2. Academic Validation
  3. XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor

XPO1/CRM1 is a promising prognostic indicator for neuroblastoma and represented a therapeutic target by selective inhibitor verdinexor

  • J Exp Clin Cancer Res. 2021 Aug 12;40(1):255. doi: 10.1186/s13046-021-02044-z.
Lijia Pan  # 1 2,  Cheng Cheng  # 1 2,  Peiwen Duan 1 2,  Kai Chen 1 2,  Yeming Wu 3 4 5,  Zhixiang Wu 6 7 8
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China.
  • 2 Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, 200092, China.
  • 3 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China. wuyeming@xinhuamed.com.cn.
  • 4 Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, 200092, China. wuyeming@xinhuamed.com.cn.
  • 5 Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, 215003, China. wuyeming@xinhuamed.com.cn.
  • 6 Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200092, China. wuzhixiang@xinhuamed.com.cn.
  • 7 Division of Pediatric Oncology, Shanghai Institute of Pediatric Research, Shanghai, 200092, China. wuzhixiang@xinhuamed.com.cn.
  • 8 Department of Pediatric Surgery, Children's Hospital of Soochow University, Suzhou, 215003, China. wuzhixiang@xinhuamed.com.cn.
  • # Contributed equally.
PMID: 34384466 DOI: 10.1186/s13046-021-02044-z
Abstract

Background: High-risk neuroblastoma patients have a 5-year survival rate of less than 50%. It's an urgent need to identify new therapeutic targets and the appropriate drugs. Exportin-1 (XPO1), also known as chromosomal region maintenance 1, plays important roles in the progression of tumorigenesis. However, the prognostic and therapeutic values of XPO1 in neuroblastoma have not been reported.

Methods: Correlations between XPO1 expression level and clinical characteristics were analyzed using the Neuroblastoma Research Consortium (NRC) dataset and tissue microarray analysis. Cell proliferation assays, colony formation assays, Apoptosis assays, cell cycle analysis were performed to analyze the anti-tumor effects of verdinexor (KPT-335) in vitro. Western blot and mRNA Sequencing were performed to explore underlying mechanism. In vivo anti-tumor effects of verdinexor were studied in a neuroblastoma xenograft model.

Results: Higher XPO1 levels were associated with advanced stage and poor prognosis in neuroblastoma patients. The specific inhibitor of XPO1 verdinexor suppressed the neuroblastoma cell growth both in vitro and in vivo. Specifically, inhibition of XPO1 suppressed the neuroblastoma cell proliferation and induced cell Apoptosis by nuclear accumulation of FOXO1 and RB1 in the neuroblastoma due to the inhibition of the PI3K/Akt pathway, and induced G0/G1 phase cell cycle arrest by activation of P53 function.

Conclusions: XPO1 is a promising prognostic indicator for neuroblastoma and a novel target for antitumor treatment with selective inhibitor verdinexor.

Keywords

KPT-335; Neuroblastoma; P53; PI3K/AKT pathway; Verdinexor; XPO1.

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