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Cancer Res., Sep 25 2023 | https://doi.org/10.1158/0008-5472.CAN-22-3965 Crosstalk between PARN and EGFR-STAT3 Signaling Facilitates Self-Renewal and Proliferation of Glioblastoma Stem Cells.

Jinlong Yin^1,2, Yoona Seo^1,3, Jiho Rhim^1,3, Xiong Jin², Tae Hoon Kim¹, Sung Soo Kim¹, Jun-Hee Hong¹, Ho-Shin Gwak^4,5, Heon Yoo^1,4, Jong Bae Park¹, and Jong Heon Kim^1,3

¹Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea.

²Henan-Macquarie University Joint Centre for Biomedical Innovation, School of Life Sciences, Henan University, Kaifeng, Henan, 475004, China.

³Cancer Molecular Biology Branch, Research Institute, National Cancer Center, Goyang 10408, Korea.

⁴Neuro-Oncology Clinic, National Cancer Center, Goyang 10408, Korea.

⁵Department of Cancer Control, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea

J. Yin and Y. Seo contributed equally to this article.

Corresponding Authors: Jong Heon Kim, Jong Bae Park

Abstract

Glioblastoma is the most common type of malignant primary brain tumor and displays highly aggressive and heterogeneous phenotypes. The transcription factor STAT3 has been reported to play a key role in glioblastoma malignancy. Thus, discovering targets and functional downstream networks regulated by STAT3 that govern glioblastoma pathogenesis may lead to improved treatment strategies. In this study, we identified that poly(A)-specific ribonuclease (PARN), a key modulator of RNA metabolism, activates EGFR-STAT3 signaling to support glioblastoma stem cells (GSCs). Functional integrative analysis of STAT3 found PARN as the top-scoring transcriptional target involved in RNA processing in glioblastoma patients, and PARN expression was strongly correlated with poor patient survival and elevated malignancy. PARN positively regulated self-renewal and proliferation of GSCs through its 3'-5' exoribonuclease activity. EGFR was identified as a clinically relevant target of PARN in GSCs. PARN positively modulated EGFR by negatively regulating the EGFR-targeting miRNA miR-7, and increased EGFR expression created a positive feedback loop to increase STAT3 activation. PARN depletion in GSCs reduced infiltration and prolonged survival in orthotopic brain tumor xenografts; similar results were observed using siRNA nanocapsule-mediated PARN targeting. Pharmacological targeting of STAT3 also confirmed PARN regulation by STAT3 signaling. In sum, these results suggest that a STAT3-PARN regulatory network plays a pivotal role in tumor progression and thus may represent a target for glioblastoma therapeutics.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-27)
연구진국내(교신)+국외 연구진
분야 생명과학 > 분자생물학

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