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1.
J Endocr Soc ; 8(6): bvae048, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38660141

RESUMO

Context: Next-generation sequencing (NGS) analysis of sporadic medullary thyroid carcinoma (sMTC) has led to increased detection of somatic mutations, including RET M918T, which has been considered a negative prognostic indicator. Objective: This study aimed to determine the association between clinicopathologic behavior and somatic mutation identified on clinically motivated NGS. Methods: In this retrospective cohort study, patients with sMTC who underwent NGS to identify somatic mutations for treatment planning were identified. Clinicopathologic factors, time to distant metastatic disease (DMD), disease-specific survival (DSS), and overall survival (OS) were compared between somatic mutations. Results: Somatic mutations were identified in 191 sMTC tumors, including RET M918T (53.4%), other RET codons (10.5%), RAS (18.3%), somatic RET indels (8.9%), and RET/RAS wild-type (WT) status (8.9%). The median age at diagnosis was 50 years (range, 11-83); 46.1% were female. When comparing patients with RET M918T, RET-Other, and RET WT (which included RAS and RET/RAS WT), there were no differences in sex, TNM category, systemic therapy use, time to DMD, DSS, or OS. On multivariate analysis, older age at diagnosis (HR 1.05, P < .001; HR 1.06, P< .001) and M1 stage at diagnosis (HR 3.17, P = .001; HR 2.98, P = .001) were associated with decreased DSS and OS, respectively, but mutation cohort was not. When comparing RET M918T to RET indels there was no significant difference in time to DMD, DSS, or OS between the groups. Conclusion: Somatic RET mutations do not portend compromised DSS or OS in a cohort of sMTC patients who underwent clinically motivated NGS.

2.
Cancer ; 124(5): 966-972, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165790

RESUMO

BACKGROUND: Genomic testing is increasingly performed in oncology, but concerns remain regarding the clinician's ability to interpret results. In the current study, the authors sought to determine the agreement between physicians and genomic annotators from the Precision Oncology Decision Support (PODS) team at The University of Texas MD Anderson Cancer Center in Houston regarding actionability and the clinical use of test results. METHODS: On a prospective protocol, patients underwent clinical genomic testing for hotspot mutations in 46 or 50 genes. Six months after sequencing, physicians received questionnaires for patients who demonstrated a variant in an actionable gene, investigating their perceptions regarding the actionability of alterations and clinical use of these findings. Genomic annotators independently classified these variants as actionable, potentially actionable, unknown, or not actionable. RESULTS: Physicians completed 250 of 288 questionnaires (87% response rate). Physicians considered 168 of 250 patients (67%) as having an actionable alteration; of these, 165 patients (98%) were considered to have an actionable alteration by the PODS team and 3 were of unknown significance. Physicians were aware of genotype-matched therapy available for 119 patients (71%) and 48 of these 119 patients (40%) received matched therapy. Approximately 46% of patients in whom physicians regarded alterations as not actionable (36 of 79 patients) were classified as having an actionable/potentially actionable mutation by the PODS team. However, many of these were only theoretically actionable due to limited trials and/or therapies (eg, KRAS). CONCLUSIONS: Physicians are aware of recurrent mutations in actionable genes on "hotspot" panels. As larger genomic panels are used, there may be a growing need for annotation of actionability. Decision support to increase awareness of genomically relevant trials and novel treatment options for recurrent mutations (eg, KRAS) also are needed. Cancer 2018;124:966-72. © 2017 American Cancer Society.


Assuntos
Predisposição Genética para Doença/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias/genética , Médicos , Genética Médica/métodos , Humanos , Oncologia/métodos , Neoplasias/diagnóstico , Neoplasias/terapia , Medicina de Precisão/métodos , Estudos Prospectivos , Inquéritos e Questionários
3.
Pharmacol Ther ; 173: 58-66, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28174090

RESUMO

The tropomyosin receptor kinase (TRK) family includes TRKA, TRKB, and TRKC proteins, which are encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Binding of neurotrophins to TRK proteins induces receptor dimerization, phosphorylation, and activation of the downstream signaling cascades via PI3K, RAS/MAPK/ERK, and PLC-gamma. TRK pathway aberrations, including gene fusions, protein overexpression, and single nucleotide alterations, have been implicated in the pathogenesis of many cancer types, with NTRK gene fusions being the most well validated oncogenic events to date. Although the NTRK gene fusions are infrequent in most cancer types, certain rare tumor types are predominately driven by these events. Conversely, in more common histologies, such as lung and colorectal cancers, prevalence of the NTRK fusions is well below 5%. Selective inhibition of TRK signaling may therefore be beneficial among patients whose tumors vary in histologies, but share underlying oncogenic NTRK gene alterations. Currently, several TRK-targeting compounds are in clinical development. The ongoing Phase 2 trials with entrectinib and LOXO-101, two of the leading TRK inhibitors, are designed as 'basket trials', inclusive of patients whose tumors harbor NTRK gene fusions, independent of histology. Additional Phase 1 studies of other TRK inhibitors, including MGCD516, PLX7486, DS-6051b, and TSR-011, are underway. Interim data examining NTRK-rearranged tumors treated with entrectinib or LOXO-101 demonstrate encouraging activity, with patients achieving rapid and durable responses. Consequently, both drugs have achieved orphan designation from regulatory agencies, and efforts are underway to further expedite their development.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Benzamidas/farmacologia , Desenho de Fármacos , Humanos , Indazóis/farmacologia , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/patologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor trkA/antagonistas & inibidores , Receptor trkA/genética , Receptor trkA/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Receptor trkB/metabolismo , Receptor trkC/antagonistas & inibidores , Receptor trkC/genética , Receptor trkC/metabolismo
4.
Cold Spring Harb Mol Case Stud ; 3(1): a001115, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28050598

RESUMO

The anaplastic lymphoma kinase (ALK) gene plays an important physiologic role in the development of the brain and can be oncogenically altered in several malignancies, including non-small-cell lung cancer (NSCLC) and anaplastic large cell lymphomas (ALCL). Most prevalent ALK alterations are chromosomal rearrangements resulting in fusion genes, as seen in ALCL and NSCLC. In other tumors, ALK copy-number gains and activating ALK mutations have been described. Dramatic and often prolonged responses are seen in patients with ALK alterations when treated with ALK inhibitors. Three of these-crizotinib, ceritinib, and alectinib-are now FDA approved for the treatment of metastatic NSCLC positive for ALK fusions. However, the emergence of resistance is universal. Newer ALK inhibitors and other targeting strategies are being developed to counteract the newly emergent mechanism(s) of ALK inhibitor resistance. This review outlines the recent developments in our understanding and treatment of tumors with ALK alterations.

5.
Invest New Drugs ; 32(6): 1105-1112, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25085205

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors (COXIBs) can reduce the risk of developing colorectal cancer (CRC) and are being considered for use as adjuvant therapy for treatment of CRC patients. However, long-term use of most NSAIDs, except aspirin, increases cardiovascular risk, hampering use of these drugs in CRC prevention and possibly for treatment. CG100649 is a new member of the COXIB family, which is proposed to inhibit both COX-2 and carbonic anhydrase-I/-II (CA-I/-II) activity. Using mouse models, we show here that CG100649 inhibits premalignant and malignant colorectal lesions in mouse models, partly through inhibiting tumor cell proliferation. These pre-clinical findings suggest a need for further exploration of CG100649 for CRC prevention and treatment. The long-term safety profile of CG100649, particularly regarding its effect on cardiovascular risk, is yet to be determined.


Assuntos
Adenoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Furanos/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Furanos/farmacologia , Humanos , Camundongos , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Lett ; 341(2): 159-65, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23916472

RESUMO

HIG2 (hypoxia-inducible gene 2) is a biomarker of hypoxia and elevated in several cancers. Here, we show that HIG2 also upregulated HIF-1α expression under hypoxic conditions and enhanced AP-1 expression under normoxic conditions, which affects colorectal cancer cell survival. Importantly, over-expression of HIG2 promoted tumor growth by suppressing apoptosis in a mouse orthotopic model. These results are likely relevant to human disease since we found that the expression of HIG2 is gradually elevated as tumors progress. Collectively, these findings suggest that HIG2 plays an important role in promoting colorectal cancer growth in hypoxia-dependent and independent manners.


Assuntos
Neoplasias Colorretais/genética , Hipóxia , Proteínas de Neoplasias/genética , Transdução de Sinais/genética , Animais , Western Blotting , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Células HCT116 , Células HT29 , Xenoenxertos/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante Heterólogo , Carga Tumoral/genética
7.
J Biol Chem ; 286(34): 30003-9, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21757690

RESUMO

Although cancer cells have traditionally been thought to rely on the glycolytic pathway to generate ATP, recent studies suggest that cancer cells can shift to the fatty acid oxidation pathway as an alternative energy source. All of the factors that induce and regulate this adaptive shift in metabolism are not known. Cyclooxygenase-2-derived prostaglandin E(2) (PGE(2)) is produced at high levels in colon cancer, and multiple lines of evidence from human-, animal-, and cell line-based studies indicate that PGE(2) plays a pro-oncogenic role in colorectal cancer progression. We have shown previously that exposure of colon cancer cells to PGE(2) promotes cell survival, in part by inducing the expression of the nuclear orphan receptor NR4A2. Here, we report that PGE(2)-induced NR4A2 increased fatty acid oxidation by inducing the expression of multiple proteins in the fatty acid oxidation pathway. NR4A2 was found to bind directly to Nur77-binding response elements located within the regulatory region of these genes. Nur77-binding response element binding also resulted in the recruitment of transcriptional coactivators and induction of gene expression. Collectively, our findings suggest that NR4A2 plays a key role as a transcriptional integration point between the eicosanoid and fatty acid metabolic pathways. Thus, PGE(2) is a potential regulator of the adaptive shift to energy utilization via fatty acid oxidation that has been observed in several types of cancer.


Assuntos
Neoplasias Colorretais/metabolismo , Dinoprostona/metabolismo , Ácidos Graxos/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Neoplasias Colorretais/genética , Dinoprostona/genética , Metabolismo Energético/genética , Ácidos Graxos/genética , Humanos , Proteínas de Neoplasias/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Oxirredução
8.
Cancer Res ; 70(2): 824-31, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20068165

RESUMO

Prostaglandin E(2) (PGE(2)), one of the downstream products of cyclooxygenase-2 enzymatic activity, promotes colorectal carcinogenesis in part by stimulating cell division. In this study, we define a critical mechanism in this process by showing that the prometastatic adapter protein human enhancer of filamentation 1 (HEF1; NEDD9) links PGE(2) to the cell cycle machinery in colorectal cancer cells. PGE(2) rapidly induced expression of HEF1 mRNA and protein in colorectal cancer cells. HEF1 overexpression elicited the same effects as PGE(2) treatment on cell proliferation, cell cycle progression, and tumor growth. Conversely, HEF1 knockdown suppressed PGE(2)-driven cell proliferation and cell cycle progression. Cell cycle alterations involved HEF1 fragmentation as well as co-distribution of HEF1 and cell cycle kinase Aurora A along spindle asters during cell division. Moreover, Aurora A co-immunoprecipitated with HEF1 and was activated by HEF1. Consistent with a role for HEF1 in colorectal carcinogenesis, we found elevated expression of HEF1 expression in 50% of human colorectal cancers examined, relative to paired normal tissues. These findings establish that PGE(2) induces HEF1 expression, which in turn promotes cell cycle progression through its interaction with and activation of Aurora A. Further, they establish that HEF1 is a crucial downstream mediator of PGE(2) action during colorectal carcinogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dinoprostona/farmacologia , Fosfoproteínas/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Aurora Quinase A , Aurora Quinases , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Humanos , Camundongos , Camundongos Nus , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
9.
Cancer Res ; 68(22): 9331-7, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19010907

RESUMO

Prostaglandin E(2) (PGE(2)) promotes cancer progression by modulating proliferation, apoptosis, angiogenesis, and the immune response. Enzymatic degradation of PGE(2) involves the NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Recent reports have shown a marked diminution of 15-PGDH expression in colorectal carcinomas (CRC). We report here that treatment of CRC cells with histone deacetylase (HDAC) inhibitors, including sodium butyrate and valproic acid, induces 15-PGDH expression. Additionally, we show that pretreatment of CRC cells with HDAC inhibitors can block epidermal growth factor-mediated or Snail-mediated transcriptional repression of 15-PGDH. We show an interaction between Snail and HDAC2 and the binding of HDAC2 to the 15-PGDH promoter. In vivo, we observe increased Hdac2 expression in Apc-deficient mouse adenomas, which inversely correlated with loss of 15-Pgdh expression. Finally, in human colon cancers, elevated HDAC expression correlated with down-regulation of 15-PGDH. These data suggest that class I HDACs, specifically HDAC2, and the transcriptional repressor Snail play a central role in the suppression of 15-PGDH expression. These results also provide a cyclooxygenase-2-independent mechanism to explain increased PGE(2) levels that contribute to progression of CRC.


Assuntos
Neoplasias do Colo/enzimologia , Histona Desacetilases/fisiologia , Hidroxiprostaglandina Desidrogenases/genética , Proteínas Repressoras/fisiologia , Fatores de Transcrição/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Histona Desacetilase 2 , Inibidores de Histona Desacetilases , Histona Desacetilases/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Fatores de Transcrição da Família Snail
10.
Cancer Prev Res (Phila) ; 1(2): 93-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19138942

RESUMO

Prostaglandin E(2) (PGE(2)) promotes cancer progression by affecting cell proliferation, apoptosis, angiogenesis, and the immune response. It has been reported that PGE(2) is transported or passes through the cell membrane via prostaglandin-specific transporters including the prostaglandin transporter (PGT, an influx transporter) and the multidrug resistance-associated protein 4 (an efflux transporter). PGT can facilitate the removal of PGE(2) from the extracellular milieu by transporting it into the cell, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) then oxidizes PGE(2) into 15-keto PGE(2). We previously reported that 15-PGDH expression is reduced in most colorectal cancers, indicating the tumor suppressor role of this gene. In the present study, we show that PGT expression is also decreased (whereas multidrug resistance-associated protein 4 expression is elevated) in human colorectal cancer specimens (compared with expression in normal mucosa) and in colorectal cancer cell lines. Furthermore, we found that PGT expression decreased in premalignant adenomas in APC(min) mice and was partially restored (in human colorectal cancer cell lines) by treatment with a DNA demethylating agent or histone deacetylase inhibitor. Forced PGT overexpression in vitro dose dependently reduced extracellular PGE(2) levels and increased intracellular levels of its catabolic product 15-keto PGE(2). Our collective data suggest that the existing model to explain increased PGE(2) in colorectal neoplasia should be modified to include the novel mechanism of coordinated up- and down-regulation of genes involved in PGE(2) transport.


Assuntos
Adenoma/genética , Proteínas de Transporte/genética , Neoplasias Colorretais/genética , Dinoprostona/metabolismo , Regulação Neoplásica da Expressão Gênica , Adenoma/metabolismo , Animais , Proteínas de Transporte/metabolismo , Neoplasias Colorretais/metabolismo , Inativação Gênica/fisiologia , Genes APC , Humanos , Pólipos Intestinais/genética , Pólipos Intestinais/metabolismo , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Transfecção , Células Tumorais Cultivadas
11.
Cancer Res ; 66(13): 6649-56, 2006 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-16818638

RESUMO

Prostaglandin E(2) (PGE(2)), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE(2) is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE(2) catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE(2) to inhibit cancer progression.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dinoprostona/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Hidroxiprostaglandina Desidrogenases/biossíntese , Fatores de Transcrição/biossíntese , Animais , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Receptores ErbB/metabolismo , Células HCT116 , Células HT29 , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição da Família Snail , Fatores de Transcrição/genética , Transfecção
12.
J Clin Invest ; 116(6): 1696-702, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16691295

RESUMO

Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10-/- mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10-/- mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Hipertensão , Rim/metabolismo , Canais de Sódio/metabolismo , Sódio na Dieta , Amilorida/metabolismo , Animais , Ácidos Araquidônicos/química , Ácidos Araquidônicos/metabolismo , Pressão Sanguínea/fisiologia , Família 2 do Citocromo P450 , Eletrofisiologia , Canais Epiteliais de Sódio , Feminino , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pirimidinas/metabolismo , Sódio/metabolismo , Bloqueadores dos Canais de Sódio/metabolismo , Canais de Sódio/genética
13.
J Biol Chem ; 281(5): 2676-82, 2006 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-16293616

RESUMO

Many lines of research implicate cyclooxygenase 2-derived prostaglandins in tumor growth and metastasis. More specifically, we have shown that prostaglandin E2 (PGE2) promotes cell proliferation and invasion through transactivation of the epidermal growth factor receptor, initiates immune evasion through induction of decay accelerating factor, and transactivates peroxisome proliferator-activated receptor delta, leading to increased polyp size and multiplicity. We continue to identify novel PGE2 target genes in colorectal carcinoma cells and report here that an immediate early gene, nuclear factor NR4A2 (Nurr1), is induced by PGE2 that in turn regulates cell death. Originally described as a critical dopaminergic neuron growth factor receptor, NR4A2 expression is rapidly but transiently induced by PGE2 in a cAMP/protein kinase A-dependent manner. NR4A2 binds to the cognate NBRE response element and enhances transcription of a reporter construct in colorectal carcinoma cells. Furthermore, NR4A2 expression is elevated in Apc-/+ mouse adenomas and its levels were further increased following PGE2 treatment. Human colorectal cancers relative to matched normal mucosa showed increased NR4A2 expression. Although not previously described in epithelial tissues, NR4A2 protein localizes to proliferating crypts of Apc-/+ mouse intestine. Finally, functional studies reveal that PGE2-mediated protection from apoptosis is completely inhibited by a dominant-negative NR4A2 construct. Building on previous reports from our group on the peroxisome proliferator-activated receptor family of nuclear receptors, these most recent data suggest that NR4A2, a member of another family of nuclear receptors can stimulate progression of colorectal cancer downstream from cyclooxygenase 2-derived PGE2.


Assuntos
Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Dinoprostona/fisiologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Progressão da Doença , Humanos , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares , Transporte Proteico , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
14.
Proc Natl Acad Sci U S A ; 102(5): 1638-42, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15668389

RESUMO

The ability of the Ras oncogene to transform normal cells has been well established. One downstream effector of Ras is the lipid hydrolyzing enzyme phospholipase D. Recent evidence has emerged indicating a role for phospholipase D in cell proliferation, membrane trafficking, and migration. To study the potential importance of phospholipase D in the oncogenic ability of Ras, we used Rat-2 fibroblasts with reduced phospholipase D1 activity (Rat-2V25). Here, we show that H-Ras transformation of Rat-2 fibroblasts requires normal phospholipase D1 activity. WT Rat-2 fibroblasts transfected with the H-RasV12 oncogene grew colonies in soft agar and tumors in nude mice. However, Rat-2V25 cells when transfected with the H-RasV12 oncogene did not form colonies in soft agar or produce tumors when xenografted onto nude mice. Interestingly, in the presence of phosphatidic acid, the product of phospholipase D, growth in soft agar and tumor formation was restored. We also observed a dramatic increase in the expression of phospholipase D1 in colorectal tumors when compared with adjacent normal mucosa. Our studies identify phospholipase D1 as a critical downstream mediator of H-Ras-induced tumor formation.


Assuntos
Transformação Celular Neoplásica , Neoplasias Colorretais/patologia , Genes ras , Fosfolipase D/metabolismo , Animais , Linhagem Celular , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/cirurgia , Humanos , Mucosa Intestinal/enzimologia , Camundongos , Camundongos Nus , Ratos
15.
J Biol Chem ; 280(5): 3217-23, 2005 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-15542609

RESUMO

Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/fisiopatologia , Hidroxiprostaglandina Desidrogenases/genética , Hidroxiprostaglandina Desidrogenases/metabolismo , Animais , Colo/enzimologia , Ciclo-Oxigenase 2 , Dinoprostona/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Prostaglandina-Endoperóxido Sintases/metabolismo , Células Tumorais Cultivadas
16.
J Biol Chem ; 280(1): 476-83, 2005 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-15520008

RESUMO

Cyclooxygenase-derived prostaglandin E(2) (PGE(2)) stimulates tumor progression by modulating several proneoplastic pathways. The mechanisms by which PGE(2) promotes tumor growth and metastasis through stimulation of cell migration, invasion, and angiogenesis have been fairly well characterized. Much less is known, however, about the molecular mechanisms responsible for the immunosuppressive effects of PGE(2). We identified PGE(2) target genes and subsequently studied their biologic role in colorectal cancer cells. The complement regulatory protein decay-accelerating factor (DAF or CD55) was induced following PGE(2) treatment of LS174T colon cancer cells. Analysis of PGE(2)-mediated activation of the DAF promoter employing 5'-deletion luciferase constructs suggests that regulation occurs at the transcriptional level via a cyclic AMP/protein kinase A-dependent pathway. Nonsteroidal anti-inflammatory drugs blocked DAF expression in HCA-7 colon cancer cells, which could be restored by the addition of exogenous PGE(2). Finally, we observed an increase in DAF expression in the intestinal mucosa of Apc(Min+/-) mice treated with PGE(2) in vivo. In summary, these results indicate a novel immunosuppressive role for PGE(2) in the development of colorectal carcinomas.


Assuntos
Antígenos CD55/metabolismo , Neoplasias Colorretais/metabolismo , Dinoprostona/metabolismo , Regulação Neoplásica da Expressão Gênica , Animais , Antígenos CD55/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/etiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinoprostona/genética , Dinoprostona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Regiões Promotoras Genéticas , Deleção de Sequência , Transdução de Sinais , Ativação Transcricional/efeitos dos fármacos
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