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Project

The role, relationship and therapeutic potential of HAS2 and AGL in bladder cancer

Funder: Bladder Cancer Advocacy Network

Funding period
USD 100 K
Funding amount
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 bladder cancer growth. Importantly, we were the first to implicate AGL in the malignant process and specifically in bladder cancer and showed that low AGL mRNA and protein levels predict poor patient outcome for bladder cancer patients. Interestingly, tumor progression driven by depletion of AGL is independent of AGL enzymatic activity and of inhibition of glycogenolysis in general. To identify how reduced levels of AGL promote bladder cancer growth, we profiled the transcription of cell lines with and without AGL to identify genes regulated by AGL and thus potential pathways driving this process. This analysis identified hyaluronic acid synthase 2 (HAS2), an enzyme responsible for hyaluronic acid (HA) synthesis, is upregulated in bladder cancer cells by AGL depletion. Increased HA synthesis has been shown to drive tumor growth and metastasis and AGL depleted cells were found to have increased HA levels. Examining mice heterozygous for an AGL knockout allele we found 50% reduced AGL and increase in HAS2 expression in normal bladder mucosa suggesting the regulatory relationship between AGL and HAS2 is present in both the normal and tumor setting. In this application, the following two hypotheses will be tested: 1) The HAS2/HA “duo” is an important driver of aggressive behavior of tumors with AGL loss; 2) Reduced AGL levels in normal bladder mucosa leads to greater risk of bladder cancer formation in mice. In summary, here we investigate if the HAS2/HA pathway is the primary driver of tumor aggressiveness in patients with AGL loss and test preclinical treatment strategies aimed at this pathway that may be translated to patients. We will also learn if AGL loss is a risk factor for bladder cancer formation allowing potential stratification of follow up strategies in patients.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science