Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 11, pp 2649–2661 | Cite as

CD44 splice variant (CD44v3) promotes progression of urothelial carcinoma of bladder through Akt/ERK/STAT3 pathways: novel therapeutic approach

  • Vivek Anand
  • Madhuram Khandelwal
  • Sandeep Appunni
  • Nidhi Gupta
  • Amlesh Seth
  • Prabhjot Singh
  • Sandeep Mathur
  • Alpana SharmaEmail author
Original Article – Cancer Research



The incidence of Urothelial carcinoma of bladder (UBC) is gradually increasing by changing lifestyle and environment. The development of a tumor has been noted to be accompanied by modifications in the extracellular matrix (ECM) consisting of CD44, hyaluronic acid (HA) and its family members. The importance of CD44 splice variants and HA family members has been studied in UBC.


The cohort of study included 50 UBC patients undergoing radical cystectomy and 50 healthy subjects. The molecular expression of CD44 and HA family members was determined. Effect of CD44 variant-specific silencing on downstream signaling in HT1376 cells was investigated. Combinatorial treatment of 4-MU (4-methylumbelliferone) with cisplatin or doxorubicin on chemosensitivity was also explored.


Higher expression of HA, HAS2, and CD44 was observed in Indian UBC patients which also showed the trend with severity of disease. Splice variant assessment of CD44 demonstrated the distinct role of CD44v3 and CD44v6 in bladder cancer progression. shRNA-mediated downregulation of CD44v3 showed an increase effect on cell cycle, apoptosis and multiple downstream signaling cascade including pAkt, pERK and pSTAT3. Furthermore, 4-MU, an HA synthesis inhibitor, observed to complement the effect of Cisplatin or Doxorubicin by enhancing the chemosensitivity of bladder cancer cells.


Our findings exhibit involvement of CD44 splice variants and HA family members in UBC and significance of 4-MU in enhancing chemosensitivity suggesting their novel therapeutic importance in disease therapeutics.


Bladder cancer Hyaluronic acid Hyaluronic acid synthase CD44 CD44 variant 3 4-Methylumbelliferone 



We acknowledge Indian Council for Medical Research (ICMR) for the grant to carry out research work. ICMR Grant No.: 5/13/50/10/NCD-III. All the authors have read the journal’s authorship agreement and policy.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

432_2019_3024_MOESM1_ESM.doc (556 kb)
Supplementary material 1 (DOC 556 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of BiochemistryAll India Institute of Medical Sciences (AIIMS)New DelhiIndia
  2. 2.Department of UrologyAll India Institute of Medical Sciences (AIIMS)New DelhiIndia
  3. 3.Department of PathologyAll India Institute of Medical Sciences (AIIMS)New DelhiIndia

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