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Tumor Suppression (tumor + suppression)
Selected AbstractsPromoter Methylation of TSLC1 and Tumor Suppression by Its Gene Product in Human Prostate CancerCANCER SCIENCE, Issue 6 2002Hiroshi Fukuhara We recently identified TSLC1, a tumor suppressor gene in human lung cancer. Gene silencing by promoter methylation has been observed frequently in adenocarcinoma of the lung, liver, and pancreas. Here, we demonstrate that TSLC1 expression is also absent or markedly reduced in 3 of 4 prostate cancer cell lines. Promoter sequences of TSLC1 were heavily methylated in PPC-1 cells that lacked TSLC1 expression, supporting the idea that promoter methylation is strongly correlated with complete loss of gene expression. Promoter sequences of TSLC1 were also methylated significantly in 7 of 22 (32%) primary prostate cancers. Hypermethylation of the promoter occurred not only in advanced tumors, but also in relatively early-stage tumors. Restoration of TSLC1 expression substantially suppressed tumor formation of PPC-1 cells in nude mice. These findings indicate that alteration of TSLC1 is involved in prostate cancer. [source] Mapping of nasopharyngeal carcinoma tumor-suppressive activity to a 1.8-megabase region of chromosome band 11q13GENES, CHROMOSOMES AND CANCER, Issue 1 2002Yue Cheng Nasopharyngeal carcinoma (NPC) is a malignancy that is particularly prevalent among populations from Southern China and Southeast Asian countries. Evidence for a genetic contribution to the disease has been documented, although the genetic basis for NPC development is not yet fully understood. Previous functional evidence of tumor-suppressive activity on chromosome band 11q13 in NPC was obtained using a microcell-mediated chromosome-transfer approach with HONE1 NPC cells. In the present study, this region was subjected to a detailed investigation of microcell hybrids and their tumor segregants using microsatellite analysis to narrow down the region of tumor-suppressive activity. Fluorescence in situ hybridization was also performed with BAC and cosmid probes to confirm the microsatellite data. The critical region responsible for tumor suppression was narrowed down to a 1.8-Mb interval, which does not tolerate an additional normal allele by chromosome transfer. One or two alleles from either endogenous or exogenous chromosomes at 11q13 were consistently eliminated during tumor growth. Results of this study suggest that a candidate tumor-suppressor gene, not the MEN1 gene, maps between D11S4907 and GSTP1 in NPC. © 2002 Wiley-Liss, Inc. [source] Liver stem cells and hepatocellular carcinoma,HEPATOLOGY, Issue 1 2009Lopa Mishra Although the existence of cancer stem cells (CSCs) was first proposed over 40 years ago, only in the past decade have these cells been identified in hematological malignancies, and more recently in solid tumors that include liver, breast, prostate, brain, and colon. Constant proliferation of stem cells is a vital component in liver tissues. In these renewing tissues, mutations will most likely result in expansion of the altered stem cells, perpetuating and increasing the chances of additional mutations and tumor progression. However, many details about hepatocellular cancer stem cells that are important for early detection remain poorly understood, including the precise cell(s) of origin, molecular genetics, and the mechanisms responsible for the highly aggressive clinical picture of hepatocellular carcinoma (HCC). Exploration of the difference between CSCs from normal stem cells is crucial not only for the understanding of tumor biology but also for the development of specific therapies that effectively target these cells in patients. These ideas have drawn attention to control of stem cell proliferation by the transforming growth factor beta (TGF-,), Notch, Wnt, and Hedgehog pathways. Recent evidence also suggests a key role for the TGF-, signaling pathway in both hepatocellular cancer suppression and endoderm formation, suggesting a dual role for this pathway in tumor suppression as well as progression of differentiation from a stem or progenitor stage. This review provides a rationale for detecting and analyzing tumor stem cells as one of the most effective ways to treat cancers such as HCC. (HEPATOLOGY 2009;49:318,329.) [source] Annexin-A7 protects normal prostate cells and induces distinct patterns of RB-associated cytotoxicity in androgen-sensitive and -resistant prostate cancer cells,INTERNATIONAL JOURNAL OF CANCER, Issue 11 2009Yelizaveta Torosyan Abstract The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(+/,)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicityin androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased low-molecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. [source] The MUC1 oncoprotein as a functional target: Immunotoxin binding to ,/, junction mediates cell killingINTERNATIONAL JOURNAL OF CANCER, Issue 1 2009Daniel B. Rubinstein Abstract MUC1, a heavily glycosylated mucin, has generated considerable interest as a target for tumor killing because of its overexpression in malignancies. Full-length MUC1 (MUC1/TM) is proteolytically cleaved after synthesis generating , and , subunits, which specifically bind in a noncovalent interaction. Although the , chain remains on the cell surface, the , chain binds in an on-and-off interaction. Most anti-MUC1 antibodies (Abs) described to date recognize epitopes within the highly immunogenic ,-chain tandem repeat. Because the ,-chain is shed, such Abs are sequestered and fail to reach MUC1-expressing cells. Immunizing with cDNA encoding MUC1/TM and the spliced MUC1/X isoform from which the tandem repeat has been deleted yielded antibodies to the MUC1 ,/, junction. Pseudomonas toxin PE38 linked to polyclonal anti-MUC1 ,/, junction Abs both bound and killed MUC1-positive malignant cells. Monoclonal DMC209 binds the MUC1 ,/, junction in both MUC1/X and MUC1/TM. When injected into SCID mice xenotransplanted with human breast cancer MDA-MB-231, monoclonal DMC209 showed significant in vivo tumor-suppressive activity. The MUC1/X ,/, junction presents a biologically-significant target in MUC1-expressing malignancies because (i) antibodies directed against cell-bound ,/, junction epitopes reach the intended cellular target, (ii) antibodies to junction epitope are internalized into cells, (iii) anti ,/, junction antibodies can effectively kill high MUC1-expressing cancer cells as antibody-toxin conjugates and (iv) antibodies targeting the MUC1 cell-bound ,/, junction results in tumor suppression in vivo. Our results indicate that cell-bound MUC1 ,/, junction, unlike shed alpha chain, represents a highly effective moiety for targeting and killing MUC1-expressing malignancies. © 2008 Wiley-Liss, Inc. [source] The screening of the second-site suppressor mutations of the common p53 mutantsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Kazunori Otsuka Abstract Second-site suppressor (SSS) mutations in p53 found by random mutagenesis have shown to restore the inactivated function of some tumor-derived p53. To screen novel SSS mutations against common mutant p53s, intragenic second-site (SS) mutations were introduced into mutant p53 cDNA in a comprehensive manner by using a p53 missense mutation library. The resulting mutant p53s with background and SS mutations were assayed for their ability to restore the p53 transactivation function in both yeast and human cell systems. We identified 12 novel SSS mutations including H178Y against a common mutation G245S. Surprisingly, the G245S phenotype is rescued when coexpressed with p53 bearing the H178Y mutation. This result indicated that there is a possibility that intragenic suppressor mutations might restore the protein function in an intermolecular manner. The intermolecular mechanism may lead to novel strategies for restoring inactivated p53 function and tumor suppression in cancer treatment. © 2007 Wiley-Liss, Inc. [source] Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cellsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2004Umadevi V. Wesley Abstract Lung cancer is the leading cause of cancer death. Lung cancers produce a variety of mitogenic growth factors that stimulate tumor cell proliferation and migration. The cell surface protease, dipeptidyl peptidase IV (DPPIV), is involved in diverse biologic functions, including peptide-mediated cellular growth and differentiation. DPPIV is expressed in various normal tissues, including lung tissue, and its expression is lost in many types of human cancers. DPPIV expression and its enzymatic activity are detected in normal bronchial and alveolar epithelium but different histologic subtypes of lung carcinomas lose DPPIV expression. To investigate the role of DPPIV in lung carcinoma, we examined the expression of DPPIV at both mRNA and protein levels in non small cell lung cancer (NSCLC) cell lines and normal human bronchial epithelial cells. DPPIV expression was detectable in normal lung epithelial cells, but was absent or markedly reduced in all NSCLC cell lines at both mRNA and protein levels. Restoration of DPPIV expression in NSCLC cells resulted in profound morphologic changes, inhibition of cell proliferation, anchorage-independent growth, in vitro cell migration and tumorigenicity in nude mice. DPPIV reexpression also correlated with increased p21 expression, leading to induction of apoptosis and cell cycle arrest in G1 stage. These effects were accompanied by increased expression of cell surface proteins, fibroblast-activating protein (Fap,) and CD44 that are associated with suppression of tumor growth and metastasis. Thus, DPPIV functions as a tumor suppressor, and its downregulation may contribute to the loss of growth control in NSCLC cells. © 2004 Wiley-Liss, Inc. [source] ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2003Stanislav Zelivianski Abstract Anticancer drugs docetaxel and vinorelbine suppress cell growth by altering microtubule assembly and activating the proapoptotic signal pathway. Vinorelbine and docetaxel have been approved for treating several advanced cancers. However, their efficacy in the management of advanced hormone-refractory prostate cancer remains to be clarified. Microtubule damage by some anticancer drugs can activate the ERK survival pathway, which conversely compromises chemotherapeutic efficacy. We analyzed the effect of ERK inhibitors PD98059 and U0126 on vinorelbine- and docetaxel-induced cell growth suppression of androgen-independent prostate cancer cells. In androgen-independent C-81 LNCaP cells, inhibition of ERK by PD98059, but not U0126, plus docetaxel resulted in enhanced growth suppression by an additional 20% compared to the sum of each agent alone (p < 0.02). The combination treatment of docetaxel plus PD98059 also increased cellular apoptosis, which was in part due to the inactivation of Bcl-2 by increasing phosphorylated Bcl-2 by more than 6-fold and Bax expression by 3-fold over each agent alone. At these dosages, docetaxel alone caused only marginal phosphorylation of Bcl-2 (10%). Docetaxel plus U0126 had only 20% added effect on Bcl-2 phosphorylation compared to docetaxel alone. Nevertheless, both U0126 and PD98059 exhibited an enhanced effect on docetaxel-induced growth suppression in PC-3 cells. No enhanced effect was observed for vinorelbine plus PD98059 or U0126. Thus, the combination therapy of docetaxel plus PD98059 may represent a new anticancer strategy, requiring lower drug dosages compared to docetaxel monotherapy. This may lower the cytotoxicity and enhance tumor suppression in vivo. This finding of a combination effect could be of potential clinical importance in treating hormone-refractory prostate cancer. © 2003 Wiley-Liss, Inc. [source] WWOX: Its genomics, partners, and functionsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2009Sara Del Mare Abstract The WW domain-containing oxidoreductase (WWOX) spans one of the most active common fragile sites (CFSs) involved in cancer, FRA16D. WWOX encodes a 46-kDa protein that contains two N-terminal WW domains and a central short-chain dehydrogenase/reductase (SDR) domain. Through its WW domain, Wwox interacts with its partners and modulates their functions. Our data indicate that Wwox suppresses the transactivation function of several transcription factors implied in neoplasia by sequestering them in the cytoplasm. Work from our laboratory and other research groups have demonstrated that Wwox participates in a number of cellular processes including growth, differentiation, apoptosis, and tumor suppression. Targeted deletion of the Wwox gene in mice causes increased spontaneous and chemically induced tumor incidence supporting bona fide tumor suppressor function of WWOX. Moreover, generation of the Wwox -deficient mice uncovers, at least in part, some of the physiological in vivo functions of the WWOX gene. This review focuses on recent progress that elucidates Wwox functions in biology and pathology. J. Cell. Biochem. 108: 737,745, 2009. © 2009 Wiley-Liss, Inc. [source] DNA methylation and histone modification regulate silencing of OPG during tumor progression,JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2009Tung-Ying Lu Abstract The identification of molecules that are down-regulated in malignant phenotype is important for understanding tumor biology and their role in tumor suppression. We compared the expression profile of four normal nasal mucosal (NNM) epithelia and a series of nasopharyngeal cancinoma (NPC) cell lines using cDNA microarray and confirmed the actual expression of the selected genes, and found osteoprotegerin (OPG) to be ubiquitously deficient in NPC cells. We also found OPG to be down-regulated in various cancer cell lines, including oral, cervical, ovarian, lung, breast, pancreas, colon, renal, prostate cancer, and hepatoma. Administration of recombinant OPG (rOPG) brought about a reduction in cancer cell growth through apoptotic mechanism. We generated eleven monoclonal antibodies (MAbs) against OPG to study OPG's expression and biological functions in cancer cells. OPG was detected in the tumor stromal regions, but not in the cancer cell per se in surgical specimens of liver cancer. Quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) revealed that OPG was down-regulated in NPC tissues compared with normal nasal polyp (NNP) tissues. In addition, we showed OPG silencing to be associated with promoter methylation as well as histone modifications. In OPG-silenced cancer cell lines, the OPG gene promoter CpG dinucleotides were highly methylated. Compared to normal cells, silenced OPG gene in cancer cells were found to have reduced histone 3 lysine 4 tri-methylation (H3K4me3) and increased histone 3 lysine 27 tri-methylation (H3K27me3). Taken together, these results suggest that OPG silencing in carcinoma cancer cells occurs through epigenetic repression. J. Cell. Biochem. 108: 315,325, 2009. © 2009 Wiley-Liss, Inc. [source] Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in miceAGING CELL, Issue 5 2010Young Sun Oh Summary Although AIMP3/p18 is normally associated with the macromolecular tRNA synthetase complex, recent reports have revealed a new role of AIMP3 in tumor suppression. In this study, we generated a transgenic mouse that overexpresses AIMP3 and characterized the associated phenotype in vivo and in vitro. Surprisingly, the AIMP3 transgenic mouse exhibited a progeroid phenotype, and the cells that overexpressed AIMP3 showed accelerated senescence and defects in nuclear morphology. We found that overexpression of AIMP3 resulted in proteasome-dependent degradation of mature lamin A, but not of lamin C, prelamin A, or progerin. The resulting imbalance in the protein levels of lamin A isoforms, namely altered stoichiometry of prelamin A and progerin to lamin A, appeared to be responsible for a phenotype that resembled progeria. An increase in the level of endogenous AIMP3 has been observed in aged human tissues and cells. The findings in this report suggest that AIMP3 is a specific regulator of mature lamin A and imply that enhanced expression of AIMP3 might be a factor driving cellular and/or organismal aging. [source] Melatonin suppresses tumor angiogenesis by inhibiting HIF-1, stabilization under hypoxiaJOURNAL OF PINEAL RESEARCH, Issue 2 2010Shi-Young Park Abstract:, Angiogenesis is an important mediator of tumor progression. As tumors expand, diffusion distances from the existing vascular supply increases, resulting in hypoxia in the cancer cells. Sustained expansion of a tumor mass requires new blood vessel formation to provide rapidly proliferating tumor cells with an adequate supply of oxygen and nutrients. The key regulator of hypoxia-induced angiogenesis is the transcription factor known as hypoxia-inducible factor (HIF)-1. HIF-1, is stabilized by hypoxia-induced reactive oxygen species (ROS) and enhances the expression of several types of hypoxic genes, including that of the angiogenic activator known as vascular endothelial cell growth factor (VEGF). In this study, we found that melatonin, a small lipophilic molecule secreted primarily by the pineal gland, destabilizes hypoxia-induced HIF-1, protein levels in the HCT116 human colon cancer cell line. This destabilization of HIF-1, resulted from the antioxidant activity of melatonin against ROS induced by hypoxia. Moreover, under hypoxia, melatonin suppressed HIF-1 transcriptional activity, leading to a decrease in VEGF expression. Melatonin also blocked in vitro tube formation and invasion and migration of human umbilical vein endothelial cells induced by hypoxia-stimulated conditioned media of HCT116 cells. These findings suggest that melatonin could play a pivotal role in tumor suppression via inhibition of HIF-1-mediated angiogenesis. [source] Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transferMOLECULAR CARCINOGENESIS, Issue 12 2009Neal A.L. Cody Abstract The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV-90 ovarian cancer cell line identified the 3p12.3-pcen region as a candidate tumor suppressor gene (TSG) locus. In the present study, polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12.3-pcen interval to a 16.1 Mb common region containing 12 known or hypothetical genes: 3ptel - ROBO2-ROBO1-GBE1-CADM2-VGLL3-CHMP2B-POU1F1-HTR1F-CGGBP1-ZNF654-C3orf38-EPHA3 -3pcen. Seven of these genes, ROBO1, GBE1, VGLL3, CHMP2B, CGGBP1, ZNF654, and C3orf38, exhibited gene expression in the hybrids, placing them as top TSG candidates for further analysis. The expression of all but one (VGLL3) of these genes was also detected in the parental OV-90 cell line. Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV-90 and donor normal chromosome 3 contig. However, the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for ROBO1, VGLL3, CHMP2B, and CGGBP1 and cDNA sequencing of the hybrids revealed biallelic expression of these genes. Interestingly, underexpression of VGLL3 and ZNF654 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors, and this occurred regardless of allelic content of 3p12.3-pcen. The results taken together suggest that dysregulation of VGLL3 and/or ZNF654 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV-90, a cell line hemizygous for 3p. Mol. Carcinog. © 2009 Wiley-Liss, Inc. [source] Interferon-inducible protein IFIX, inhibits cell invasion by upregulating the metastasis suppressor maspin,MOLECULAR CARCINOGENESIS, Issue 10 2008Hirohito Yamaguchi Abstract IFIX,, a member of the interferon-inducible HIN-200 family, has been identified as a putative tumor suppressor. However, the molecular mechanisms underlying IFIX,-mediated tumor suppression are poorly understood. In the present study, we demonstrated that the metastasis suppressor maspin acts as the downstream target of IFIX,. IFIX, suppressed the invasion activity of MDA-MB-468 breast cancer cells, and its inhibitory effect was reversed by the knockdown of maspin. Both Maspin mRNA and protein were upregulated by IFIX,. Histone deacetylase (HDAC) inhibitors, but not DNA methyltransferase inhibitor upregulated maspin, and HDAC1 inhibited the transactivation of maspin promoter. Although the HDAC1 protein was downregulated in IFIX,-expressing cells, IFIX, did not affect HDAC1 mRNA levels. Conversely, a proteasome inhibitor restored the level of HDAC1 protein in IFIX,-expressing cells, and the polyubiqutination of HDAC1 was promoted by IFIX,, suggesting that HDAC1 is regulated by IFIX, through a ubiquitin-proteasome pathway. Together, these data provide novel insights into the tumor-suppressive function of IFIX,. © 2008 Wiley-Liss, Inc. [source] DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanismsMOLECULAR CARCINOGENESIS, Issue 5 2008Kevin D. Healy Abstract Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-,1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC. © 2007 Wiley-Liss, Inc. [source] Distinct roles of individual Smads in skin carcinogenesisMOLECULAR CARCINOGENESIS, Issue 8 2007Sophia Bornstein Abstract Transforming growth factor , (TGF,) signaling has both tumor suppression and promotion roles. Smads are transcription factors that primarily mediate intracellular signaling for the TGF, superfamily. Loss of Smad2 and Smad4, but not Smad3 is common in human cancers. Given the complex nature of TGF, signaling, dissection of the distinct role of each Smad in mediating the multiple functions of TGF, signaling is warranted. To further analyze Smad deregulation during carcinogenesis, Smad2, Smad3, Smad4, and Smad7 were genetically modified in murine epidermis, and each alteration resulted in distinct skin phenotypes. Based on data from human cancer samples and from experimental models, Smad2 and Smad4 mainly function as tumor suppressors in skin carcinogenesis in vivo, whereas Smad3 and Smad7 may have dual roles in cancer. This review intends to summarize recent advances in the elucidation of the roles of Smad2, Smad3, Smad4, and Smad7 in skin carcinogenesis. © 2007 Wiley-Liss, Inc. [source] Prostate-specific antitumor activity by probasin promoter-directed p202 expression,MOLECULAR CARCINOGENESIS, Issue 3 2003Yong Wen Abstract p202, an interferon (IFN) inducible protein, arrests cell cycle at G1 phase leading to cell growth retardation. We previously showed that ectopic expression of p202 in human prostate cancer cells renders growth inhibition and suppression of transformation phenotype in vitro. In this report, we showed that prostate cancer cells with stable expression of p202 were less tumorigenic than the parental cells. The antitumor activity of p202 was further demonstrated by an ex vivo treatment of prostate cancer cells with p202 expression vector that showed significant tumor suppression in mouse xenograft model. Importantly, to achieve a prostate-specific antitumor effect by p202, we employed a prostate-specific probasin (ARR2PB) gene promoter to direct p202 expression (ARR2PB-p202) in an androgen receptor (AR),positive manner. The ARR2PB-p202/liposome complex was systemically administered into mice bearing orthotopic AR-positive prostate tumors. We showed that parenteral administration of an ARR2PB-p202/liposome preparation led to prostate-specific p202 expression and tumor suppression in orthotopic prostate cancer xenograft model. Furthermore, with DNA array technique, we showed that the expression of p202 was accompanied by downregulation of G2/M phase cell-cycle regulators, cyclin B, and p55cdc. Together, our results suggest that p202 suppresses prostate tumor growth, and that a prostate-specific antitumor effect can be achieved by systemic administration of liposome-mediated delivery of ARR2PB-p202. © 2003 Wiley-Liss, Inc. [source] The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cellsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 8 2010Jun Cheng Abstract MicroRNAs are small non-coding RNA molecules that play essential roles in biological processes ranging from cell cycle to cell migration and invasion. Accumulating evidence suggests that miR-34a, as a key mediator of p53 tumor suppression, is aberrantly expressed in human cancers. In the present study, we aimed to explore the precise biological role of miR-34a and the global protein changes in HCC cell line HepG2 cells transiently transfected with miR-34a. Transfection of miR-34a into HepG2 cells caused suppression of cell proliferation, inhibition of cell migration and invasion. It also induced an accumulation of HepG2 cells in G1 phase. Among 116 protein spots with differential expression separated by 2-DE method, 34 proteins were successfully identified by MALDI-TOF/TOF analysis. Of these, 15 downregulated proteins may be downstream targets of miR-34a. Bioinformatics analysis produced a protein,protein interaction network, which revealed that the p53 signaling pathway and cell cycle pathway were two major hubs containing most of the proteins regulated by miR-34a. Cytoskeletal proteins such as LMNA, GFAP, MACF1, ALDH2, and LOC100129335 are potential targets of miR-34a. In conclusion, abrogation of miR-34a function could cause downstream molecules to switch on or off, leading to HCC development. [source] Proteomic analysis of acute myeloid leukemia: Identification of potential early biomarkers and therapeutic targetsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue S1 2006Chary López-Pedrera Dr. Abstract The main goal of this study was to analyze, using proteomic techniques, changes in protein expression of acute myeloid leukemia (AML) cells that could give insights into a better early prognosis for tumor pathophysiology. Proteomic analysis of different subtypes of AML cells was carried out using 2-DE and MALDI-TOF,PMF analysis. Proteins identified as more significantly altered between the different AMLs belonged to the group of suppressor genes, metabolic enzymes, antioxidants, structural proteins and signal transduction mediators. Among them, seven identified proteins were found significantly altered in almost all the AML blast cells analyzed in relation to normal mononuclear blood cells: alpha-enolase, RhoGDI2, annexin,A10, catalase, peroxiredoxin,2, tromomyosin,3, and lipocortin,1 (annexin,1). These differentially expressed proteins are known to play important roles in cellular functions such as glycolysis, tumor suppression, apoptosis, angiogenesis and metastasis, and they might contribute to the adverse evolution of the disease. Proteomic analysis has identified for the first time novel proteins that may either help to form a differential prognosis or be used as markers for disease outcome, thus providing potential new targets for rational pathogenesis-based therapies of AML. [source] A differential proteome in tumors suppressed by an adenovirus-based skin patch vaccine encoding human carcinoembryonic antigenPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 4 2005Chun-Ming Huang Abstract We created an anti-tumor vaccine by using adenovirus as a vector which contains a cytomegalovirus early promoter-directed human carcinoembryonic antigen gene (AdCMV-hCEA). In an attempt to develop the skin patch vaccine, we epicutaneously vaccinated Balb/c mice with AdCMV-hCEA. After nine weeks post-immunization, vaccinated mice evoked a robust antibody titer to CEA and demonstrated the capability of suppressing in vivo growth of implanted murine mammay adenocarioma cell line (JC-hCEA) tumor cells derived from a female Balb/c mouse. Proteomic analysis of the tumor masses in the non-vaccinated naďve and vaccinated mice reveal that six proteins change their abundance in the tumor mass. The levels of adenylate kinase 1, ,-enolase, creatine kinase M chain, hemoglobin beta chain and prohibitin were statistically increased whereas the level of a creatine kinase fragment, which is undocumented, was decreased in the tumor of vaccinated mice. These proteins may provide a vital link between early-stage tumor suppression and immune response of skin patch vaccination. [source] Cellular senescence: Its role in tumor suppression and agingCANCER SCIENCE, Issue 5 2009Naoko Ohtani In normal tissue, cell division is carefully regulated to maintain the correct proliferative balance. Abnormal cell division underlies many hypoproliferative and hyperproliferative disorders, including cancer, and a better understanding of the mechanisms involved could lead to new strategies for treatment and prevention. Cellular senescence, a state of irreversible growth arrest, was first described as a limit to the replicative life span of somatic cells after serial cultivation in vitro. Recently, however, it has also been shown to be triggered prematurely by potentially oncogenic stimuli such as oncogene expression, oxidative stress, and DNA damage in cell culture studies. These data suggest that cellular senescence is therefore acting as a tumor-protective fail-safe mechanism. However, the significance of cellular senescence has remained an issue of debate over the years, with the possibility that it might be a cell culture-related artifact. Recent reports on oncogene-induced senescence detected in premalignant tumors have provided evidence to validate its role as a physiological response to prevent oncogenesis in vivo. In this review, we discuss the mechanisms for cellular senescence and its roles in vivo. (Cancer Sci 2009; 100: 792,797) [source] Potent antitumor effect elicited by superantigen-linked tumor cells transduced with heat shock protein 70 geneCANCER SCIENCE, Issue 2 2004Changxin Huang Heat shock proteins (HSP) induce antitumor-specific immunity via a unique mechanism, but HSP alone fails to produce a satisfactory antitumor efficacy. We considered that the potent immune-activation of superantigen (SAg) might assist HSP to elicit a strong tumor-antigen-specific immunity. We initially prepared B16 melanoma cells linked to SAg SEA via a fusion protein with a trans-membrane sequence (TM), and demonstrated that SEA thus anchored on the tumor cell surface could elicit strong antitumor immunity. We then prepared cells transduced with an inducible heat shock protein 70 (HSP70) gene, and bearing SEA-TM fusion protein on the cell surface, and used these cells as a dual-modified vaccine. In this study, either in a therapeutic setting or in a pre-immune model, the SEA-anchored vaccine or the HSP70 gene-modified vaccine induced marked tumor suppression, prolonged survival, augmented lymphocyte proliferation and higher NK and CTL activity in C57BL/6 mice compared with their controls (P<0.01), though they were less effective than the dual-modified vaccine. Among these vaccines, the dual-modified vaccine showed the best therapeutic efficacy in B16 melanoma-bearing mice and gave the greatest protection against wild-type B16 melanoma challenge. The results indicated that the dual-modified vaccine could induce a potent tumor-antigen-specific immune response in addition to an increase of non-specific immunity. This study offers a novel approach to bridging specific and non-specific immunity for cancer therapy. [source] Annexin VII as a Novel Marker for Invasive Phenotype of Malignant MelanomaCANCER SCIENCE, Issue 1 2000Tatsuki R. Kataoka Both F10 and BL6 sublines of B16 mouse melanoma cells are metastatic after intravenous injection, but only BL6 cells are metastatic after subcutaneous injection. While examining the genetic difference between the two sublines, we found a marked reduction of annexin VII expression in BL6 cells. In addition, fusion cell clones of both sublines, were as poorly metastatic as F10 cells after subcutaneous injection, and contained the annexin VII message as abundantly as F10 cells. Hence, we examined whether the annexin VII expression was correlated with the less malignant phenotype of clinical cases by immunohistochemistry. Immunoreactivities to anti-annexin VII antibody in melanoma cells were evaluated quantitatively by using skin mast cells as an internal positive control. Eighteen patients with malignant melanoma were divided into two groups: lymph node metastasis-negative and positive groups. The ratio of numbers of patients positive versus negative to the antibody was significantly larger in the former than in the latter group. These results not only indicated that annexin VII serves as a marker for less invasive phenotype of malignant melanoma, but also suggested a possible role of annexin VII in tumor suppression. [source] | |||||||||||||