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  • American Association for Cancer Research (AACR)  (4)
  • Hirata, Yoshihiro  (4)
  • Medicine  (4)
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  • American Association for Cancer Research (AACR)  (4)
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  • Medicine  (4)
RVK
  • 1
    Online Resource
    Online Resource
    Abstract 2740: The role of JNK in the development of pancreatic cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2740-2740
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2740-2740
    Abstract: C-Jun NH2-terminal kinase (JNK) is a member of mitogen-activated protein kinase (MAPK) family, and it is known to regulate a variety of cellular activities including apoptosis, survival, differentiation, and proliferation. Recently, it has been suggested that JNK is involved in the development of several cancers, but the role of JNK in pancreatic cancer is not fully elucidated. In this study, we examined the role of JNK in the development of pancreatic cancer and evaluated the therapeutic effect of JNK inhibition on pancreatic cancer. In immunohistochemical staining, JNK activation was observed in human pancreatic cancer specimens. Growth of pancreatic cancer cell lines was inhibited by treatment with JNK inhibitor SP600125 or by transfection of siRNAs against JNK1 or JNK2. Expression of cyclin D1 in pancreatic cancer cells was decreased by JNK inhibition, and cell cycle analysis showed accumulation of cells in G0/G1 phase by JNK1 and JNK2 inhibition. Induction of oncogenic Ras into pancreatic cancer cells promoted JNK activation, and KRAS knockdown by siRNA decreased phosphorylation of JNK. Cyclin D1 expression was shown to be regulated through JNK activation by luciferase assay and real-time RT-PCR. Pancreas-specific KrasG12D expression and type II TGFβreceptor knockout mice (KrasG12D+Tgfbr2KO mice) was used as a mouse model of pancreatic cancer, and pancreatic cancer developed in KrasG12D+Tgfbr2KO mice showed higher activation of JNK than PanIN tissue of KrasG12D mice or normal pancreas of wild-type mice. Treating KrasG12D+Tgfbr2KO mice with JNK inhibitor for 4 weeks led to less progression of pancreatic cancer, and immunohistochemical staining showed reduced expression of phosphorylated JNK, c-jun, cyclin D1 and PCNA in the pancreatic cancer tissues compared to control vehicle. The survival time of KrasG12D+Tgfbr2KO mice was significantly prolonged by SP600125 treatment. Decreased number of blood vessels was observed in pancreatic cancer tissue of KrasG12D+Tgfbr2KO mice treated by SP600125. Secretion of angiogenic cytokines from pancreatic cancer cell lines was decreased by JNK inhibition, and angiogenesis by HUVEC was inhibited by incubating in the conditioned medium of pancreatic cancer cells treated by SP600125 or transfected with siRNAs against JNK1 or JNK2, indicating the effect of JNK inhibition on tumor angiogenesis. These data indicate that oncogenic K-ras activates JNK JNK is involved in the development of pancreatic cancer through the regulation of cell cycle and tumor angiogenesis. Inhibiting JNK may be a potential therapy for pancreatic cancer. Citation Format: Ryota Takahashi, Yoshihiro Hirata, Kosuke Sakitani, Wachiko Nakata, Hiroto Kinoshita, Yoku Hayakawa, Hayato Nakagawa, Hideaki Ijichi, Shin Maeda, Kazuhiko Koike. The role of JNK in the development of pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2740. doi:10.1158/1538-7445.AM2013-2740
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2740
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 2065: DDX20 deficiency enhances NF-κB by impairing NF-κB suppressive-microRNA function and leads to hepatocarcinogenesis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2065-2065
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2065-2065
    Abstract: Hepatocellular carcinoma is the third leading cause of cancer mortality worldwide, but the molecular mechanisms in tumorigenesis remain largely unknown. Here, we show that DDX20, a DEAD-box protein identified as a tumor suppressor in a recent comprehensive in vivo screening of murine liver cancer, might have a role in human hepatocellular oncogenesis through previously undefined mechanisms. DDX20 expression was frequently decreased in hepatocellular carcinoma cells compared with the hepatocytes in the noncancerous liver tissues from the same patient, as determined by immunohistochemistry using tissue arrays. DDX20-knockdown cells showed enhanced NF-κB activity and higher interleukin-6 expression, a cytokine known to be related to hepatocarcinogenesis. Our microRNA library screening revealed that several microRNAs expressed in hepatocytes, such as miR-140, normally suppress NF-κB activities. The deficiency of DDX20, a component of microRNA-containing ribonucleoprotein complexes, impaired microRNA function and this led to the impairment of the NF-κB-suppressive microRNA function, and consequently, enhanced NF-κB activity. These results indicate that DDX20 deficiency enhances NF-κB activity by impairing NF-κB-suppressive microRNA function and may contribute to hepatocarcinogenesis. “Functional impairment of microRNAs” identified here, induced by aberrant expression or functional abnormalities of the molecules involved in the microRNA pathway, may also be one of the mechanisms of oncogenesis even in other organs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2065.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-2065
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Abstract 3978: DDX20, a suppressor of hepatocarcinogenesis, controls NF-κB activity through regulating the function of miRNA-22 and miRNA-140-3p targeting transcriptional coactivators
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3978-3978
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3978-3978
    Abstract: MiRNA expression profile of human cancers has been characterized by an overall miRNA downregulation. While the causes include a transcriptional silencing and a failure of miRNA maturation, another possibility is that the deregulation of the machinery components for executing miRNA function also may cause similar consequences. Then, we screened the protein expression levels of the established members of the miRNA-containing ribonucleoproteins (Dicer, Ago2, TRBP2, DDX20 also known as Gemin3, and Gemin4) in various organ cancers by immunohisotchemistry. We detected reduced expression of DDX20 only in hepatocellular carcinoma tissues, while the levels of other genes were not drastically changed. We show that DDX20 suppresses NF-κB activity through regulating a subset of miRNA function. A microRNA library screen revealed that miR-140-3p and miR-22 suppress NF-κB activation by targeting the expression of NRIP1 and NCOA1, both are coactivators of NF-κB. However, in DDX20 deficient cells, this suppressive effect was lost, leading to NF-κB activation, a key regulator of hepatocarcinogenesis. In addition, DDX20 knockdown indeed induced cell transformation, revealed by a sphere-forming assay. These results indicate that DDX20 deficiency enhances NF-κB activity by impairing the NF-κB-suppressive action of microRNAs, and suggest that deregulation of the microRNA machinery may be one of the mechanisms of oncogenesis in liver cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3978. doi:10.1158/1538-7445.AM2011-3978
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3978
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Abstract 3133: Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3133-3133
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3133-3133
    Abstract: Gastric cancer is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established. Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and have been demonstrated to be highly active in many types of human cancers, and we have previously reported that c-Jun-N-terminal kinase 1 (JNK1) is important for gastric tumorigenesis. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK known to be involved in apoptosis, inflammation, and carcinogenesis. In the current study, we investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression compared to non-tumor epithelium, while we found no difference between colon cancer and non-tumor colon epithelium. Using the chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice displayed both a lower number and smaller tumor size compared to wild-type mice. In gastric cancer cell lines, immunoprecipitation analysis revealed constitutive ASK1 activation in several cell lines. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, while these effects were uncommon in other cancer cells, suggesting that the ASK1-dependent regulation of the cyclin D1 level and cellular proliferation is specific to gastric cancer. Overexpression of ASK1 induced the transcription of cyclin D1 through AP-1 activation in a kinase-dependent manner. In addition, we found that the expression of ASK1 was elevated following epidermal growth factor (EGF) or Helicobacter pylori (H.pylori) treatment in control cells but not in cyclin D1 silencing cells. Overexpression of cyclin D1 enhanced phosphorylation of Rb, followed by the increase in ASK1 expression. Chromatin immunoprecipitation (ChIP) assay showed that cyclin D1 expression increase E2F1 binding to ASK1 promoter, suggesting that the levels of ASK1 were regulated by cyclin D1 through the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by an elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Through targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3133. doi:10.1158/1538-7445.AM2011-3133
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-3133
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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