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PIK3CA and APC mutations are synergistic in the development of intestinal cancers.
Deming DA, Leystra AA, Nettekoven L, Sievers C, Miller D, Middlebrooks M, Clipson L, Albrecht D, Bacher J, Washington MK, Weichert J, Halberg RB
(2014) Oncogene 33: 2245-54
MeSH Terms: Adenocarcinoma, Adenomatous Polyposis Coli Protein, Animals, Cell Nucleus, Colorectal Neoplasms, Cyclin D1, Disease Models, Animal, Epistasis, Genetic, Female, Gene Expression, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microsatellite Instability, Phosphatidylinositol 3-Kinases, Tumor Burden, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added April 12, 2016
Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.
0 Communities
1 Members
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20 MeSH Terms
Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers.
French JD, Ghoussaini M, Edwards SL, Meyer KB, Michailidou K, Ahmed S, Khan S, Maranian MJ, O'Reilly M, Hillman KM, Betts JA, Carroll T, Bailey PJ, Dicks E, Beesley J, Tyrer J, Maia AT, Beck A, Knoblauch NW, Chen C, Kraft P, Barnes D, González-Neira A, Alonso MR, Herrero D, Tessier DC, Vincent D, Bacot F, Luccarini C, Baynes C, Conroy D, Dennis J, Bolla MK, Wang Q, Hopper JL, Southey MC, Schmidt MK, Broeks A, Verhoef S, Cornelissen S, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Fasching PA, Loehberg CR, Ekici AB, Beckmann MW, Peto J, dos Santos Silva I, Johnson N, Aitken Z, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Guénel P, Truong T, Laurent-Puig P, Menegaux F, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Zamora MP, Arias Perez JI, Benitez J, Anton-Culver H, Brenner H, Müller H, Arndt V, Stegmaier C, Meindl A, Lichtner P, Schmutzler RK, Engel C, Brauch H, Hamann U, Justenhoven C, GENICA Network, Aaltonen K, Heikkilä P, Aittomäki K, Blomqvist C, Matsuo K, Ito H, Iwata H, Sueta A, Bogdanova NV, Antonenkova NN, Dörk T, Lindblom A, Margolin S, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, kConFab Investigators, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Lambrechts D, Peeters S, Smeets A, Floris G, Chang-Claude J, Rudolph A, Nickels S, Flesch-Janys D, Radice P, Peterlongo P, Bonanni B, Sardella D, Couch FJ, Wang X, Pankratz VS, Lee A, Giles GG, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Simard J, Goldberg MS, Labrèche F, Dumont M, Teo SH, Yip CH, Ng CH, Vithana EN, Kristensen V, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Devilee P, Seynaeve C, García-Closas M, Figueroa J, Chanock SJ, Lissowska J, Czene K, Klevebring D, Schoof N, Hooning MJ, Martens JW, Collée JM, Tilanus-Linthorst M, Hall P, Li J, Liu J, Humphreys K, Shu XO, Lu W, Gao YT, Cai H, Cox A, Balasubramanian SP, Blot W, Signorello LB, Cai Q, Pharoah PD, Healey CS, Shah M, Pooley KA, Kang D, Yoo KY, Noh DY, Hartman M, Miao H, Sng JH, Sim X, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Sangrajrang S, Gaborieau V, McKay J, Toland AE, Ambrosone CB, Yannoukakos D, Godwin AK, Shen CY, Hsiung CN, Wu PE, Chen ST, Swerdlow A, Ashworth A, Orr N, Schoemaker MJ, Ponder BA, Nevanlinna H, Brown MA, Chenevix-Trench G, Easton DF, Dunning AM
(2013) Am J Hum Genet 92: 489-503
MeSH Terms: Binding Sites, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromatin, Chromatin Immunoprecipitation, Chromosomes, Human, Pair 11, Cyclin D1, Electrophoretic Mobility Shift Assay, Enhancer Elements, Genetic, Female, GATA3 Transcription Factor, Gene Expression Regulation, Neoplastic, Humans, Luciferases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4
Show Abstract · Added March 10, 2014
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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23 MeSH Terms
Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, Berndt SI, Bézieau S, Brenner H, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Chen LS, Coetzee GA, Coetzee SG, Conti DV, Curtis KR, Duggan D, Edwards T, Fuchs CS, Gallinger S, Giovannucci EL, Gogarten SM, Gruber SB, Haile RW, Harrison TA, Hayes RB, Henderson BE, Hoffmeister M, Hopper JL, Hudson TJ, Hunter DJ, Jackson RD, Jee SH, Jenkins MA, Jia WH, Kolonel LN, Kooperberg C, Küry S, Lacroix AZ, Laurie CC, Laurie CA, Le Marchand L, Lemire M, Levine D, Lindor NM, Liu Y, Ma J, Makar KW, Matsuo K, Newcomb PA, Potter JD, Prentice RL, Qu C, Rohan T, Rosse SA, Schoen RE, Seminara D, Shrubsole M, Shu XO, Slattery ML, Taverna D, Thibodeau SN, Ulrich CM, White E, Xiang Y, Zanke BW, Zeng YX, Zhang B, Zheng W, Hsu L, Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium
(2013) Gastroenterology 144: 799-807.e24
MeSH Terms: Age Distribution, Aged, Aged, 80 and over, Colorectal Neoplasms, Cyclin D2, DNA-Binding Proteins, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Laminin, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, T-Box Domain Proteins
Show Abstract · Added March 10, 2014
BACKGROUND & AIMS - Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
METHODS - We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
RESULTS - Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).
CONCLUSIONS - In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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3 Members
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20 MeSH Terms
Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer.
Jia WH, Zhang B, Matsuo K, Shin A, Xiang YB, Jee SH, Kim DH, Ren Z, Cai Q, Long J, Shi J, Wen W, Yang G, Delahanty RJ, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colon Cancer Family Registry (CCFR), Ji BT, Pan ZZ, Matsuda F, Gao YT, Oh JH, Ahn YO, Park EJ, Li HL, Park JW, Jo J, Jeong JY, Hosono S, Casey G, Peters U, Shu XO, Zeng YX, Zheng W
(2013) Nat Genet 45: 191-6
MeSH Terms: Asian Continental Ancestry Group, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 20, Chromosomes, Human, Pair 5, Colorectal Neoplasms, Cyclin D2, European Continental Ancestry Group, Far East, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Principal Component Analysis
Show Abstract · Added March 18, 2014
To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10(-7) to 3.77 × 10(-10) in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10(-10) for rs647161 (5q31.1), 6.64 × 10(-9) for rs2423279 (20p12.3) and 3.06 × 10(-8) for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.
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3 Members
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17 MeSH Terms
Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling.
Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ, Schmidt AM
(2012) J Exp Med 209: 2339-50
MeSH Terms: Animals, Cell Line, Tumor, Cyclin D1, Female, Humans, Lysophospholipids, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle, Smooth, Vascular, Neoplasms, Proto-Oncogene Proteins c-akt, Rats, Receptor for Advanced Glycation End Products, Receptors, Immunologic, Recombinant Proteins, Signal Transduction
Show Abstract · Added March 12, 2014
The endogenous phospholipid lysophosphatidic acid (LPA) regulates fundamental cellular processes such as proliferation, survival, motility, and invasion implicated in homeostatic and pathological conditions. Hence, delineation of the full range of molecular mechanisms by which LPA exerts its broad effects is essential. We report avid binding of LPA to the receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, and mapping of the LPA binding site on this receptor. In vitro, RAGE was required for LPA-mediated signal transduction in vascular smooth muscle cells and C6 glioma cells, as well as proliferation and migration. In vivo, the administration of soluble RAGE or genetic deletion of RAGE mitigated LPA-stimulated vascular Akt signaling, autotaxin/LPA-driven phosphorylation of Akt and cyclin D1 in the mammary tissue of transgenic mice vulnerable to carcinogenesis, and ovarian tumor implantation and development. These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA.
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1 Members
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18 MeSH Terms
XZH-5 inhibits STAT3 phosphorylation and enhances the cytotoxicity of chemotherapeutic drugs in human breast and pancreatic cancer cells.
Liu A, Liu Y, Jin Z, Hu Q, Lin L, Jou D, Yang J, Xu Z, Wang H, Li C, Lin J
(2012) PLoS One 7: e46624
MeSH Terms: Animals, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Cyclin D1, Female, HeLa Cells, Histidine, Humans, Inhibitor of Apoptosis Proteins, Interleukin-6, Mice, Mice, SCID, Pancreatic Neoplasms, Phenylurea Compounds, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, STAT1 Transcription Factor, STAT3 Transcription Factor, Survivin
Show Abstract · Added June 14, 2013
Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in breast and pancreatic cancer. Inhibiting constitutive STAT3 signaling represents a promising molecular target for therapeutic approach. Using structure-based design, we developed a non-peptide cell-permeable, small molecule, termed as XZH-5, which targeted STAT3 phosphorylation. XZH-5 was found to inhibit STAT3 phosphorylation (Tyr705) and induce apoptosis in human breast and pancreatic cancer cell lines expressing elevated levels of phosphorylated STAT3. XZH-5 could also inhibit interleukin-6-induced STAT3 phosphorylation in cancer cell lines expressing low phosphorylated STAT3. Inhibition of STAT3 signaling by XZH-5 was confirmed by the down-regulation of downstream targets of STAT3, such as Cyclin D1, Bcl-2, and Survivin at mRNA level. In addition, XZH-5 inhibited colony formation, cell migration, and enhanced the cytotoxicity of chemotherapeutic drugs when combined with Doxorubicin or Gemcitabine. Our results indicate that XZH-5 may be a potential therapeutic agent for breast and pancreatic cancers with constitutive STAT3 signaling.
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1 Members
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23 MeSH Terms
Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina.
Das G, Clark AM, Levine EM
(2012) Dev Dyn 241: 941-52
MeSH Terms: Animals, Cell Cycle, Cell Differentiation, Cell Proliferation, Cyclin D1, Cyclin D2, Cyclin D3, Mice, Mice, Knockout, Retina, Stem Cells
Show Abstract · Added November 2, 2015
BACKGROUND - The cell-cycle regulator Cyclin D1 is expressed in embryonic retinal progenitor cells (RPCs) and regulates their cell-cycle rate and neurogenic output. We report here that Cyclin D1 also has important functions in postnatal retinal histogenesis.
RESULTS - The initial production of Müller glia and bipolar cells was enhanced in Cyclin D1 knockout (Ccnd1(-/-) ) retinas. Despite a steeper than normal rate of depletion of the RPC population at embryonic ages, postnatal Ccnd1(-/-) retinas exhibited an extended window of proliferation, neurogenesis, and gliogenesis. Cyclin D3, normally confined to Müller glia, was prematurely expressed in Ccnd1(-/-) RPCs. However, Cyclin D3 did not compensate for Cyclin D1 in regulating cell-cycle kinetics or neurogenic output.
CONCLUSIONS - The data presented in this study along with our previous finding that Cyclin D2 was unable to completely compensate for the absence of Cyclin D1 indicate that Cyclin D1 regulates retinal histogenesis in ways not shared by the other D-cyclins.
Copyright © 2012 Wiley Periodicals, Inc.
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11 MeSH Terms
RAF265 inhibits the growth of advanced human melanoma tumors.
Su Y, Vilgelm AE, Kelley MC, Hawkins OE, Liu Y, Boyd KL, Kantrow S, Splittgerber RC, Short SP, Sobolik T, Zaja-Milatovic S, Dahlman KB, Amiri KI, Jiang A, Lu P, Shyr Y, Stuart DD, Levy S, Sosman JA, Richmond A
(2012) Clin Cancer Res 18: 2184-98
MeSH Terms: Animals, Apoptosis, Base Sequence, Cell Cycle Proteins, Cell Proliferation, Cyclin D1, Extracellular Signal-Regulated MAP Kinases, Female, Gene Expression Profiling, Humans, Imidazoles, Ki-67 Antigen, MAP Kinase Signaling System, Male, Melanoma, Mice, Mice, Nude, Mutation, Oligonucleotide Array Sequence Analysis, Protein Kinase Inhibitors, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-kit, Proto-Oncogene Proteins p21(ras), Pyridines, Sequence Analysis, DNA, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, bcl-X Protein
Show Abstract · Added June 14, 2013
PURPOSE - The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.
EXPERIMENTAL DESIGN - Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.
RESULTS - Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAF(V600E/K)), whereas eight of 17 (47%) tumors were BRAF wild type (BRAF(WT)). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAF(WT), of which 1 carried c-KIT(L576P) and another N-RAS(Q61R) mutation, while only 2 (29%) of the responding tumors were BRAF(V600E/K). Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.
CONCLUSIONS - Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles.
©2012 AACR.
2 Communities
11 Members
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30 MeSH Terms
Mir-33 regulates cell proliferation and cell cycle progression.
Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramírez CM, Chamorro-Jorganes A, Wanschel AC, Lasuncion MA, Morales-Ruiz M, Suarez Y, Baldan Á, Esplugues E, Fernández-Hernando C
(2012) Cell Cycle 11: 922-33
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Cyclin D1, Cyclin-Dependent Kinase 6, G1 Phase Cell Cycle Checkpoints, HeLa Cells, Humans, Liver Regeneration, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Oligonucleotides, Antisense, Phosphates
Show Abstract · Added February 12, 2016
Cholesterol metabolism is tightly regulated at the cellular level and is essential for cellular growth. microRNAs (miRNAs), a class of noncoding RNAs, have emerged as critical regulators of gene expression, acting predominantly at posttranscriptional level. Recent work from our group and others has shown that hsa-miR-33a and hsa-miR-33b, miRNAs located within intronic sequences of the Srebp genes, regulate cholesterol and fatty acid metabolism in concert with their host genes. Here, we show that hsa-miR-33 family members modulate the expression of genes involved in cell cycle regulation and cell proliferation. MiR-33 inhibits the expression of the cyclin-dependent kinase 6 (CDK6) and cyclin D1 (CCND1), thereby reducing cell proliferation and cell cycle progression. Overexpression of miR-33 induces a significant G 1 cell cycle arrest in Huh7 and A549 cell lines. Most importantly, inhibition of miR-33 expression using 2'fluoro/methoxyethyl-modified (2'F/MOE-modified) phosphorothioate backbone antisense oligonucleotides improves liver regeneration after partial hepatectomy (PH) in mice, suggesting an important role for miR-33 in regulating hepatocyte proliferation during liver regeneration. Altogether, these results suggest that Srebp/miR-33 locus may cooperate to regulate cell proliferation, cell cycle progression and may also be relevant to human liver regeneration.
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15 MeSH Terms
NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the β-catenin pathway.
Thu YM, Su Y, Yang J, Splittgerber R, Na S, Boyd A, Mosse C, Simons C, Richmond A
(2012) Oncogene 31: 2580-92
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cyclin D2, Down-Regulation, Enzyme Activation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, bcl-2, Genes, myc, Humans, Melanoma, Melanoma, Experimental, Mice, Neoplasm Metastasis, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Signal Transduction, beta Catenin
Show Abstract · Added June 14, 2013
Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates β-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other β-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both β-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.
2 Communities
2 Members
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21 MeSH Terms