한빛사논문
- 조회693
Jungwhoi Lee1 · Eunsoo Kim2 · Kyuha Chong3,4,5 · Seung‑Wook Ryu2 · Chungyeul Kim6 · Kyungsun Choi2 · Jae‑Hoon Kim1 · Chulhee Choi2,7
1 Department of Applied Life Science, Sustainable Agriculture Research Institute (SARI), Jeju National University, 102 Jejudaehak-ro, Jeju, Jeju-do 63243, Republic of Korea
2 ILIAS Biologics Inc, 40-20, Techno 6-ro, Yuseong-gu, Daejeon 34014, Republic of Korea
3 Department of Neurosurgery, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu,
Seoul 08308, Republic of Korea
4 Laboratory of Photo-Theranosis and Bioinformatics for Tumors, Department of Neurosurgery, Samsung Medical Center, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of Korea
5 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul 06351, Republic of Korea
6 Department of Pathology, Korea University Guro Hospital, Korea University Medicine, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Republic of Korea
7 Department of Bio and Brain Engineering, KAIST, 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea
Jungwhoi Lee, Eunsoo Kim and Kyuha Chong have contributed to this work equally.
Corresponding authors: Correspondence to Jungwhoi Lee or Chulhee Choi.
Abstract
Contact-based pericellular interactions play important roles in cancer progression via juxtacrine signaling pathways. The present study revealed that hypoxia-inducible factor-1α (HIF-1α), induced even in non-hypoxic conditions by cell-to-cell contact, was a critical cue responsible for the malignant characteristics of glioblastoma multiforme (GBM) cells through Notch1 signaling. Densely cultured GBM cells showed enhanced viability and resistance to temozolomide (TMZ) compared to GBM cells at a low density. Ablating Notch1 signaling by a γ-secretase inhibitor or siRNA transfection resensitized resistant GBM cells to TMZ treatment and decreased their viability under dense culture conditions. The expression of HIF-1α was significantly elevated in highly dense GBM cells even under non-hypoxic conditions. Atypical HIF-1α expression was associated with the Notch1 signaling pathway in both GBM and glioblastoma stem cells (GSC). Proteasomal degradation of HIF-1α was prevented by binding with Notch1 intracellular domain (NICD), which translocated to the nuclei of GBM cells. Silencing Notch1 signaling using a doxycycline-inducible Notch1 RNA-interfering system or treatment with chetomin, a HIF pathway inhibitor, retarded tumor development with a significant anti-cancer effect in a murine U251-xenograft model. Using GBM patient tissue microarray analysis, a significant increase in HIF-1α expression was identified in the group with Notch1 expression compared to the group without Notch1 expression among those with positive HIF-1α expression. Collectively, these findings highlight the critical role of cell-to-cell contact-dependent signaling in GBM progression. They provide a rationale for targeting HIF-1α signaling even in a non-hypoxic microenvironment.
논문정보
- Research article
- 2022년 10월 (BRIC 등록일 2022-12-13)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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