis in SK-NEP-1 Wilms tumor cells.
BMC Cancer. 2012; 12:619 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Survivin, a member of the family of inhibitor of apoptosis proteins, functions as a key regulator of mitosis and programmed cell death. YM155, a novel molecular targeted agent, suppresses survivin, which is overexpressed in many tumor types. The aim of this study was to determine the antitumor activity of YM155 in SK-NEP-1 cells.
METHODS: SK-NEP-1 cell growth in vitro and in vivo was assessed by MTT and nude mice experiments. Annexin V/propidium iodide staining followed by flow cytometric analysis was used to detect apoptosis in cell culture. Then gene expression profile of tumor cells treated with YM155 was analyzed with real-time PCR arrays. We then analyzed the expression data with MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profile derived from cluster analyses were imported into the Ingenuity Pathway Analysis tool.
RESULTS: YM155 treatment resulted in inhibition of cell proliferation of SK-NEP-1cells in a dose-dependent manner. Annexin V assay, cell cycle, and activation of caspase-3 demonstrates that YM155 induced apoptosis in SK-NEP-1 cells. YM155 significantly inhibited growth of SK-NEP-1 xenografts (YM155 5 mg/kg: 1.45 ± 0.77 cm3; YM155 10 mg/kg: 0.95 ± 0.55 cm3) compared to DMSO group (DMSO: 3.70 ± 2.4 cm3) or PBS group cells (PBS: 3.78 ± 2.20 cm3, ANOVA P < 0.01). YM155 treatment decreased weight of tumors (YM155 5 mg/kg: 1.05 ± 0.24 g; YM155 10 mg/kg: 0.72 ± 0.17 g) compared to DMSO group (DMSO: 2.06 ± 0.38 g) or PBS group cells (PBS: 2.36 ± 0.43 g, ANOVA P < 0.01). Real-time PCR array analysis showed between Test group and control group there are 32 genes significantly up-regulated and 54 genes were significantly down-regulated after YM155 treatment. Ingenuity pathway analysis (IPA) showed cell death was the highest rated network with 65 focus molecules and the significance score of 44. The IPA analysis also groups the differentially expressed genes into biological mechanisms that are related to cell death, cellular function maintenance, cell morphology, carbohydrate metabolism and cellular growth and proliferation. Death receptor signaling (3.87E-19), TNFR1 signaling, induction of apoptosis by HIV1, apoptosis signaling and molecular mechanisms of cancer came out to be the top four most significant pathways. IPA analysis also showed top molecules up-regulated were BBC3, BIRC3, BIRC8, BNIP1, CASP7, CASP9, CD5, CDKN1A, CEBPG and COL4A3, top molecules down-regulated were ZNF443, UTP11L, TP73, TNFSF10, TNFRSF1B, TNFRSF25, TIAF1, STK17A, SST and SPP1, upstream regulator were NR3C1, TP53, dexamethasone , TNF and Akt.
CONCLUSIONS: The present study demonstrates that YM155 treatment resulted in apoptosis and inhibition of cell proliferation of SK-NEP-1cells. YM155 had significant role and little side effect in the treatment of SK-NEP-1 xenograft tumors. Real-time PCR array analysis firstly showed expression profile of genes dyes-regulated after YM155 treatment. IPA analysis also represents new molecule mechanism of YM155 treatment, such as NR3C1 and dexamethasone may be new target of YM155. And our results may provide new clues of molecular mechanism of apoptosis induced by YM155.

Cheung KF, Zhao J, Hao Y, et al.
CITED2 is a novel direct effector of peroxisome proliferator-activated receptor γ in suppressing hepatocellular carcinoma cell growth.
Cancer. 2013; 119(6):1217-26 [PubMed] Related Publications
BACKGROUND: Previous reports from these authors found that activation of peroxisome proliferator-activated receptor gamma (PPARγ) suppressed hepatocellular carcinoma (HCC). This study sought to identify the molecular target of PPARγ and characterize its antitumor effect in HCC.
METHODS: Optimal PPARγ binding activity was obtained using the PPARγ agonist rosiglitazone (100 μM) as determined by enzyme-linked immunosorbent assay. Under PPARγ activation, 114 PPARγ downstream targets associated with cancer development were identified by oligonucleotide microarray and Gene Ontology analysis. Among them, Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain, 2 (CITED2) was the most prominent PPARγ-bound target, as determined by chromatin immunoprecipitation-polymerase chain reaction.
RESULTS: CITED2 messenger RNA and protein was significantly down-regulated in primary HCCs compared with their adjacent nontumor tissues. PPARγ induced expression of CITED2 in HCC cell lines after adenovirus-PPARγ transduction. The biological function of CITED2 was evaluated by loss- and gain-of-function assays. CITED2 knockdown in the hepatocyte cell line LO2 and HCC cell line Hep3B significantly increased cell viability and clonogenicity, and promoted G1 -S phase transition in both cell lines. In contrast, ectopic expression of CITED2 in HepG2 and BEL7404 HCC cell lines significantly suppressed cell growth. The tumor suppressive effect of CITED2 was associated with up-regulation of cyclin-dependent kinase inhibitors p15(INK4B) , p21(Wat1/Cip1) , p27(Kip1) , antiproliferative regulator interferon alpha 1, proapoptotic mediators including tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), TNFRSF25, caspase-8, granzyme A, and the tumor suppressor gene maspin. CITED2 was also associated with the down-regulation of cell cycle regulator cyclin D1, oncogene telomerase reverse transcriptase, and proinvasion/metastasis gene matrix metallopeptidase 2.
CONCLUSIONS: CITED2 is a direct effector of PPARγ for tumor suppression. Cancer 2013. © 2012 American Cancer Society.

Copeland BT, Bowman MJ, Ashman LK
Genetic ablation of the tetraspanin CD151 reduces spontaneous metastatic spread of prostate cancer in the TRAMP model.
Mol Cancer Res. 2013; 11(1):95-105 [PubMed] Related Publications
Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. TNFRSF25, Cancer Genetics Web: http://www.cancer-genetics.org/TNFRSF25.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 25 June, 2015     Cancer Genetics Web, Established 1999