1. Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1
- Author
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Byung Lan Lee, Sue Youn Kim, Jung-Soo Pyo, Jong Wan Park, Jinju Park, Jae Seon Lee, Young Hoon Kim, Yiseul Choi, Young Bok Yoo, and Young San Ko
- Subjects
Vascular Endothelial Growth Factor A ,endocrine system ,Cancer Research ,Angiogenesis ,Stomach neoplasms ,Mice, Nude ,FOXO1 ,Human FOXO1 protein ,Biology ,medicine.disease_cause ,Angiogenesis modulating agents ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Sirtuin 1 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gene silencing ,Transcription factor ,Cell Proliferation ,Human SIRT1 protein ,Neovascularization, Pathologic ,Forkhead Box Protein O1 ,Cell growth ,food and beverages ,Hypoxia-Inducible Factor 1, alpha Subunit ,Xenograft Model Antitumor Assays ,Cell Hypoxia ,Vascular endothelial growth factor ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Original Article ,lipids (amino acids, peptides, and proteins) ,030211 gastroenterology & hepatology ,Carcinogenesis ,hormones, hormone substitutes, and hormone antagonists - Abstract
Purpose We previously reported that forkhead transcription factors of the O class 1 (FOXO1) expression in gastric cancer (GC) was associated with angiogenesis-related molecules. However, there is little experimental evidence for the direct role of FOXO1 in GC. In the present study, we investigated the effect of FOXO1 on the tumorigenesis and angiogenesis in GC and its relationship with SIRT1. Materials and methods Stable GC cell lines (SNU-638 and SNU-601) infected with a lentivirus containing FOXO1 shRNA were established for animal studies as well as cell culture experiments. We used xenograft tumors in nude mice to evaluate the effect of FOXO1 silencing on tumor growth and angiogenesis. In addition, we examined the association between FOXO1 and SIRT1 by immunohistochemical tissue array analysis of 471 human GC specimens and Western blot analysis of xenografted tumor tissues. Results In cell culture, FOXO1 silencing enhanced hypoxia inducible factor-1α (HIF-1α) expression and GC cell growth under hypoxic conditions, but not under normoxic conditions. The xenograft study showed that FOXO1 downregulation enhanced tumor growth, microvessel areas, HIF-1α activation and vascular endothelial growth factor (VEGF) expression. In addition, inactivated FOXO1 expression was associated with SIRT1 expression in human GC tissues and xenograft tumor tissues. Conclusion Our results indicate that FOXO1 inhibits GC growth and angiogenesis under hypoxic conditions via inactivation of the HIF-1α-VEGF pathway, possibly in association with SIRT1. Thus, development of treatment modalities aiming at this pathway might be useful for treating GC.
- Published
- 2016