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  • American Association for Cancer Research (AACR)  (39)
  • 1
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    Abstract 3158: DLL3 regulates migration and invasion of small cell lung cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3158-3158
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3158-3158
    Abstract: Background: Delta-like protein 3 (DLL3) is a ligand of Notch signaling, which is reported to be a tumor suppressor in small cell lung cancer (SCLC). Previous studies suggest that DLL3 might be associated with neuroendocrine tumorigenesis through inhibition of Notch signaling unlike other activating ligands. Moreover, DLL3 was highly expressed in SCLC, but not in normal lung tissue. However, little is known about function of DLL3 in SCLC. In this study, we examine the effect of DLL3 in tumorigenesis of SCLC. Methods: The mRNA expression levels and proteins of DLL3, Notch receptors (Notch1, Notch2, Notch3 and Notch4), Hes1 and EMT markers (E-cadherin, Snail and Vimentin) were examined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot in 9 SCLC cell lines (SBC-3, SBC-5, MS-1, RERF-LC-MA, H69, H82, H209, H529 and H1688). We used small interfering RNA (siRNA) to down-regulate the expression of DLL3 in SCLC cell lines. Anchorage-dependent and anchorage-independent cell growth was measured by MTT assay and migration and invasion were assessed by transwell assay. Results: The mRNA of DLL3 was expressed in all of 9 SCLC cell lines. The expression of DLL3 was especially higher in H82, H69, H209, H529 and H1688 cells. Notch1 protein was expressed in SBC-3, SBC-5, MS-1 and H82. Based on DLL3 expression analysis data, we used H82 and H69 in the following experiments. The suppression of DLL3 by siRNA resulted in the moderate inhibition of cell growth of H82 cells in both anchorage-dependent and anchorage-independent cell proliferation. The depletion of DLL3 prevented migration and invasion in the two cell lines. The expressions of Notch1 and Notch target gene, Hes1 were downregulated by DLL3 knockdown in both SCLC cells. Because Notch pathway was reported to regulate EMT, we evaluated the EMT markers when DLL3 was inhibited in SCLC cells. Snail was downregulated in DLL3 knockdown SCLC cells, while protein expression levels of E-cadherin and Vimentin were not changed in these DLL3 knockdown cells compared to control cells. Conclusions: DLL3 promotes the migration and invasion in SCLC cells by modulating Notch1 and Snail. Citation Format: Megumi Furuta, Jun Konishi Sakakibara, Tetsuaki Shoji, Yuta Takashima, Hajime Kikuchi, Eiki Kikuchi, Junko Kikuchi, Ichiro Kinoshita, Hirotoshi Dosaka Akita, Masaharu Nishimura. DLL3 regulates migration and invasion of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3158.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3158
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
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    Abstract 332: The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 332-332
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 332-332
    Abstract: Background: The bromodomain and extraterminal domain (BET) inhibitors are broadly active in different cancer types, including non-small cell lung cancer (NSCLC). Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the mechanism of BET inhibition on the cytotoxicity remain unknown. BET proteins have been also reported to interact with some DNA damage repair-related genes. AZD1775, a selective WEE1 G2 checkpoint kinase inhibitor, induces DNA damage and consequent apoptosis by abrogating G2 cell cycle arrest and inducing premature mitotic entry. We hypothesized that repression of BET activity would increase WEE1 inhibitor-induced cytotoxicity by impairing DNA damage repair. Here, we evaluate the efficacy and mechanistic rationale for combining AZD1775 and JQ1 as a potential therapy for NSCLC. Methods: NSCLC cell lines (A549, H1299, H1975) and human embryonic kidney cells line (293T) were used in the present study. Anti-tumor activities of JQ1, AZD1775, or the combination were analyzed using MTT survival assay. Changes in protein expression were analyzed by Western Blot analysis. mRNA expressions were evaluated by quantitative rt-PCR. Cell cycle was analyzed by flow cytometry using PI staining. Activity of non-homologous end joining (NHEJ) was evaluated using NHEJ reporter plasmid. Results: The combination of AZD1775 and JQ1 showed synergistic effects for NSCLC cell lines in vitro with combination indices of 0.1-0.5. The JQ1 monotherapy did not induce gamma-H2AX expression, but JQ1 increased and prolonged AZD1775-induced gamma-H2AX expression. The mRNA analysis showed that JQ1 significantly repressed NHEJ-related genes, such as XRCC4 and LIG4. Moreover, NHEJ reporter assay revealed JQ1 diminished NHEJ activity. Conclusions: Our data demonstrate that the combination of JQ1 and AZD1775 has a synergistic effect against NSCLC cell lines via a mechanism of compromised DNA damage repair by JQ1. This combination therapy can be a novel therapeutic strategy for NSCLC. Citation Format: Yuta Takashima, Eiki Kikuchi, Junko Kikuchi, Tetsuaki Shoji, Megumi Furuta, Hajime Kikuchi, Jun Sakakibara-Konishi, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura. The BET bromodomain inhibitor JQ1 synergizes with WEE1 inhibitor AZD1775 by impairing non-homologous end joining and enhancing DNA damages in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 332.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-332
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Abstract 1172: Expression of notch1, numb, and musashi1 in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1172-1172
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1172-1172
    Abstract: Background: Deregulation of Notch pathway is associated with carcinogenesis, and Notch signaling is identified as tumor activator in non-small cell lung cancer(NSCLC). The function of Musashi1 has been found to activate Notch signaling through the translational repression of Numb, which represses an intracellular Notch signaling. In NSCLC, the association between Numb or Musashi1 expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1, Numb, and Musashi1 in NSCLC. Methods: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Notch1, Numb, and Musashi1 expression. Only cytoplasm and nuclear staining was considered in the evaluation of activated Notch1 expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes was analyzed. Results: Immunohistochemical reactivity for Numb, and Musashi1 was detected in the cytoplasm and nuclear of the tumor cells. Notch1 expression was associated with several clinicopathological factors, including pathological histology (p = 0.002), and differentiation of tumor (p = 0.024). Numb expression was also associated with several clinicopathological factors, including sex (p = 0.037), smoking habit (p = 0.033), pathological histology (p = 0.002), and differentiation of tumor (p = 0.015). No correlations were noted between Musashi1 expression and any of the variables. Analysis of cellular biological expression demonstrated a link between low Numb expression and high Notch expression. Multivariate Cox regression analysis showed that positive Numb expression was an independent favorable prognostic factor. Conclusions: We demonstrate that Numb expression was associated with better prognosis in NSCLC. Numb might have the function as tumor suppressor in NSCLC. Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Yasuyuki Ikezawa, Taichi Takashina, Hidenori Mizugaki, Eiki Kikuchi, Junko Kikuchi, Naofumi Shinagawa, Satoshi Oizumi, Yasuhiro Hida, Kichizo Kaga, Ichiro Kinoshita, Hirotoshi Dosaka-Akita, Masaharu Nishimura. Expression of notch1, numb, and musashi1 in non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1172.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-1172
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Abstract 2011: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A against non-small cell lung cancer cells
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2011-2011
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 2011-2011
    Abstract: Background: The polycomb group gene, EZH2, mediates the histone methyltransferase activity, and functions as transcriptional repressor involved in gene silencing. It is involved in the malignant transformation and biological aggressiveness of several human cancers. We have previously shown that high EZH2 expression is correlated with tumor aggressiveness and is an independent unfavorable prognostic factor in non-small cell lung cancers (NSCLCs). However, the role of EZH2 in lung cancer cells has not been fully determined. Methods: In the present study, we evaluated the effect of a histone methyltransferase EZH2 inhibitor, 3-Deazaneplanocin A (DZNep), in NSCLC cell lines. Results: DZNep depleted cellular levels of EZH2 and SUZ12, and inhibited histone H3 lysine 27 trimethylation. DZNep inhibited proliferation of NSCLC cells dose- dependently through apoptosis and G1 cell cycle arrest which was partially associated with cyclin A decrease and p27Kip1 accumulation. Conclusion: Epigenetic therapy with the histone methyltransferase EZH2 inhibitor DZNep may constitute a novel approach for NSCLCs. 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 2011. doi:10.1158/1538-7445.AM2011-2011
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-2011
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
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    Abstract 3263: Expression of Bim, Noxa, and Puma in non-small cell lung cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3263-3263
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3263-3263
    Abstract: Background: The BH3-only members of the Bcl-2 protein family have been proposed to play a key role in the control of apoptosis and in the initiation of the apoptotic pathways. In this study, we evaluated the expression of Bim, Noxa, and Puma in non-small cell lung cancer (NSCLC). Methods: A total of 135 surgically resected NSCLCs were immunohistochemically assessed for Bim, Noxa, and Puma expression. The immunoscores were determined, and then its correlation with either the clinicopathological variables or the survival outcomes were analyzed. Results: Immunohistochemical reactivity for Bim, Noxa, and Puma was detected in the cytoplasm of the tumor cells. Bim expression was associated with several clinicopathological factors, including sex (p & lt;0.001), smoking habit (p=0.03), pathological histology (p=0.001), pathological T stage (p=0.03), pathological disease stage (p=0.02), and differentiation of tumor (p & lt;0.001). Multivariate logistic regression analysis showed a significant correlation between low Bim expression and squamous cell carcinoma (p=0.04), in addition to a correlation between high Bim expression and well differentiated tumors (p=0.02). Analysis of cellular biological expression demonstrated a link between low Bim expression and high Ki67. While Noxa expression was also shown to be correlated with both smoking habit (p=0.02) and the pathological histology (p=0.03), there was no strong association observed between the expression and the clinical features when they were examined by a multivariate logistic regression analysis. No correlations were noted between Puma expression and any of the variables. Our analyses also indicated that the expression levels of the BH3-only proteins were not pertinent to the survival outcome. Conclusions: The current analyses demonstrated that Bim expression in the NSCLCs was associated with both squamous cell carcinoma histology and tumor proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3263. doi:1538-7445.AM2012-3263
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-3263
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 6
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    Abstract 4118: Expression of CD133 as a prognostic marker of non-small cell lung cancers
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4118-4118
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4118-4118
    Abstract: [Background] CD133 is a membrance glycoprotein with five transmembrance loops. Previous reports have suggested that CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal abilities has biological features as a cancer stem cell. In addition, it has been reported that the presence of CD133-positive cells was associated with a significantly poorer prognosis compared with the CD133-negative cells in some solid tumors, including colon cancer, hepatocellular carcinoma and glioma. However, little is known about the relationship between the expression of CD133 and clinical and clinicopathological characteristics in lung cancer. [Aim and Method] We conducted immunohistochemical assessment of 161 surgically resected non-small cell lung cancers (NSCLCs) at Hokkaido University Hospital between 1982 and 1994 to evaluate the correlation between CD133 expression and various features, including clinical and clinicopathological characteristics. [Results] Normal alveoli were used as negative controls and Bowman's capsule basement membrane as positive controls. CD133 expression was significantly correlated with advanced p-Stage (p=0.040). The Kaplan-Meier method demonstrated that NSCLC patients with CD133 expression in tumor cells showed poor prognosis compared to those without CD133 expression in p-Stage II, III and IV (p=0.0098). CD133 expression alone was an independent factor for unfavorable prognostic in those patients (Hazard Ratio=3.157, p=0.015). [Conclusion] CD133 expression was correlated with p-Stage and was an independent factor for unfavorable prognosis in patients with p-Stage II, III and IV NSCLCs. CD133 expression may be a novel prognostic marker for NSCLCs. 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 4118. doi:10.1158/1538-7445.AM2011-4118
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-4118
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 7
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    Abstract 4641: Distinctive expression of polycomb group proteins Bmi1 and EZH2 in non-small cell lung cancers and their clinical and clinicopathological significance
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4641-4641
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4641-4641
    Abstract: Background: The polycomb group genes, Bmi1 and EZH2, function as transcriptional repressors involved in gene silencing. They are involved in the malignant transformation and biological aggressiveness of several human carcinomas. In the present study, we evaluated Bmi1 and EZH2 protein expression in specimens of human non-small cell lung cancers (NSCLCs). Methods: We conducted an immunohistochemical assessment of 157 surgically resected NSCLCs to evaluate the correlation between Bmi1 and EZH2 expression and various features, including clinical, clinicopathological and biological characteristics. Results: Normal bronchial epithelia showed abundant expression of Bmi1 and sporadic expression of EZH2. NSCLC patients with high EZH2 expression in tumor cells showed poorer prognosis than those with low EZH2 expression in all pStages (p = 0.001) and in pStage I (p = 0.006). Multivariate analysis showed that high EZH2 expression was a independent unfavorable prognostic factor in pStage I patients (p = 0.048). High EZH2 expression was significantly correlated with non-adenocarcinoma histology (p = 0.001), moderate and poor differentiation (p = 0.001), advanced pT stage (p = 0.02), and high Ki-67 and cyclin E labeling index (p & lt; 0.001). Bmi1 expression, in contrast, was not a significant prognostic factor, and was not correlated with any clinicopathological factors other than early pT stage. Conclusion: Bmi1 and EZH2 show characteristic and distinctive expression in NSCLCs. High EZH2 expression is correlated with tumor aggressiveness, and may provide a novel prognostic marker for NSCLCs. 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 4641.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM10-4641
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
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  • 8
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    Degradation of Tob1 Mediated by SCFSkp2-Dependent Ubiquitination
    American Association for Cancer Research (AACR) ; 2006
    In:  Cancer Research Vol. 66, No. 17 ( 2006-09-01), p. 8477-8483
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 66, No. 17 ( 2006-09-01), p. 8477-8483
    Abstract: Tob1, a member of the Tob/BTG family, is involved in the control of G1-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2−/− mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase. (Cancer Res 2006; 66(17): 8477-83)
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-1603
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 2036785-5
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  • 9
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    Abstract B115: The epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. B115-B115
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. B115-B115
    Abstract: Colorectal cancers (CRC) displaying DNA microsatellite instability (MSI) are associated with a favorable natural history, but the molecular basis for this observation has not been defined. We sought to determine whether the epithelial-to-mesenchymal transition (EMT), a highly conserved process involved in embryogenesis as well as in tumor progression, invasion, and metastasis, is impaired in MSI-positive CRCs that characteristically have a mutant transforming growth factor-β receptor type II (TGFBR2) gene. The induction of EMT by TGF-β1 was analyzed by phase contrast microscopy, immunofluorescence, qRT-PCR, immunoblotting, and cellular migration and invasion assays in MSS (SW480 and HT29) and MSI (DLD1 and HCT116) colon cancer cell lines. Expression of epithelial (E-cadherin) and mesenchymal (vimentin and N-cadherin) markers was evaluated by immunohistochemistry and qRT-PCR in 129 human colorectal tumors. TGF-β1 induced changes in cellular morphology from an epithelial to a fibroblasticlike morphology, changes in gene and protein expression with a reduction in E-cadherin and induction of vimentin, and changes in motility and invasion consistent with the occurrence of EMT only in MSS colon cancer cells. These effects did not require Smad4 but depended upon the recruitment of ERK. Cells with MSI and mutant TGFBR2 failed to exhibit any of these changes in response to TGF-β1. However, tumor cells with MSI but wildtype TGFBR2 underwent EMT in response to TGF-β1, indicating that TGFBR2 genotype is a key determinant of the EMT response in tumors with MSI. In human colorectal tumors, expression of the EMT markers N-cadherin and vimentin was significantly associated with adverse clinicopathologic features and the absence of MSI. These findings define a unique genotype-phenotype relationship between TGFBR2 and EMT that may contribute to the improved prognosis consistently observed in colon cancers with MSI. Furthermore, these results suggest a potential rationale for the therapeutic inhibition of TGF-β signaling in MSS colorectal tumors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B115.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-B115
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
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  • 10
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    Abstract 2170: Microarray analysis reveals distinct gene set profiles between gastric and intestinal gastrointestinal stromal tumors
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2170-2170
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2170-2170
    Abstract: Background: Gastrointestinal stromal tumor (GIST) is known to originate from the interstitial cells of Cajal or its precursors with a gain-of-function mutation of the c-kit or PDGFRA gene. GISTs are most commonly found in the stomach, followed by the small intestine. It is known that patients with intestinal GIST have markedly higher risks for recurrence compared to those with gastric GISTs. According to Miettinen's risk classification, intestinal GISTs are categorized in higher risk group compared with gastric GISTs at the same size and mitotic index. In this study, we sought to address mechanisms underlying the clinically malignant phenotype of intestinal GISTs. Methods: Fresh frozen samples of 6 primary gastric GISTs, 3 primary intestinal GISTs and 6 metastatic liver GISTs were utilized for cDNA microarray analysis. None of the patients had received imatinib therapy before surgery. Gene expression levels were compared between primary gastric and intestinal GISTs using gene set enrichment analysis (GSEA). Protein levels of SLIT2 were analyzed by immunohistochemistry in 25 primary gastric GISTs and 10 intestinal GISTs. Results: Microarray analysis of primary gastric and intestinal GISTs and metastatic liver GISTs classified them into two groups according their gene expressions. One group consisted of primary gastric GISTs without postoperative recurrence and the other consisted of clinically malignant GISTs, intestinal GISTs and metastatic liver GISTs, suggesting that intestinal GISTs potentially show gene expression profile similar to clinically malignant and metastatic GISTs. GSEA revealed that the gene set MITOTIC_CELL_CYCLE was upregulated in intestinal GISTs compared with gastric GISTs, consistent with previous reports that intestinal GISTs show higher mitotic count. The gene set NEURON_DIFFERENTIATION was downgulated in intestinal GISTs compared with gastric GISTs that may help explain mitosis-independent mechanisms underlying the clinically malignant phenotype of intestinal GISTs. In this gene set, we focused on SLIT2, downregulation of which has been reported to be associated with aggressive phenotypes in human cancers. Immunohistochemistry revealed that intestinal GISTs expressed lower SLIT2 protein than gastric GISTs, and that high-risk gastric GISTs and intestinal GISTs express comparable levels of SLIT2 protein which were lower than low-risk gastric GISTs. In SLIT2-high GISTs, tumor size was significantly smaller than in SLIT2-low GISTs, whereas mitotic counts and MIB-1 index were comparable among three groups according to SLIT2 intensity. Conclusions: Gene expression profile of intestinal GISTs was similar to that in metastatic liver GISTs. Expression levels of SLIT2 protein were lower in intestinal GISTs compared with gastric GISTs. Besides higher proliferative activity, downregulation of SLIT2 could be involved in clinically malignant phenotypes of intestinal GISTs. Citation Format: Hirotoshi Kikuchi, Ryuhei Hara, Shinichiro Miyazaki, Yoshihiro Hiramatsu, Kinji Kamiya, Manabu Ohta, Takanori Sakaguchi, Satoshi Baba, Haruhiko Sugimura, Hiroyuki Konno. Microarray analysis reveals distinct gene set profiles between gastric and intestinal gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 1 06th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2170. doi:10.1158/1538-7445.AM2015-2170
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-2170
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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