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1.
Kobe J Med Sci ; 64(6): E200-E209, 2019 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31327863

RESUMO

Mammalian target of rapamycin complex 1 (mTORC1), a protein complex containing the serine/threonine kinase mTOR, integrates various growth stimulating signals. mTORC1 is expressed in intestinal epithelial cells (IECs), whereas the physiological roles of this protein complex in homeostasis of IECs remain virtually unknown. We here generated mice, in which tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, was specifically ablated in IECs (Tsc2 CKO mice). Ablation of Tsc2 enhanced the phosphorylation of mTORC1 downstream molecules such as ribosomal S6 protein and 4E-BP1 in IECs. Tsc2 CKO mice manifested the enhanced proliferative activity of IECs in intestinal crypts as well as the promoted migration of these cells along the crypt-villus axis. The mutant mice also manifested the increased apoptotic rate of IECs as well as the increased ectopic Paneth cells, which are one of the major differentiated IECs. In addition, in vitro study showed that ablation of Tsc2 promoted the development of intestinal organoids without epidermal growth factor, while mTORC1 inhibitor, rapamycin, diminished this phenotype. Our results thus suggest that Tsc2-mTORC1 signaling regulates the proliferation, migration, and positioning of IECs, and thereby contributes to the proper regulation of intestinal homeostasis.

2.
Gan To Kagaku Ryoho ; 46(4): 655-671, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164504

RESUMO

On 5 September 2018 the UICC-Asia Regional Office(UICC-ARO)convened the second Japan Public-Private Dialogue Forum at the House of Councilors Members' Building as a follow-up to the previous meeting held at United Nations University in Tokyo in April 2018. Senior representatives of government, academia and industry met to discuss the progress made since April, noting the significance of the Japanese government having included specific reference to cancer in its revised basic policy on the Asia Health and Wellbeing Initiative, which was adopted in July 2018. The meeting provided an opportunity for all stakeholders to discuss ways forward for improving access to cancer care, with the WHO Cancer Report and other global initiatives in mind.


Assuntos
Neoplasias , Cobertura Universal do Seguro de Saúde , Ásia , Humanos , Japão , Neoplasias/terapia , Tóquio
3.
5.
Cancer Sci ; 110(4): 1293-1305, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30724425

RESUMO

Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation, demonstrating that the IFN/STAT pathway is causally associated with the tumor-forming potential of APC-deficient tumors. Mechanistically, STAT1 is downstream target of KRAS and is phosphorylated by its activating mutations. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the stratification of CRC patients.


Assuntos
Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Interferons/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos , Modelos Biológicos , Organoides , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Sci ; 110(4): 1352-1363, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30771244

RESUMO

Gastric cancer in young adults has been pointed out to comprise a subgroup associated with distinctive clinicopathological features, including an equal gender distribution, advanced disease, and diffuse-type histology. Comprehensive molecular analyses of gastric cancers have led to molecular-based classifications and to specific and effective treatment options. The molecular traits of gastric cancers in young adults await investigations, which should provide a clue to explore therapeutic strategies. Here, we studied 146 gastric cancer patients diagnosed at the age of 40 years or younger at the Cancer Institute Hospital (Tokyo, Japan). Tumor specimens were examined for Helicobacter pylori infection, Epstein-Barr virus positivity, and for the expression of mismatch repair genes to indicate microsatellite instability. Overexpression, gene amplifications, and rearrangements of 18 candidate driver genes were examined by immunohistochemistry and FISH. Although only a small number of cases were positive for Epstein-Barr virus and microsatellite instability (n = 2 each), we repeatedly found tumors with gene fusion between a tight-junction protein claudin, CLDN18, and a regulator of small G proteins, ARHGAP, in as many as 22 cases (15.1%), and RNA sequencing identified 2 novel types of the fusion. Notably, patients with the CLDN18-ARHGAP fusion revealed associations between aggressive disease and poor prognosis, even when grouped by their clinical stage. These observations indicate that a fusion gene between CLDN18 and ARHGAP is enriched in younger age-onset gastric cancers, and its presence could contribute to their aggressive characteristics.


Assuntos
Claudinas/genética , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Fusão Oncogênica/genética , Neoplasias Gástricas/etiologia , Adolescente , Adulto , Feminino , Amplificação de Genes , Perfilação da Expressão Gênica , Infecções por Helicobacter/complicações , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Análise de Sequência de DNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Adulto Jovem
7.
Cancer Med ; 8(1): 408-417, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30575318

RESUMO

Because circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance, the development of cell-free DNA (cfDNA) panel covering hundreds of mutation hot spots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon-based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next-generation sequencing (NGS) was carried out to evaluate the feasibility of this assay and was compared with their clinical parameters and RAS status in matched tissue samples. Somatic mutations of the 14 genes in plasma cfDNA were detected in 88 patients (87.1%) with mCRC. Mutations in TP53, KRAS, and APC genes were detected in 70 (69.3%), 39 (38.6%), and 24 (23.7%) patients, respectively. Mutant allele frequencies in plasma were significantly associated with metastasis (liver, P = 0.00004, lymph node, P = 0.008, number of metastatic organs, P = 0.0006), tumor markers (CEA, P = 0.000007, CA19-9, P = 0.006, LDH, P = 0.00001), and tumor diameter (maximum, P = 0.00002, sum of diameter, P = 0.00009). The overall concordance rate of RAS status between ctDNA and matched tissue was 77.2% (78/101). Our data confirmed that mutant allele in cfDNA can be sensitively detected by amplicon-based NGS system. These results suggest that ctDNA could be a novel diagnostic biomarker to monitor changes in mutational status and tumor burden in patients with mCRC.

8.
Sci Rep ; 8(1): 15858, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30374020

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

9.
Nat Immunol ; 19(12): 1391-1402, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374130

RESUMO

Foxp3+ regulatory T cells (Treg cells) are the central component of peripheral immune tolerance. Whereas a dysregulated Treg cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-γ and IL-10 as a shared Treg signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human Treg subpopulations revealed ß-catenin as a key regulator of IFN-γ and IL-10 expression. The activated ß-catenin signature was enriched in human IFN-γ+ Treg cells, as confirmed in vivo with Treg-specific ß-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional Treg phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a high-salt environment, with skewed activation of the ß-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-ß-catenin loop in Treg cells linking environmental high-salt conditions to autoimmunity.

10.
Gan To Kagaku Ryoho ; 45(9): 1259-1277, 2018 Sep.
Artigo em Japonês | MEDLINE | ID: mdl-30237367

RESUMO

UICC-Asia Regional Office(UICC-ARO)successfully convened a fruitful Multi-stakeholder Dialogue at United Nations University in Aoyama, Tokyo, which brought together parliamentarians, representatives ofthe WHO and Japanese government agencies and NGOs, senior executives ofpharmaceutical and other companies, and leading members ofJapan 's cancer research community. This meeting provided a valuable opportunity for stakeholders from all sectors of society to discuss ways in which Japan can develop a multi-sectoral approach that will promote access to cancer care and support initiatives for UHC for cancer in Asia. UICC-ARO Director Hideyuki Akaza and Haruhiko Hirate(Chair of International Affairs Committee, JPMA) co-chaired the meeting. At the outset it was noted that with cancer now firmly on the global health agenda with the adoption ofthe WHA Cancer Resolution, countries around the world are coming to grips with the necessity for concerted and cooperative action on cancer prevention and control. This dialogue marks the first step in efforts to pool resources and information, and noted that with various key international meetings due to be held in 2018 and 2019, now was the time to coalesce opinions and identify a concrete direction for action.

11.
BMC Med Ethics ; 19(1): 61, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29914459

RESUMO

BACKGROUND: Platforms for sharing genomic and phenotype data have been developed to promote genomic research, while maximizing the utility of existing datasets and minimizing the burden on participants. The value of genomic analysis of trios or family members has increased, especially in rare diseases and cancers. This article aims to argue the necessity of protection when sharing data from both patients and family members. MAIN TEXT: Sharing patients' and family members' data collectively raises an ethical tension between the value of datasets and the rights of participants, and increases the risk of re-identification. However, current data-sharing policies have no specific safeguards or provisions for familial data sharing. A quantitative survey conducted on 10,881 general adults in Japan indicated that they expected stronger protection mechanisms when their family members' clinical and/or genomic data were shared together, as compared to when only their data were shared. A framework that respects decision-making and the right of withdrawal of participants, including family members, along with ensuring usefulness and security of data is needed. To enable this, we propose recommendations on ancillary safeguards for familial data sharing according to the stakeholders, namely, initial researchers, genomic researchers, data submitters, database operators, institutional review boards, and the public and participants. CONCLUSIONS: Families have played significant roles in genetic research, and its value is re-illuminated in the era of genomic medicine. It is important to make progress in data sharing while simultaneously protecting the privacy and interests of patients and families, and return its benefits to them.

12.
Oncotarget ; 9(28): 19555-19568, 2018 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-29731965

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a TP53 mutation and 17p deletion. Sixteen mutations were identified in OSBPL10 in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, TP53 mutations and TP53 deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. OSBPL10 mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups-OSBPL10 mutation (best prognosis), the coexistence of both TP53 mutation and TP53 deletion (poorest prognosis), and others. In this study, the presence of both TP53 mutation and 17p/TP53 deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified OSBPL10 mutation as a marker for patients with excellent prognosis in the R-CHOP era.

13.
Cell Discov ; 4: 1, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29423269

RESUMO

The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through modulating the Rab GTPase-regulated process. TUFT1 promoted tumor growth and metastasis. Consistently, the expression of TUFT1 correlated with poor prognosis in lung, breast and gastric cancers. Mechanistically, TUFT1 physically interacted with RABGAP1, thereby modulating intracellular lysosomal positioning and vesicular trafficking, and promoted mTORC1 signaling. In addition, expression of TUFT1 predicted sensitivity to perifosine, an alkylphospholipid that alters the composition of lipid rafts. Perifosine treatment altered the positioning and trafficking of cellular compartments to inhibit mTORC1. Our observations indicate that TUFT1 is a key regulator of the mTORC1 pathway and suggest that it is a promising therapeutic target or a biomarker for tumor progression.

14.
Stem Cell Reports ; 7(6): 1023-1036, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27840044

RESUMO

Mutation of the Gap Junction Beta 2 gene (GJB2) encoding connexin 26 (CX26) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss cases in some populations. Therefore, cochlear CX26-gap junction plaque (GJP)-forming cells such as cochlear supporting cells are thought to be the most important therapeutic target for the treatment of hereditary deafness. The differentiation of pluripotent stem cells into cochlear CX26-GJP-forming cells has not been reported. Here, we detail the development of a novel strategy to differentiate induced pluripotent stem cells into functional CX26-GJP-forming cells that exhibit spontaneous ATP- and hemichannel-mediated Ca2+ transients typical of the developing cochlea. Furthermore, these cells from CX26-deficient mice recapitulated the drastic disruption of GJPs, the primary pathology of GJB2-related hearing loss. These in vitro models should be useful for establishing inner-ear cell therapies and drug screening that target GJB2-related hearing loss.


Assuntos
Cálcio/metabolismo , Cóclea/embriologia , Cóclea/metabolismo , Conexina 26/metabolismo , Junções Comunicantes/metabolismo , Perda Auditiva/metabolismo , Modelos Biológicos , Animais , Células Cultivadas , Ectoderma/metabolismo , Espaço Extracelular/metabolismo , Junções Comunicantes/ultraestrutura , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Agregados Proteicos , Fatores de Transcrição/metabolismo
15.
Nat Commun ; 7: 12977, 2016 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-27708333

RESUMO

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as 'selective insulin resistance'. Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop 'selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop 'total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that 'selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.


Assuntos
Antígenos CD/metabolismo , Diabetes Mellitus/metabolismo , Resistência à Insulina , Fígado/metabolismo , Obesidade/metabolismo , Receptor de Insulina/metabolismo , Animais , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/metabolismo , Gluconeogênese , Homeostase , Humanos , Hiperinsulinismo/metabolismo , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais
16.
Sci Rep ; 6: 32849, 2016 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-27618981

RESUMO

Deoxyinosine (dI) occurs in DNA either by oxidative deamination of a previously incorporated deoxyadenosine residue or by misincorporation of deoxyinosine triphosphate (dITP) from the nucleotide pool during replication. To exclude dITP from the pool, mammals possess specific hydrolysing enzymes, such as inosine triphosphatase (ITPA). Previous studies have shown that deficiency in ITPA results in cell growth suppression and DNA instability. To explore the mechanisms of these phenotypes, we analysed ITPA-deficient human and mouse cells. We found that both growth suppression and accumulation of single-strand breaks in nuclear DNA of ITPA-deficient cells depended on MLH1/PMS2. The cell growth suppression of ITPA-deficient cells also depended on p53, but not on MPG, ENDOV or MSH2. ITPA deficiency significantly increased the levels of p53 protein and p21 mRNA/protein, a well-known target of p53, in an MLH1-dependent manner. Furthermore, MLH1 may also contribute to cell growth arrest by increasing the basal level of p53 activity.


Assuntos
Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Instabilidade Genômica/genética , Inosina/metabolismo , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Pirofosfatases/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , DNA/metabolismo , Células HCT116 , Células HeLa , Humanos , Inosina/análise , Nucleotídeos de Inosina/metabolismo , Camundongos , Camundongos Knockout , Pirofosfatases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética
17.
Biochem Biophys Res Commun ; 476(4): 175-182, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27131742

RESUMO

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1-4] and humans to Darier disease (DD) [14-17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells of any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca(2+)-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Células Epiteliais/patologia , Mutação , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Alelos , Animais , Carcinoma de Células Escamosas/metabolismo , Regulação Neoplásica da Expressão Gênica , Perda de Heterozigosidade , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Conformação Proteica , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo
18.
Sci Rep ; 6: 25009, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27146149

RESUMO

Activation of ß-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/ß-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of ß-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of ß-catenin, which activates Wnt/ß-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/ß-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/ß-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.


Assuntos
Células Endoteliais/fisiologia , Receptores ErbB/antagonistas & inibidores , Insuficiência Cardíaca/fisiopatologia , Neuregulina-1/antagonistas & inibidores , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Modelos Animais de Doenças , Camundongos , Análise de Sobrevida
19.
Carcinogenesis ; 37(5): 452-60, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26964870

RESUMO

ROS1-fusion genes, resulting from chromosomal rearrangement, have been reported in 1-2% of human non-small cell lung cancer cases. More than 10 distinct ROS1-fusion genes, including break-point variants, have been identified to date. In this study, to investigate the in vivo oncogenic activities of one of the most frequently detected fusions, CD74-ROS1, as well as another SDC4-ROS1 fusion that has also been reported in several studies, we generated transgenic (TG) mouse strains that express either of the two ROS1-fusion genes specifically in lung alveolar type II cells. Mice in all TG lines developed tumorigenic nodules in the lung, and a few strains of both TG mouse lines demonstrated early-onset nodule development (multiple tumor lesions present in the lung at 2-4 weeks after birth); therefore, these two strains were selected for further investigation. Tumors developed progressively in the untreated TG mice of both lines, whereas those receiving oral administration of an ALK/MET/ROS1 inhibitor, crizotinib, and an ALK/ROS1 inhibitor, ASP3026, showed marked reduction in the tumor burden. Collectively, these data suggest that each of these two ROS1-fusion genes acts as a driver for the pathogenesis of lung adenocarcinoma in vivo The TG mice developed in this study are expected to serve as valuable tools for exploring novel therapeutic agents against ROS1-fusion-positive lung cancer.


Assuntos
Neoplasias Hepáticas Experimentais/genética , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adenoma/genética , Adenoma/patologia , Administração Oral , Animais , Antígenos de Diferenciação de Linfócitos B/genética , Crizotinibe , Fusão Gênica , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazóis/farmacologia , Piridinas/farmacologia , Sulfonas/farmacologia , Sindecana-4/genética , Triazinas/farmacologia
20.
J Biol Chem ; 291(12): 6316-30, 2016 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-26786103

RESUMO

B lymphocyte-induced maturation protein 1 (Blimp-1) encoded by Prdm1 is a master regulator of plasma cell differentiation. The transcription factor Bach2 represses Blimp-1 expression in B cells to stall terminal differentiation, by which it supports reactions such as class switch recombination of the antibody genes. We found that histones H3 and H4 around the Prdm1 intron 5 Maf recognition element were acetylated at higher levels in X63/0 plasma cells expressing Blimp-1 than in BAL17 mature B cells lacking its expression. Conversely, methylation of H3-K9 was lower in X63/0 cells than BAL17 cells. Purification of the Bach2 complex in BAL17 cells revealed its interaction with histone deacetylase 3 (HDAC3), nuclear co-repressors NCoR1 and NCoR2, transducin ß-like 1X-linked (Tbl1x), and RAP1-interacting factor homolog (Rif1). Chromatin immunoprecipitation confirmed the binding of HDAC3 and Rif1 to the Prdm1 locus. Reduction of HDAC3 or NCoR1 expression by RNA interference in B cells resulted in an increased Prdm1 mRNA expression. Bach2 is suggested to cooperate with HDAC3-containing co-repressor complexes in B cells to regulate the stage-specific expression of Prdm1 by writing epigenetic modifications at the Prdm1 locus.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/fisiologia , Inativação Gênica , Histona Desacetilases/fisiologia , Fatores de Transcrição/genética , Acetilação , Animais , Linfócitos B , Linhagem Celular Tumoral , Epigênese Genética , Células HEK293 , Histonas/metabolismo , Humanos , Camundongos , Correpressor 1 de Receptor Nuclear/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a Telômeros/metabolismo , Fatores de Transcrição/metabolismo
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