Yoshitaka Sekido

Aichi Cancer Center, Nagoya, Aichi, Japan

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Publications (154)862.53 Total impact

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    ABSTRACT: Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKIs. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose to describe this phenomenon as "oncogene swap". Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKIs. This possibility should be considered in order to avoid futile inhibition of the original oncogene. This article is protected by copyright. All rights reserved.
    No preview · Article · Feb 2016 · Cancer Science
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    ABSTRACT: Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.
    Full-text · Article · Dec 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Background: Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of EGFR mutation on CRT efficacy. Methods: From 2006-2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting, and compared the clinical outcomes and recurrence patterns according to mutation status. Results: Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR-mutant and wild-type patients (72.4% vs. 72.0%, p=0.607). The median progression-free survival (PFS) in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95%CI: 7.6-19.0] vs. 16.5 [95%CI: 11.8-19.9] months, p=0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR-mutant and wild-type patients, respectively (p=0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% vs. 40%, p=0.001). The brain was the most commonly affected site in EGFR-mutant patients (35%). However, locoregional recurrence was less common in EGFR-mutant patients than in the wild-type population (14% vs. 35%, p=0.027). Overall survival (OS) was similar between EGFR-mutant and wild-type patients (51.1 [95%CI: 28.2-70.2] vs. 42.9 [95%CI: 35.3-NA] months, p=0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras-mutant patients had significantly worse OS than Kras wild-type patients (21.6 vs. 49.8 months, p=0.024). Conclusion: Concurrent CRT resulted in shorter PFS in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly due to distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-TKIs for EGFR-mutant, locally advanced adenocarcinoma patients receiving definitive CRT may be needed.
    No preview · Article · Sep 2015 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
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    ABSTRACT: The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM-Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas.
    No preview · Article · Jun 2015
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    ABSTRACT: Malignant mesothelioma (MM) shows inactivation of the BRCA1-associated protein 1 (BAP1) gene. In this study, we found BAP1 mutations in 5 (26%) of the 19 cell lines that we established from Japanese MM patients, and examined functional differences between the wild-type and mutant BAP1. First, we studied the subcellular localization of BAP1, demonstrating that the wild-type primarily resides in the nucleus and that the mutant BAP1 is found in the cytoplasm of the cells. Transduction of the wild-type BAP1 vector into MM cells with homozygous deletion (HD) at the BAP1 3' side resulted in both inhibition of cell proliferation and anchorage-independent cell growth, while BAP1 mutants of a missense or C-terminal truncated form showed impaired growth inhibitory effects. Next, we studied how BAP1 is involved in MM cell survival after irradiation (IR) which causes DNA damage. After IR, we found that both wild-type and mutant BAP1 were similarly phosphorylated and phospho-BAP1 localized mainly in the nucleus. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and that transduction of the mutants as well as wild-type BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through stabilizing BRCA1. Furthermore, using the MM cells with BAP1 deletion, we found that the wild-type, and even a missense mutant, BAP1 conferred a higher survival rate after IR compared to the control vector. Our results suggested that, while wild-type BAP1 suppresses MM cell proliferation and restores cell survival after IR-damage, some mutant BAP1 may also moderately retain these functions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Preview · Article · May 2015 · Cancer Science
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    ABSTRACT: Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.
    Preview · Article · Apr 2015 · PLoS ONE
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    ABSTRACT: Both pro- and anti-oncogenic roles of miR-221 and miR-222 microRNAs are reported in several types of human cancers. A previous study suggested their oncogenic role in invasiveness in lung cancer, albeit only one cell line (H460) was used. To further evaluate involvement of miR-221 and miR-222 in lung cancer, we investigated the effects of miR-221 and miR-222 overexpression on six lung cancer cell lines, including H460, as well as one immortalized normal human bronchial epithelial cell line, HBEC4. miR-221 and miR-222 induced epithelial-to-mesenchymal transition (EMT)-like changes in a minority of HBEC4 cells but, unexpectedly, both the microRNAs rather suppressed their invasiveness. Consistent with the prior report, miR-221 and miR-222 promoted growth in H460; however, miR-221 suppressed growth in four other cell lines with no effects in one, and miR-222 suppressed growth in three cell lines but promoted growth in two. These are the first results to show tumor-suppressive effects of miR-221 and miR-222 in lung cancer cells, and we focused on clarifying the mechanisms. Cell cycle and apoptosis analyses revealed that growth suppression by miR-221 and miR-222 occurred through intra-S-phase arrest and/or apoptosis. Finally, lung cancer cell lines transfected with miR-221 or miR-222 became more sensitive to the S-phase targeting drugs, possibly due to an increased S-phase population. In conclusion, our data are the first to show tumor-suppressive effects of miR-221 and miR-222 on lung cancer, warranting testing their potential as therapeutics for the disease.
    Preview · Article · Jan 2015 · Cancer Medicine

  • No preview · Article · Jan 2015 · Cancer Science
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive neoplasm that arises from the pleural, pericardial or peritoneal lining. Although surgery, chemotherapy, radiotherapy and combinations of these therapies are used to treat MPM, the median survival of such patients is dismal. Therefore, there is a compelling need to develop novel therapeutics with different modes of action. Ganglioside GM2 is a glycolipid that has been shown to be overexpressed in various types of cancer. However, there is currently no literature regarding the use of GM2 as a potential therapeutic target in cases of MPM. In this study, we evaluated the efficacy of the anti-GM2 antibody BIW-8962 as an anti-MPM therapeutic using in vitro and in vivo assays. Consequently, the GM2 expression in the MPM cell lines was confirmed using flow cytometry. In addition, eight of 11 cell lines were GM2-positive (73%), although the GM2 expression was variable. BIW-8962 showed a significant ADCC activity against the GM2-expressing MPM cell line MSTO-211H, the effect of which depended on the antibody concentration and effector/target ratio. In an in vivo orthotropic mouse model using MSTO-211H cells, BIW-8962 significantly decreased the incidence and size of tumors. Additionally, the GM2 expression was confirmed in the MPM clinical specimens. Fifty-eight percent of the MPM tumors were positive for GM2, with individual variation in the intensity and frequency of staining. These data suggest that anti-GM2 antibodies may become a therapeutic option for MPM patients This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Preview · Article · Nov 2014 · Cancer Science

  • No preview · Article · Nov 2014 · European Journal of Cancer
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    ABSTRACT: Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. Materials and methods: We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined. Results and conclusion: In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations.
    No preview · Article · Jun 2014 · Lung cancer (Amsterdam, Netherlands)
  • W Gao · Y Gu · Z Li · H Cai · Q Peng · M Tu · Y Kondo · K Shinjo · Y Zhu · J Zhang · Y Sekido · B Han · Z Qian · Y Miao
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis. Although microRNA (miRNA) transcripts have a crucial role in carcinogenesis and development, little information is known regarding the aberrant DNA methylation of miRNAs in PDAC. Using methylated DNA immunoprecipitation-chip analysis, we found that miR-615-5p was hypermethylated in its putative promoter region, which silenced its expression in PDAC cell lines. In addition, the overexpression of miR-615-5p in pancreatic cancer cells suppressed cell proliferation, migration and invasion. Insulin-like growth factor 2 (IGF2) is an imprinted gene, and its abnormal expression contributes to tumor growth. Here, we identified IGF2 as a target of miR-615-5p using a luciferase reporter assay. IGF2 upregulation in PDAC tissues was not correlated with a loss of imprinting but was inversely correlated with miR-615-5p downregulation. In addition, miR-615-5p suppressed pancreatic cancer cell proliferation, migration and invasion by directly targeting IGF2, and this effect could be reversed by co-transfection with IGF2. Furthermore, the stable overexpression of miR-615-5p inhibited tumor growth in vivo and was correlated with IGF2 expression. Using RNA sequencing, we further identified miR-615-5p as potentially targeting other genes, such as the proto-oncogene JUNB, and interfering with the insulin signaling pathway. Taken together, our results demonstrate that miR-615-5p was abnormally downregulated in PDAC cells due to promoter hypermethylation, which limited its inhibition of IGF2 and other target genes, thereby contributing to tumor growth, invasion and migration. These data demonstrate a novel and important role of miR-615-5p as a tumor suppressor in PDAC.Oncogene advance online publication, 28 April 2014; doi:10.1038/onc.2014.101.
    No preview · Article · Apr 2014 · Oncogene
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    ABSTRACT: The condensin complex is required for chromosome condensation during mitosis; however, the role of this complex during interphase is unclear. Neuroblastoma is the most common extracranial solid tumor of childhood, and it is often lethal. In human neuroblastoma, MYCN gene amplification is correlated with poor prognosis. This study demonstrates that the gene encoding the condensin complex subunit SMC2 is transcriptionally regulated by MYCN. SMC2 also transcriptionally regulates DNA damage response genes in cooperation with MYCN. Downregulation of SMC2 induced DNA damage and showed a synergistic lethal response in MYCN-amplified/overexpression cells, leading to apoptosis in human neuroblastoma cells. Finally, this study found that patients bearing MYCN-amplified tumors showed improved survival when SMC2 expression was low. These results identify novel functions of SMC2 in DNA damage response, and we propose that SMC2 (or the condensin complex) is a novel molecular target for the treatment of MYCN-amplified neuroblastoma.
    Preview · Article · Feb 2014 · Cell cycle (Georgetown, Tex.)
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    ABSTRACT: Objectives Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790 M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. Materials and Methods We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined. Results and Conclusion In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations.
    No preview · Article · Jan 2014
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    ABSTRACT: Malignant mesothelioma (MM) is one of the most aggressive neoplasms usually associated with asbestos exposure and is highly refractory to current therapeutic modalities. MMs show frequent activation of a transcriptional coactivator Yes-associated protein (YAP), which is attributed to the neurofibromatosis type 2 (NF2)-Hippo pathway dysfunction, leading to deregulated cell proliferation and acquisition of a malignant phenotype. However, the whole mechanism of disordered YAP activation in MMs has not yet been well clarified. In the present study, we investigated various components of the NF2-Hippo pathway, and eventually found that MM cells frequently showed downregulation of LIM-domain protein AJUBA, a binding partner of large tumor suppressor type 2 (LATS2), which is one of the last-step kinases of the NF2-Hippo pathway. Although loss of AJUBA expression was independent of the alteration status of other Hippo pathway components, MM cell lines with AJUBA inactivation showed a more dephosphorylated (activated) level of YAP. Immunohistochemical analysis showed frequent downregulation of AJUBA in primary MMs, which was associated with YAP constitutive activation. We found that AJUBA transduction into MM cells significantly suppressed promoter activities of YAP-target genes, and the suppression of YAP activity by AJUBA was remarkably canceled by knockdown of LATS2. In connection with these results, transduction of AJUBA-expressing lentivirus significantly inhibited the proliferation and anchorage-independent growth of the MM cells that harbored ordinary LATS family expression. Taken together, our findings indicate that AJUBA negatively regulates YAP activity through the LATS family, and inactivation of AJUBA is a novel key mechanism in MM cell proliferation.Oncogene advance online publication, 16 December 2013; doi:10.1038/onc.2013.528.
    Preview · Article · Dec 2013 · Oncogene
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    ABSTRACT: Ras-Association Family1A (RASSF1A) is a well-established tumor suppressor. Ten RASSF homologues comprise this family, and each member is considered a tumor suppressor. RASSF3 is one of the RASSF family members, but its function has not yet been clarified. Recently, we found that RASSF3 interacts with MDM2 and facilitates its ubiquitination, which induces apoptosis through p53 stabilization. However, the role of RASSF3 in human malignancies remains largely unknown. Ninety-five non-small cell lung cancer (NSCLC) patients from Nagoya University Hospital and 45 NSCLC patients from Aichi Cancer Center Hospital underwent pulmonary resection at each hospital, and lung cancer and corresponding non-cancerous lung tissues were collected. The expression levels of RASSF3 were analyzed using quantitative real-time reverse transcription PCR. We performed statistical analysis to investigate the correlation with RASSF3 expression and the clinicopathological characteristics. We also transfected RASSF3-siRNA into NSCLC cells, and performed motility assays to evaluate the influence on migration ability. RASSF3 expression levels were downregulated in 125 of a total 140 NSCLCs. In a multivariate logistic regression analysis, the low RASSF3 expression group below the median value was independently correlated with progressive phenotypes (lymph node metastasis and pleural invasion), non-adenocarcinoma histology and wild-type epidermal growth factor receptor (EGFR) status. In motility assays, RASSF3-knockdown NSCLC cells increased the migration rate compared to the control cells. We found that the expression levels of RASSF3 were frequently downregulated in NSCLCs. Downregulation of RASSF3 strongly correlated with the progressive phenotypes of NSCLCs and EGFR wild-type status. In vitro studies also suggested that RASSF3 downregulation increases migration ability of lung cancer cells. Together, our findings indicate RASSF3 is a candidate tumor suppressor gene of NSCLCs.
    No preview · Article · Oct 2013 · Lung cancer (Amsterdam, Netherlands)
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    ABSTRACT: Cells of tumors associated with chronic inflammation frequently have altered patterns of DNA methylation, including hepatocellular carcinomas (HCCs). Chronic hepatitis has also been associated with aberrant DNA methylation, but little is known about their relationship. Pyrosequencing was used to determine the methylation status of cultured Huh7.5.1 hepatoma cells following hepatitis C virus (HCV) infection. We also studied mice with severe combined immunodeficiency carrying the urokinase-type plasminogen activator transgene controlled by an albumin promoter (uPA/SCID mice), in which up to 85% of hepatocytes were replaced by human hepatocytes (chimeric mice). Mice were given intravenous injections of hepatitis B virus (HBV) or HCV; liver tissues were collected and DNA methylation profiles were determined at different time points after infection. We also compared methylation patterns between paired samples of HCC and adjacent non-tumor liver tissues from patients. No reproducible changes in DNA methylation were observed following infection of Huh7.5.1 cells with HCV. Livers from HBV- and HCV-infected mice had genome-wide, time-dependent changes in DNA methylation, compared with uninfected uPA/SCID mice. There were changes in 160±63 genes in HBV-infected and 237±110 genes in HCV-infected mice. Methylation of 149 common genes increased in HBV- and HCV-infected mice; methylation of some of these genes also increased in HCC samples from patients, compared with non-tumor tissues. Expression of Ifng, which is expressed by natural killer (NK) cells, increased significantly in chimeric livers, in concordance with induction of DNA methylation, after infection with HBV or HCV. Induction of Ifng was reduced following administration of an inhibitor of NK cell function (anti-asialo GM1). In chimeric mice with humanized livers, infection with HBV and HCV appear to activate an NK cell-dependent innate immune response. This contributes to the induction and accumulation of aberrant DNA methylation in human hepatocytes.
    Full-text · Article · Oct 2013 · Gastroenterology
  • Ichidai Tanaka · Hirotaka Osada · Makiko Fujii · Yoshitaka Sekido

    No preview · Article · Aug 2013 · Cancer Research
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    ABSTRACT: Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse-transcription PCR revealed that adipocytes respond directly to asbestos exposure with an increased production of pro-inflammatory adipocytokines (e.g. MCP-1) while the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a pro-inflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.
    Full-text · Article · Aug 2013 · Carcinogenesis
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    ABSTRACT: Tumor cell plasticity contributes to functional and morphological heterogeneity. To uncover the underlying mechanisms of this plasticity, we examined glioma stem-like cells (GSC) where we found that the biological interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of PRC2, a complex that modifies chromatin structure. PRC2 mediates lysine 27 trimethylation on histone H3 and in GSC it affected pluripotency or development associated genes (e.g. Nanog, Wnt1, BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. Intriguingly, exogenous expression of EZH2-dNLS, which lacks nuclear localization sequence, impaired the repression of Nanog expression under differentiation conditions. RNAi-mediated attenuation or pharmacological inhibition of EZH2 had little to no effect on apoptosis or BrdU incorporation in GSCs, but it disrupted morphological interconversion and impaired GSC integration into the brain tissue, thereby improving survival of GSC-bearing mice. Pathological analysis of human glioma specimens revealed that the number of tumor cells with nuclear EZH2 is larger around tumor vessels and the invasive front, suggesting that nuclear EZH2 may help reprogram tumor cells in close proximity to this microenvironment. Our results indicate that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of glioblastoma cells to their microenvironment. Thus, PRC2-targeted therapy may reduce tumor cell plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment.
    Full-text · Article · May 2013 · Cancer Research

Publication Stats

7k Citations
862.53 Total Impact Points

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Institutions

  • 2002-2015
    • Aichi Cancer Center
      Nagoya, Aichi, Japan
    • University of Birmingham
      Birmingham, England, United Kingdom
  • 2001-2015
    • Nagoya University
      • • Division of of Internal Medicine
      • • Department of Preventive Medicine
      Nagoya, Aichi, Japan
  • 2013
    • Nagoya City University
      Nagoya, Aichi, Japan
  • 2011
    • Okayama University
      Okayama, Okayama, Japan
  • 1998-2000
    • University of Texas at Dallas
      Richardson, Texas, United States
    • University of North Texas at Dallas
      Dallas, Texas, United States
  • 1997-1998
    • University of Texas Southwestern Medical Center
      • Hamon Center for Therapeutic Oncology Research
      Dallas, Texas, United States