CD44 and RHAMM are essential for rapid growth of bladder cancer driven by loss of Glycogen Debranching Enzyme (AGL)

BMC Cancer

Research Article

Yuanbin Ru¹  Dan Theodorescu²  Darby Oldenburg³  Sunny Guin³  Steve Cash³  Benjamin Weinhaus⁴ 

[1] BioMarin Pharmaceutical Inc, 300 Bel Merin Keys Blvd, 94949, Novato, CA, USA;Department of Surgery (Urology), University of Colorado, 13001 E 17th Pl, 80045, Aurora, CO, USA;Department of Pharmacology, University of Colorado, 13001 E 17th Pl, 80045, Aurora, CO, USA;University of Colorado Comprehensive Cancer Center, 13001 E 17th Pl, 80045, Aurora, CO, USA;Gundersen Medical Foundation, 1300 Badger Street, 54601, La Crosse, WI, USA;University of Wisconsin-La Crosse, 1725 State St, 54601, La Crosse, WI, USA;

关键词: AGL;    HAS2;    CD44;    RHAMM;    Bladder cancer;   

DOI  :  10.1186/s12885-016-2756-5

 received in 2016-05-27, accepted in 2016-08-31,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundLoss of Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) drives rapid proliferation of bladder cancer cells by upregulating Hyaluronic acid(HA) Synthase (HAS2) mediated HA synthesis. However the role of HA receptors CD44 and Hyaluronan Mediated Motility Receptor (RHAMM) in regulating the growth of bladder cancer cells driven by loss of AGL has not been studied.MethodsWestern blot analysis and Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay was carried out to study cellular apoptosis with HAS2, CD44 and RHAMM loss in bladder cancer cells with and without AGL expression. Proliferation and softagar assays were carried out to study cellular anchorage dependent and independent growth. Clinicopathologic analysis was carried out on bladder cancer patient datasets.ResultsHigher amounts of cleaved Cas3, Cas9 and PARP was observed in AGL low bladder cancer cell with loss of HAS2, CD44 or RHAMM. TUNEL staining showed more apoptotic cells with loss of HAS2, CD44 or RHAMM in AGL low bladder cancer cells. This revealed that bladder cancer cells whose aggressive growth is mediated by loss of AGL are susceptible to apoptosis with loss of HAS2, CD44 or RHAMM. Interestingly loss of either CD44 or RHAMM induces apoptosis in different low AGL expressing bladder cancer cell lines. Growth assays showed that loss of CD44 and RHAMM predominantly inhibit anchorage dependent and independent growth of AGL low bladder cancer cells. Clinicopathologic analysis revealed that high RHAMM mRNA expression is a marker of poor patient outcome in bladder cancer and patients with high RHAMM and low AGL tumor mRNA expression have poor survival.ConclusionOur findings strongly point to the importance of the HAS2-HA-CD44/RHAMM pathway for rapid growth of bladder cancer cells with loss of AGL and provides rational for targeting this pathway at various steps for “personalized” treatment of bladder cancer patients based of their AGL expression status.

【 授权许可】

CC BY   
© The Author(s). 2016