Abstract | BACKGROUND: 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.
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Authors | 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 |
Journal | Journal of biomedical science
(J Biomed Sci)
Vol. 29
Issue 1
Pg. 20
(Mar 22 2022)
ISSN: 1423-0127 [Electronic] England |
PMID | 35313878
(Publication Type: Journal Article)
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Copyright | © 2022. The Author(s). |
Chemical References |
- STAT1 Transcription Factor
- STAT1 protein, human
- Stat1 protein, mouse
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Topics |
- Animals
- Colorectal Neoplasms
(drug therapy, genetics, pathology)
- Humans
- Mice
- Mice, Knockout
- Neoplastic Stem Cells
(pathology)
- Neovascularization, Pathologic
(drug therapy, genetics)
- Oncogenes
- STAT1 Transcription Factor
(genetics, metabolism)
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