Hypoxia‐induced ELF3 promotes tumor angiogenesis through IGF1/IGF1R

• Published in: EMBO reports 2022-08, Vol.23 (8), p.e52977-n/a
• Main Authors: Seo, Seung Hee, Hwang, Soo‐Yeon, Hwang, Seohui, Han, Sunjung, Park, Hyojin, Lee, Yun‐Sil, Rho, Seung Bae, Kwon, Youngjoo
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Antiangiogenics; Anticancer properties; Attenuation; Cell migration; Cell proliferation; Depletion; ELF3; EMBO03; EMBO37; EMBO46; Endothelial cells; Hypoxia; Insulin-like growth factor I; Microenvironments; Ovarian cancer; Pathogenesis; Secretion; Transcription factors; tumor angiogenesis; Tumor cells; Tumorigenesis; Tumors; Vascular endothelial growth factor; Xenografts; Xenotransplantation
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202152977

Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers despite a relatively low incidence. Angiogenesis, one of the hallmarks of cancer, is essential for the pathogenesis of EOC, which is related to the induction of angiogenic factors. We found that ELF3 was highly expressed in EOCs under hypoxia and functioned as a transcription factor for IGF1. The ELF3‐mediated increase in the secretion of IGF1 and VEGF promoted endothelial cell proliferation, migration, and EOC angiogenesis. Although this situation was much exaggerated under hypoxia, ELF3 silencing under hypoxia significantly attenuated angiogenic activity in endothelial cells by reducing the expression and secretion of IGF1 and VEGF. ELF3 silencing attenuated angiogenesis and tumorigenesis in ex vivo and xenograft mouse models. Consequently, ELF3 plays an important role in the induction of angiogenesis and tumorigenesis in EOC as a transcription factor of IGF1. A detailed understanding of the biological mechanism of ELF3 may both improve current antiangiogenic therapies and have anticancer effects for EOC. Synopsis The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis. ELF3 is a transcription factor that induces angiogenesis by transcriptionally increasing IGF1 expression. Hypoxia enhances the effect of ELF3 on angiogenesis. ELF3 depletion in the ovarian cancer cells attenuates angiogenesis and tumorigenesis ex vivo and in xenograft models. Graphical Abstract The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis.