2. Academic Validation
  3. Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy

Inhibition of ID1-BMPR2 Intrinsic Signaling Sensitizes Glioma Stem Cells to Differentiation Therapy

  • Clin Cancer Res. 2018 Jan 15;24(2):383-394. doi: 10.1158/1078-0432.CCR-17-1529.
Xiong Jin  # 1 2,  Xun Jin  # 3 4 5,  Leo J Y Kim 6,  Deobrat Dixit 6,  Hee-Young Jeon 1 2,  Eun-Jung Kim 1 2,  Jun-Kyum Kim 1 2,  Seon Yong Lee 1,  Jinlong Yin 7,  Jeremy N Rich 6,  Hyunggee Kim 8 2
Affiliations

Affiliations

  • 1 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
  • 2 Institute of Animal Molecular Biotechnology, Korea University, Seoul, Republic of Korea.
  • 3 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio. hg-kim@korea.ac.kr jinx2354@163.com.
  • 4 Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
  • 5 Institute of Translational Medicine, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 6 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
  • 7 Specific Organ Cancer Division, Research Institute and hospital, National Cancer Center, Goyang, Republic of Korea.
  • 8 Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. hg-kim@korea.ac.kr jinx2354@163.com.
  • # Contributed equally.
PMID: 29208670 DOI: 10.1158/1078-0432.CCR-17-1529
Abstract

Purpose: Normal stem cells tightly control self-renewal and differentiation during development, but their neoplastic counterparts, Cancer Stem Cells (CSCs), sustain tumorigenicity both through aberrant activation of stemness and evasion of differentiation. Although regulation of CSC stemness has been extensively studied, the molecular mechanisms suppressing differentiation remain unclear.Experimental Design: We performed in silico screening and in vitro validation studies through Western blotting, qRT-PCR for treatment of Wnt and SHH signaling inhibitors, and BMP signaling inducer with control and ID1-overexpressing cells. We also performed in vivo drug treatment assays with Balb/c nude mice.Results: Inhibitor of differentiation 1 (ID1) abrogated differentiation signals from bone morphogenetic protein receptor (BMPR) signaling in glioblastoma stem cells (GSCs) to promote self-renewal. ID1 inhibited BMPR2 expression through miRNAs, miR-17 and miR-20a, which are transcriptional targets of MYC. ID1 increases MYC expression by activating Wnt and SHH signaling. Combined pharmacologic blockade of Wnt and SHH signaling with BMP treatment significantly suppressed GSC self-renewal and extended survival of tumor-bearing mice.Conclusions: Collectively, our results suggested that ID1 simultaneously regulates stemness through Wnt and SHH signaling and differentiation through BMPR-mediated differentiation signaling in GSCs, informing a novel therapeutic strategy of combinatorial targeting of stemness and differentiation. Clin Cancer Res; 24(2); 383-94. ©2017 AACR.

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