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  • 1
    Online Resource
    Online Resource
    Abstract 4949: HAS2 is a critical effector for AGL mediated regulation of tumor growth
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4949-4949
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4949-4949
    Abstract: In bladder cancer, reduced levels of Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL), an enzyme involved in glycogenolysis and mutated in glycogen storage disease type III, enhances proliferation in vitro and tumor growth in vivo. To identify how reduced levels of AGL promote bladder cancer growth, we gene expression profiled two bladder cancer cell lines with and without siRNA mediated AGL depletion. This identified that hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis, is upregulated with AGL depletion. We validated this finding in several additional bladder cancer cell lines and also found that HA levels were 2-fold higher bladder cancer cells with low AGL compared to control. Interestingly, siRNA induced knockdown of HAS2 preferentially reduced monolayer, anchorage independent and xenograft growth in bladder cancer cells with low AGL. 4-Methylumbelliferone (4-MU), an inhibitor of HA synthesis, had similar effects. Analysis of human bladder cancer tissues showed that AGL and HAS2 mRNA expression are negatively correlated in 5/8 patient datasets (N = 725). Bladder cancer patients with high HAS2 and low AGL expression had worse survival than patients with the reciprocal relationship between these two genes suggesting that HAS2 is a driver of bladder tumor growth with AGL loss establish the HAS2/HA axis as a major driver and target of therapy in bladder tumors with low AGL. Citation Format: Sunny Guin, Yuanbin Ru, Carolyn R. Lew, Neeraj Agarwal, Charles Owens, Dan Theodorescu. HAS2 is a critical effector for AGL mediated regulation of tumor growth. [abstract]. In: Proceedings of the 106th 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 4949. doi:10.1158/1538-7445.AM2015-4949
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4949
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 2
    Online Resource
    Online Resource
    Loss of Glycogen Debranching Enzyme AGL Drives Bladder Tumor Growth via Induction of Hyaluronic Acid Synthesis
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 5 ( 2016-03-01), p. 1274-1283
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 5 ( 2016-03-01), p. 1274-1283
    Abstract: Purpose: We demonstrated that amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) is a tumor growth suppressor and prognostic marker in human bladder cancer. Here we determine how AGL loss enhances tumor growth, hoping to find therapeutically tractable targets/pathways that could be used in patients with low AGL–expressing tumors. Experimental Design: We transcriptionally profiled bladder cell lines with different AGL expression. By focusing on transcripts overexpressed as a function of low AGL and associated with adverse clinicopathologic variables in human bladder tumors, we sought to increase the chances of discovering novel therapeutic opportunities. Results: One such transcript was hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis. HAS2 expression was inversely proportional to that of AGL in bladder cancer cells and immortalized and normal urothelium. HAS2-driven HA synthesis was enhanced in bladder cancer cells with low AGL, and this drove anchorage-dependent and independent growth. siRNA-mediated depletion of HAS2 or inhibition of HA synthesis by 4-methylumbelliferone (4MU) abrogated in vitro and xenograft growth of bladder cancer cells with low AGL. AGL and HAS2 mRNA expression in human tumors was inversely correlated in patient datasets. Patients with high HAS2 and low AGL tumor mRNA expression had poor survival, lending clinical support to xenograft findings that HAS2 drives growth of tumors with low AGL. Conclusions: Our study establishes HAS2-mediated HA synthesis as a driver of growth of bladder cancer with low AGL and provides preclinical rationale for personalized targeting of HAS2/HA signaling in patients with low AGL–expressing tumors. Clin Cancer Res; 22(5); 1274–83. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-15-1706
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 3
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    Online Resource
    Contributions of KRAS and RAL in Non–Small-Cell Lung Cancer Growth and Progression
    Elsevier BV ; 2013
    In:  Journal of Thoracic Oncology Vol. 8, No. 12 ( 2013-12), p. 1492-1501
    Details
    In: Journal of Thoracic Oncology, Elsevier BV, Vol. 8, No. 12 ( 2013-12), p. 1492-1501
    Type of Medium: Online Resource
    ISSN: 1556-0864
    URL: Article
    DOI: 10.1097/JTO.0000000000000007
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
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  • 4
    Online Resource
    Online Resource
    Role in Tumor Growth of a Glycogen Debranching Enzyme Lost in Glycogen Storage Disease
    Oxford University Press (OUP) ; 2014
    In:  JNCI: Journal of the National Cancer Institute Vol. 106, No. 5 ( 2014-5)
    Details
    In: JNCI: Journal of the National Cancer Institute, Oxford University Press (OUP), Vol. 106, No. 5 ( 2014-5)
    Type of Medium: Online Resource
    ISSN: 1460-2105 , 0027-8874
    URL: Article
    DOI: 10.1093/jnci/dju062
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
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  • 5
    Online Resource
    Online Resource
    CD44 and RHAMM are essential for rapid growth of bladder cancer driven by loss of Glycogen Debranching Enzyme (AGL)
    Springer Science and Business Media LLC ; 2016
    In:  BMC Cancer Vol. 16, No. 1 ( 2016-12)
    Details
    In: BMC Cancer, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2016-12)
    Type of Medium: Online Resource
    ISSN: 1471-2407
    URL: Article
    DOI: 10.1186/s12885-016-2756-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
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  • 6
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    Online Resource
    Abstract 2138: Tumorigenic and migratory potential of Ral GTPases in non-small cell lung cancers
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2138-2138
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 2138-2138
    Abstract: The Ral GTPase family, consisting of the Ral A and B isoforms contributes to tumor formation, invasion and metastasis, however their role in non-small cell lung cancer (NSCLC) is yet to be validated. Recently, we investigated the role of Ral GTPases in NSCLC by in vitro expression, colony formation and migration assay, in vivo tumor formation experiments, and analysis of microarray data from NSCLC patients. In vitro, Ral A and Ral B was expressed in all NSCLC cell lines studied (14) to varying levels. Increased expression of Ral A or Ral B was more frequent in Ras mutant cell lines (Ral A elevated in 2/8 cell lines with mutant KRas vs. 0/6 cell lines with WT KRas, Ral B elevated in 5/8 cell lines with mutant KRas vs. 2/6 WT KRas). Soft agar experiments with transient knockdown of Ral A, Ral B and Ral A+B in these cell lines demonstrated significant decrease (p & lt;0.05) in colony formation. Dual knockdown of Ral A and B had a 2 to 3 fold decrease (p & lt;0.05) in NSCLC cell motility in wound healing assays. In vivo, knockdown of Ral GTPases resulted in reduced subcutaneous tumor growth (p & lt;0.05) in mice injected with the knockdown cells. Microarray data from NSCLC patients was analyzed to study the correlation between Ral A and B expression with overall patient survival. High Ral A expression was associated with poor patient survival in these microarray datasets (p & lt;0.05). The above observations demonstrate that Ral GTPases play a role in lung cancer tumorigenesis and migration. In the Ras signaling cascade, Ral GTPases are downstream of Ras along with PI3K and MAPK signaling pathways. KRas mutations in NSCLC carry a poor patient prognosis. Based on our observations, we posit that Ral GTPases can be a valid target for drug development against KRas mutated lung cancers along with PI3K and MEK inhibitors. 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 2138. doi:1538-7445.AM2012-2138
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-2138
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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