論文

査読有り 最終著者 国際誌
2018年3月

Stemness Is Enhanced in Gastric Cancer by a SET/PP2A/E2F1 Axis.

Molecular cancer research : MCR
  • Shuhei Enjoji
  • Ryotaro Yabe
  • Shunya Tsuji
  • Kazuhiro Yoshimura
  • Hideyoshi Kawasaki
  • Masashi Sakurai
  • Yusuke Sakai
  • Hiroko Takenouchi
  • Shigefumi Yoshino
  • Shoichi Hazama
  • Hiroaki Nagano
  • Hiroko Oshima
  • Masanobu Oshima
  • Michael P Vitek
  • Tetsuya Matsuura
  • Yoshitaka Hippo
  • Tatsuya Usui
  • Takashi Ohama
  • Koichi Sato
  • 全て表示

16
3
開始ページ
554
終了ページ
563
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1158/1541-7786.MCR-17-0393

Gastric cancer is the fifth most common malignancy and the third leading cause of cancer-related deaths worldwide. Chemotherapies against gastric cancer often fail, with cancer recurrence due potentially to the persistence of cancer stem cells. This unique subpopulation of cells in tumors possesses the ability to self-renew and dedifferentiate. These cancer stem cells are critical for initiation, maintenance, metastasis, and relapse of cancers; however, the molecular mechanisms supporting cancer stemness remain largely unknown. Increased kinase and decreased phosphatase activity are hallmarks of oncogenic signaling. Protein phosphatase 2A (PP2A) functions as a tumor-suppressor enzyme, and elevated levels of SET/I2PP2A, an endogenous PP2A protein inhibitor, are correlated with poor prognosis of several human cancers. Here, it was determined that SET expression was elevated in tumor tissue in a gastric cancer mouse model system, and SET expression was positively correlated with poor survival of human gastric cancer patients. Mechanistically, SET knockdown decreased E2F1 levels and suppressed the stemness of cancer cell lines. Immunoprecipitations show SET associated with the PP2A-B56 complex, and the B56 subunit interacted with the E2F1 transcription factor. Treatment of gastric cancer cells with the SET-targeting drug OP449 increased PP2A activity, decreased E2F1 protein levels, and suppressed stemness of cancer cells. These data indicate that a SET/PP2A/E2F1 axis regulates cancer cell stemness and is a potential target for gastric cancer therapy.Implications: This study highlights the oncogenic role of SET/I2PP2A in gastric cancer and suggests that SET maintains cancer cell stemness by suppressing PP2A activity and stabilizing E2F1. Mol Cancer Res; 16(3); 554-63. ©2018 AACR.

リンク情報
DOI
https://doi.org/10.1158/1541-7786.MCR-17-0393
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29330298
ID情報
  • DOI : 10.1158/1541-7786.MCR-17-0393
  • ISSN : 1541-7786
  • PubMed ID : 29330298

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