- 作者: Pei-Hsuan Chou, Cong-Kai Luo, Niaz Wali, Wen-Yen Lin, Shang-Kok Ng, Chun-Hao Wang, Mingtao Zhao, Sheng-Wei Lin, Pei-Ming Yang, Pin-Jung Liu, Jiun-Jie Shie & Tzu-Tang Wei
- 作者服務機構: 1.Center for Cardiovascular Research, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH, 43210, USA 2.Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics (TIGP-CBMB), Academia Sinica, Taipei, 11529, Taiwan 3.Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, 1st Section, Taipei, 10051, Taiwan 4.Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA 5.Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan 6.Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, 10617, Taiwan 7.Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan 8.Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Taipei, 11529, Taiwan 9.School of Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan 10.School of Pharmacy, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan 11.School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan 12.The Heart Center, Nationwide Children’s Hospital, Columbus, OH, 43210, USA
- 中文摘要:
- 英文摘要:
Background
Colorectal cancer (CRC) is a worldwide cancer with rising annual incidence. New medications for patients with CRC are still needed. Recently, fluorescent chemical probes have been developed for cancer imaging and therapy. Signal transducer and activator of transcription 1 (STAT1) has complex functions in tumorigenesis and its role in CRC still needs further investigation.
Methods
RNA sequencing datasets in the NCBI GEO repository were analyzed to investigate the expression of STAT1 in patients with CRC. Xenograft mouse models, tail vein injection mouse models, and azoxymethane/dextran sodium sulfate (AOM/DSS) mouse models were generated to study the roles of STAT1 in CRC. A ligand-based high-throughput virtual screening approach combined with SWEETLEAD chemical database analysis was used to discover new STAT1 inhibitors. A newly designed and synthesized fluorescently labeled 4’,5,7-trihydroxyisoflavone (THIF) probe (BODIPY-THIF) elucidated the mechanistic actions of STAT1 and THIF in vitro and in vivo. Colonosphere formation assay and chick chorioallantoic membrane assay were used to evaluate stemness and angiogenesis, respectively.
Results
Upregulation of STAT1 was observed in patients with CRC and in mouse models of AOM/DSS-induced CRC and metastatic CRC. Knockout of STAT1 in CRC cells reduced tumor growth in vivo. We then combined a high-throughput virtual screening approach and analysis of the SWEETLEAD chemical database and found that THIF, a flavonoid abundant in soybeans, was a novel STAT1 inhibitor. THIF inhibited STAT1 phosphorylation and might bind to the STAT1 SH2 domain, leading to blockade of STAT1-STAT1 dimerization. The results of in vitro and in vivo binding studies of THIF and STAT1 were validated. The pharmacological treatment with BODIPY-THIF or ablation of STAT1 via a CRISPR/Cas9-based strategy abolished stemness and angiogenesis in CRC. Oral administration of BODIPY-THIF attenuated colitis symptoms and tumor growth in the mouse model of AOM/DSS-induced CRC.
Conclusions
This study demonstrates that STAT1 plays an oncogenic role in CRC. BODIPY-THIF is a new chemical probe inhibitor of STAT1 that reduces stemness and angiogenesis in CRC. BODIPY-THIF can be a potential tool for CRC therapy as well as cancer cell imaging. - 中文關鍵字:
- 英文關鍵字: STAT1, Colorectal cancer, Stemness, Angiogenesis, 4’,5,7-trihydroxyisofavone (THIF), BODIPY-THIF