방사선생물학

본문글자크기
  • [Oncogene.] PARK7 maintains the stemness of glioblastoma stem cells by stabilizing epidermal growth factor receptor variant III EGFRvIII를 안정화시키는 PARK7에 의해 glioblastoma의 stemness가 유지되고 therapeutic resistance가 발생한다는 것을 보고

    KIRAMS / 김정엽, 박명진*

  • 출처
    Oncogene.
  • 등재일
    2020 Nov 13. doi: 10.1038/s41388-020-01543-1.
  • 저널이슈번호
  • 내용

    바로가기  >

    Abstract
    PARK7 is involved in many key cellular processes, including cell proliferation, transcriptional regulation, cellular differentiation, oxidative stress protection, and mitochondrial function maintenance. Deregulation of PARK7 has been implicated in the pathogenesis of various human diseases, including cancer. Here, we aimed to clarify the effect of PARK7 on stemness and radioresistance of glioblastoma stem cells (GSCs). Serum differentiation and magnetic cell sorting of GSCs revealed that PARK7 was preferentially expressed in GSCs rather than differentiated GSCs. Immunohistochemical staining showed enhanced expression of PARK7 in glioma tissues compared to that in normal brain tissues. shRNA-mediated knockdown of PARK7 inhibited the self-renewal activity of GSCs in vitro, as evidenced by the results of neurosphere formation, limiting dilution, and soft-agar clonogenic assays. In addition, PARK7 knockdown suppressed GSC invasion and enhanced GSC sensitivity to ionizing radiation (IR). PARK7 knockdown suppressed expression of GSC signatures including nestin, epidermal growth factor receptor variant III (EGFRvIII), SOX2, NOTCH1, and OCT4. Contrarily, overexpression of PARK7 in CD133- non-GSCs increased self-renewal activities, migration, and IR resistance, and rescued the reduction of GSC factors under shPARK7-transfected and serum-differentiation conditions. Intriguingly, PARK7 acted as a co-chaperone of HSP90 by binding to it, protecting EGFRvIII from proteasomal degradation. Knockdown of PARK7 increased the production of reactive oxygen species, inducing partial apoptosis and enhancing IR sensitivity in GSCs. Finally, PARK7 knockdown increased mouse survival and IR sensitivity in vivo. Based on these data, we propose that PARK7 plays a pivotal role in the maintenance of stemness and therapeutic resistance in GSCs.

     

     

    Affiliations

    Jeong-Yub Kim  1 , Hee-Jin Kim  1   2 , Chan-Woong Jung  1   3 , Byung-Il Choi  4 , Dea-Hee Lee  5 , Myung-Jin Park  6
    1 Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
    2 School of Biomedical Science, Korea University, Seoul, Republic of Korea.
    3 Department of Life Sciences, Korea University, Seoul, Republic of Korea.
    4 Division of Gastroenterology, Department of Internal Medicine, Korea University College of Medicine Guro Hospital, 148, Gurodong-ro, Guro-gu, Seoul, Republic of Korea.
    5 Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangwon, Republic of Korea. neogene@gwnu.ac.kr.
    6 Radiation Therapeutics Development Team, Division of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea. mjpark@kirams.re.kr.

  • 편집위원

    PARK7은 세포증식, 전자조절, 세포분화 등의 핵심 조절자로 알려져 있으며, Cancer pathtogenesis와도 깊은 연관성이 있는 것으로 알려졌다. 본 연구는 PARK7이 HSP90의 co-chaperone으로 작용하여 EGFRvIII을 안정화시킴으로써, GBM의 stemness를 유지하고 방사선 치료 저항성을 유도함을 규명하였다.

    2021-01-05 16:57:39

  • 편집위원2

    EGFRvIII를 안정화시키는 PARK7가 GBM의 줄기세포 능력을 유지하는 기능과, 이것 때문에 치료에 저항성이 생기는 특성을 규명함.

    2021-01-05 16:58:02

  • 덧글달기
    덧글달기
       IP : 44.200.175.255

    등록