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  • American Association for Cancer Research (AACR)  (8)
  • 1
    Online Resource
    Online Resource
    bHLH-zip Transcription Factor Spz1 Mediates Mitogen-Activated Protein Kinase Cell Proliferation, Transformation, and Tumorigenesis
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 10 ( 2005-05-15), p. 4041-4050
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 10 ( 2005-05-15), p. 4041-4050
    Abstract: BHLH-zip proteins usually play important regulatory roles in cell growth and differentiation. In this study, we show that Spz1, a bHLH-zip transcription factor, acts downstream of mitogen-activated protein kinase (MAPK, extracellular signal-regulated kinase 1/2) to up-regulate cell proliferation and tumorigenesis. In addition, through an interaction with proliferating cell nuclear antigen (PCNA) promoter, Spz1 induced cell proliferation concomitant with an increase in PCNA gene expression. Spz1-transfected cells formed colony foci on soft agar and developed fibrosarcoma tumors in nude mice. MAPK directly interacted and phosphorylated Spz1 protein, which increased PCNA transcription and cell tumorigenic activities. Reduction of endogenous Spz1 expression via RNA interference decreased cell proliferation in p19 embryonic carcinoma cells. High levels of Spz1 expression were detected in murine tumor cell lines and tumor samples of both human and Spz1 transgenic mice. Thus, Spz1 may act as a proto-oncogene, participating in the MAPK signal pathway, and be a potential therapeutic target in the treatment of Ras-induced tumors.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-04-3658
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
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    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    β-1,4-Galactosyltransferase III Enhances Invasive Phenotypes Via β1-Integrin and Predicts Poor Prognosis in Neuroblastoma
    American Association for Cancer Research (AACR) ; 2013
    In:  Clinical Cancer Research Vol. 19, No. 7 ( 2013-04-01), p. 1705-1716
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 7 ( 2013-04-01), p. 1705-1716
    Abstract: Purpose: Neuroblastoma (NB) is a neural crest-derived tumor that commonly occurs in childhood. β-1,4-Galactosyltransferase III (B4GALT3) is highly expressed in human fetal brain and is responsible for the generation of poly-N-acetyllactosamine, which plays a critical role in tumor progression. We therefore investigated the expression and role of B4GALT3 in NB. Experimental Design: We examined B4GALT3 expression in tumor specimens from 101 NB patients by immunohistochemistry and analyzed the correlation between B4GALT3 expression and clinicopathologic factors or survival. The functional role of B4GALT3 expression was investigated by overexpression or knockdown of B4GALT3 in NB cells for in vitro and in vivo studies. Results: We found that B4GALT3 expression correlated with advanced clinical stages (P = 0.040), unfavorable Shimada histology (P & lt; 0.001), and lower survival rate (P & lt; 0.001). Multivariate analysis showed that B4GALT3 expression is an independent prognostic factor for poor survival of NB patients. B4GALT3 overexpression increased migration, invasion, and tumor growth of NB cells, whereas B4GALT3 knockdown suppressed the malignant phenotypes of NB cells. Mechanistic investigation showed that B4GALT3-enhanced migration and invasion were significantly suppressed by β1-integrin blocking antibody. Furthermore, B4GALT3 overexpression increased lactosamine glycans on β1-integrin, increased expression of mature β1-integrin via delayed degradation, and enhanced phosphorylation of focal adhesion kinase. Conversely, these properties were decreased by knockdown of B4GALT3 in NB cells. Conclusions: Our findings suggest that B4GALT3 predicts an unfavorable prognosis for NB and may regulate invasive phenotypes through modulating glycosylation, degradation, and signaling of β1-integrin in NB cells. Clin Cancer Res; 19(7); 1705–16. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-2367
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Genomic and Transcriptomic Landscape of an Oral Squamous Cell Carcinoma Mouse Model for Immunotherapy
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Immunology Research ( 2023-09-28), p. OF1-OF15
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), ( 2023-09-28), p. OF1-OF15
    Abstract: The immune checkpoint inhibitor (ICI), anti–programmed death-1 (anti–PD-1), has shown moderate efficacy in some patients with head and neck squamous cell carcinoma (HNSCC). Because of this, it is imperative to establish a mouse tumor model to explore mechanisms of antitumor immunity and to develop novel therapeutic options. Here, we examined the 4-nitroquinoline-1-oxide (4NQO)–induced oral squamous cell carcinoma (OSCC) model for genetic aberrations, transcriptomic profiles, and immune cell composition at different pathologic stages. Genomic exome analysis in OSCC-bearing mice showed conservation of critical mutations found in human HNSCC. Transcriptomic data revealed that a key signature comprised of immune-related genes was increased beginning at the moderate dysplasia stages. We first identified that macrophage composition in primary tumors differed across pathologic stages, leading to an oncogenic evolution through a change in the M1/M2 macrophage ratio during tumorigenesis. We treated the 4NQO-induced OSCC-bearing mice with anti–PD-1 and agonistic anti-CD40, which modulated multiple immune responses. The growth of tumor cells was significantly decreased by agonistic anti-CD40 by promoting an increase in the M1/M2 ratio. By examining cross-species genomic conservation in human and mouse tumors, our study demonstrates the molecular mechanisms underlying the development of OSCC and the regulation of contributing immune-related factors, and aims to facilitate the development of suitable ICI-based treatments for patients with HNSCC.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-23-0133
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Online Resource
    Definition of PKC-α, CDK6, and MET as Therapeutic Targets in Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 17 ( 2014-09-01), p. 4822-4835
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 17 ( 2014-09-01), p. 4822-4835
    Abstract: Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-α, MET, and CDK6 correlated with poorer survival outcomes. In cases coexpressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and tumorigenic potential in a cooperative manner. A combination of PKC-α-MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC. Cancer Res; 74(17); 4822–35. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0584
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Abstract 4626: Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4626-4626
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4626-4626
    Abstract: Developing realistic preclinical models using clinical samples that reflect complex tumor biology is critical to advancing cancer research. Patient-derived preclinical tumor models are the optimal tool for understanding drug action patterns and resistance mechanisms. In order to improve the capability of drug R & D in our institute (NHRI-IBPR), we have generated several patient-derived xenograft (PDX) models and characterized the genomic signature and responsiveness to standard-of-care (SOC) therapy. DBPR216, an orally bioavailable multikinase inhibitor, showed potent effect for treatment of gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML) through targeting of c-KIT and FLT-3, respectively. In order to further discover other indications of DBPR216 for clinical application, we investigated the anti-tumor effect of DBPR216 in several in-house PDX models. Among them, we found that DBPR216 was effectively to suppress PDX tumor growth in the immuno-deficient mice in two colorectal adenocarcinoma PDX models, C008 and C015. These PDX models showed similar genomic features with original tumor samples from patients when test using targeted sequencing of cancer related genes. To further identify if DBPR216 is superior to other kinase inhibitors and SOC therapy, we used in vitro PDX cell proliferation assay to quickly examine the anti-tumor effect of DBPR216 compared to a panel of therapeutic drugs. The result demonstrated that DBPR216 appeared to be superior in potency to kinase inhibitors (Regorafenib, Afatinib, Sunitinib, and Imatinib) and SOC therapy (Irinotecan, 5-FU, and Oxaliplatin). Combining the kinase profiling of DBPR216 and mutational analysis of C008 and C015 PDX models, we proposed that DDR2, FLT1, PDGFRα, PDGFRβ, RET, and SRC may be the potential targets of DBPR216 in these PDX models, and need further elucidation. Taken together, we found that DBPR216 exhibits potent anticancer effect against colorectal cancer and may bring the better opportunity than Regorafenib, a therapeutic agent for metastatic colorectal cancer in clinical. DBPR216 is now under preclinical development for further IND submission. Citation Format: Ching-Chuan Kuo, Weir-Torn Jiaang, Jing-Jim Ou, Chiung-Tong Chen, Shu-Ching Hsu, Chuan Shih, Li-Mei Lin, Manwu Sun, Yi-Hsin Wang, Zih-Ting Huang, Jang-Yang Chang, Shau-Hua Ueng. Use of integrated genomic analyses in patient-derived tumor model to discover new clinical indications for the multikinase inhibitor drug candidate, DBPR216 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4626.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4626
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 2 ( 2017-01-15), p. 494-508
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 2 ( 2017-01-15), p. 494-508
    Abstract: Aurora A–dependent NF-κB signaling portends poor prognosis in acute myeloid leukemia (AML) and other cancers, but the functional basis underlying this association is unclear. Here, we report that Aurora A is essential for Thr9 phosphorylation of the TRAF-interacting protein TIFA, triggering activation of the NF-κB survival pathway in AML. TIFA protein was overexpressed concurrently with Aurora A and NF-κB signaling factors in patients with de novo AML relative to healthy individuals and also correlated with poor prognosis. Silencing TIFA in AML lines and primary patient cells decreased leukemic cell growth and chemoresistance via downregulation of prosurvival factors Bcl-2 and Bcl-XL that support NF-κB–dependent antiapoptotic events. Inhibiting TIFA perturbed leukemic cytokine secretion and reduced the IC50 of chemotherapeutic drug treatments in AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiated the clearance of myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity. Collectively, our results showed that TIFA supports AML progression and that its targeting can enhance the efficacy of AML treatments. Cancer Res; 77(2); 494–508. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-16-1004
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract 2120: Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2120-2120
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2120-2120
    Abstract: Signal transducer and activator of transcription 3 (Stat3), a common transcription factor, has been reported to regulate cancer development, including prostate cancer. Stat3 has also been suggested that its transcriptional activity is initiated by phosphorylation. The tyrosine 705 (Y705) and serine 727 (S727) phosphorylation of Stat3 were documented to Stat3 activation. Androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. Cyclin-dependent kinase 5 (Cdk5), which belongs to Cdk family, is a proline-directed serine/threonine kinase. Our previous results indicate that Cdk5 may phosphorylate AR at serine 81 site (S81) and increase AR stabilization and transactivation. On the other hand, previous studies have shown that Interleukin-6 (IL-6), which is a cytokine, activates androgen receptor (AR) via MAPK and Stat3-related pathway. Therefore, the aim of this study is to investigate if Cdk5 regulates S81 phosphorylation-related AR activation through S727 Stat3 phosphorylation under IL-6 treatment. First we observed IL-6 enhanced S727 phosphorylation of Stat3 and S81 phosphorylation of AR as well as AR protein level. Next, IL-6 increased AR biochemical interaction with Stat3 and AR stabilization, nuclear localization, and transactivation, which is correlated to S727 phosphorylation of Stat3. Subsequently, we found that IL-6 induced tyrosine 15 (Y15) phosphorylation of Cdk5, which is an indicator of Cdk5 activation, and this phosphorylation was inhibited by AG490 (JAK inhibitor). We also found that Y15-Cdk5 mutant (Y15F) decreased IL-6-induced phosphorylation of AR S81 and Stat3 S727 and the biochemical interaction between AR and Stat3 was also affected. In summary, these results suggest that IL-6 activated AR by S81 phosphorylation via S727 phosphorylation of Stat3 and Cdk5 might be an upstream regulator in the pathway. Citation Format: Jo-Hsin Wang, Pei-Chi Li, Li-Chiung Lin, Fu-Ning Hsu, Mei-Chih Chen, Ho Lin. Cdk5 involves in interleukin-6 induces AR activation through phosphorylation of serine 727 Stat3 and serine 81 AR in prostate cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2014-2120
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2120
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Abstract A022: Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Immunology Research Vol. 11, No. 12_Supplement ( 2023-12-01), p. A022-A022
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 11, No. 12_Supplement ( 2023-12-01), p. A022-A022
    Abstract: Multiple Copies in T-cell Malignancy-1 (MCT-1 or MCTS1) is a prognostic biomarker for aggressive breast cancers. Overexpressed MCT-1 stimulates the IL-6/IL-6R/gp130/STAT3 axis, promoting epithelial-to-mesenchymal transition, cancer cell stemness and tumor progression. To study the mechanism underlying TNBC immunity and aggressiveness, TNBC cell lines with different MCT-1 expression levels were evaluated. Primary tumor invasion and postsurgical local recurrence and distant metastasis were assessed in orthotopic syngeneic mice given indicated immunotherapy and/or MCT-1 silencing (shMCT-1). We found that shMCT-1 suppresses the transcriptome of inflammatory response and metastatic signaling in TNBC cells and inhibits TNBC progression, metastasis and mortality in xenograft mice. Combined IL-6R immunotherapy and shMCT-1 effect further decreased intratumoral M2 macrophages and T regulatory cells (Tregs) and avoided postsurgical TNBC expansion. Multiple positive feedback loops of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 axis were identified in TNBC cells, which boost metastatic niches and immunosuppressive microenvironments. MCT-1high/PD-L1high/CXCL7high and CXCL7high/IL-6high/IL-6Rhigh expression patterns predict worse prognosis and poorer survival in breast cancer patients. IL-6R-based immunotherapy more effectively prevented postsurgical TNBC metastasis, recurrence and mortality than anti-PD-L1 immunotherapy. Anti-IL-6R improved helper T, cytotoxic T and natural killer (NK) cells in lymphatic system and decreased Tregs in the recurrent and metastatic tumors, but anti-PD-L1 incapably elevated NK cells. Combined IL-6R and PD-L1 immunotherapies abridged TNBC cell stemness and M2 macrophage activity better than monotherapy. Sequential immunotherapy of PD-L1 and IL-6R demonstrated the best survival outcome, lowest postoperative recurrence and metastasis than synchronized therapy, particularly in shMCT-1 context. Conclusion: Systemic targeting of the MCT-1/IL-6/IL-6R/CXCL7/PD-L1 interconnection enhances the immune surveillance that inhibits aggressiveness of TNBC. Citation Format: Aushia Tanzih Al Haq, Pao-Pao Yang, Christopher Jin, Jou-Ho Shih, Li-Mei Chen, Lu-Hai Wang, Michael P. Snyder, Hsin-Ling Hsu. Immunotherapy of IL-6R Prevents Relapse and Metastasis of Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A022.
    Type of Medium: Online Resource
    ISSN: 2326-6074
    URL: Article
    DOI: 10.1158/2326-6074.TUMIMM23-A022
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2732517-9
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