Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer

Wei Ching Chen, Yung Sheng Chang, Hui Ping Hsu, Meng Chi Yen, Hau Lun Huang, Chien Yu Cho, Chih Yang Wang, Tzu Yang Weng, Po Ting Lai, Ching Shih Chen, Yih Jyh Lin, Ming Derg Lai

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.

Original languageEnglish
Pages (from-to)42923-42937
Number of pages15
JournalOncotarget
Volume6
Issue number40
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Keywords

  • AMPK
  • Cancer stem cell marker
  • Integrin
  • MTOR
  • OSU-CG5

ASJC Scopus subject areas

  • Oncology

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