Forkhead Transcription Factor FOXO1 Inhibits Angiogenesis in Gastric Cancer in Relation to SIRT1

Abstract

PurposeWe 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 MethodsStable 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.ResultsIn 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.ConclusionOur 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.

Deciphering the roles of FOXO1 in human neoplasms

“…Specifically, the bound 3′UTR of FOXO1 inhibits the metastasis of breast cancer cells via out competing E‐cadherin . Additionally, FOXO1 silencing enhances angiogenesis of gastric cancer by upregulating the heat shock factor HIF‐1α and vascular endothelial growth factor (VEGF), while FOXO1 activation reverses this process and restrains tumor progression . Taken together, this research reveals that FOXO1 exerts antineoplastic mechanisms via antiprogression, antiproliferation and proapoptosis mechanisms (Fig.…”

Sirtuin-1 and Its Relevance in Vascular Calcification

“…CR is a dietary regimen that induces eNOS expression and is accompanied by enhanced Sirt1 levels, which is considered a link to delay aging and extend the lifespan in mammals [53]. The Forkhead box O (FoxO) transcription factor is an important element to maintain endothelial morphology [54], inducing EC apoptosis [55] and inhibiting angiogenesis [56][57][58], which have protective roles against oxidative injury. FoxO activity is mainly regulated by protein kinase B (Akt), which directly phosphorylates FoxO factors and leads to nuclear/cytoplasmic shuttling of FoxOs [59,60].…”

Metabolism of Reactive Oxygen Species in Osteosarcoma and Potential Treatment Applications

“…Epigenetic regulation, especially phosphorylation by AKT serine/threonine kinase (Akt), could promote its degradation and dysfunction [6]. Importantly, FoxO factors have been identified as tumour suppressors involved in the biological behaviours of cancer cells, such as extracellular matrix degradation, angiogenesis and migration [7][8][9]. FoxO factors are involved in regulating the genes associated with cellular cycle progression and inducing apoptosis [10].…”

“…FoxO factors are involved in regulating the genes associated with cellular cycle progression and inducing apoptosis [10]. It has also been proven that FoxO proteins play a suppressive role in cancers of multiple systems, such as gastric cancer, bladder cancer, liver cancer and breast cancer [8,[11][12][13]. FoxO factors are also involved in regulating reactive oxygen species (ROS) detoxification by upregulating mitochondrial superoxide dismutase (SOD2) [14].…”