SIX4 activates Akt and promotes tumor angiogenesis

Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not...

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Bibliographic Details
Published in:Experimental cell research 2019-10, Vol.383 (1), p.111495-111495, Article 111495
Main Authors: Sun, Xuling, Hu, Fuqing, Hou, Zhenlin, Chen, Qianzhi, Lan, Jingqin, Luo, Xuelai, Wang, Guihua, Hu, Junbo, Cao, Zhixin
Format: Article
Language:English
Subjects:
Akt activation
Angiogenesis
Animals
Apoptosis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cell Proliferation
Colorectal cancer
Colorectal Neoplasms - blood supply
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Female
Gene Expression Regulation, Neoplastic
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Lymphatic Metastasis
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Neovascularization, Pathologic - metabolism
Neovascularization, Pathologic - pathology
Prognosis
Proto-Oncogene Proteins c-akt - genetics
Proto-Oncogene Proteins c-akt - metabolism
Signal Transduction
SIX4
Survival Rate
Trans-Activators - genetics
Trans-Activators - metabolism
Tumor Cells, Cultured
Wound Healing
Xenograft Model Antitumor Assays
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Summary:Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not been fully understood. Here, we demonstrate that the Sine Oculis Homeobox Homolog 4 (SIX4) is up-regulated in colorectal cancer (CRC) and high expression of SIX4 predicts a poor prognosis. Overexpression of SIX4 enhances tumor growth and angiogenesis in vitro and in vivo, while knockdown of SIX4 inhibits tumor growth and angiogenesis. Furthermore, we show that SIX4 increases the expression of VEGF-A by coordinating with the HIF-1α. Mechanically, we explore that SIX4 up-regulates the expression of HIF-1α depending on Akt activation. Collectively, we demonstrate that SIX4 is functional in regulating tumor angiogenesis and SIX4 might be used as anti-angiogenic therapy in CRC.
ISSN:0014-4827
1090-2422
DOI:10.1016/j.yexcr.2019.111495