Journal Article

Akirin2 is modulated by miR-490-3p and facilitates angiogenesis in cholangiocarcinoma through the IL-6/STAT3/VEGFA signaling pathway

Cai, Hailong, Huang, Lining, Leng, Kaiming, Ji, Daolin, Kang, Pengcheng, Li, Zhenglong, Li, Jinglin, Xu, Yi, Qin, Wei, Cui, Yunfu, Jiang, Xingming, Zhong, Xiangyu, Wang, Zhidong, Sun, Xueying, Wang, Hao

2019

Overview

Akirin2 is a key regulator of embryonic development and the innate immunity response. However, this regulator’s role in tumorigenesis especially in cholangiocarcinoma (CCA) development has not been thoroughly elucidated to date. In the current work, we used RT-qPCR, western blot analysis, and immunohistochemistry (IHC) to explore the expression level of Akirin2, and the relationship between Akirin2 levels and clinicopathological characteristics was evaluated. The biological functions of Akirin2 were examined in vitro and in vivo by using a lentiviral vector system. Luciferase reporter assays were applied to detect the direct binding relationship between the 3′-UTR of Akirin2 mRNA and miR-490-3p. The results showed that Akirin2 was overexpressed in CCA and this upregulation was associated with a shorter overall survival. Silencing or overexpressing Akirin2 by lentiviral approaches significantly influenced CCA cell proliferation, migration, invasion, and angiogenesis. An in vivo tumor model further validated the oncogenic effect of Akirin2 on CCA cell growth, metastasis, and angiogenesis. Mechanistic studies demonstrated that Akirin2 induced angiogenesis by increasing the expression of VEGFA by activating the IL-6/STAT3 signaling pathway. Akirin2 promoted cell migratory and invasive potential by affecting the epithelial–mesenchymal transition (EMT) process. In addition, Akirin2 expression was negatively controlled by miR-490-3p in CCA cells, and miR-490-3p attenuated cell migration and angiogenesis in CCA cells by silencing Akirin2. Taken together, the data indicated that Akirin2 could be regulated by miR-490-3p at the posttranscriptional level and facilitate CCA cell progression via the IL-6/STAT3/VEGFA signaling pathway. The present study may expedite the development of novel therapeutic strategies for CCA.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13/1 / 13/89 / 14/63 / 3' Untranslated regions / 38/77 / 42/44 / 631/67/2328 / 631/67/322 / 631/67/395 / 64/60 / 96/1 / Angiogenesis / Animals / Antibodies / Bile Duct Neoplasms - blood supply / Bile Duct Neoplasms - genetics / Bile Duct Neoplasms - metabolism / Bile Duct Neoplasms - mortality / Biochemistry / Biomedical and Life Sciences / Cell adhesion & migration / Cell Biology / Cell Culture / Cell growth / Cell migration / Cell Movement - genetics / Cell proliferation / Cell Proliferation - genetics / Cholangiocarcinoma / Cholangiocarcinoma - blood supply / Cholangiocarcinoma - genetics / Cholangiocarcinoma - metabolism / Cholangiocarcinoma - mortality / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Embryogenesis / Gene Expression Regulation, Neoplastic / Human Umbilical Vein Endothelial Cells / Humans / Immunohistochemistry / Immunology / Innate immunity / Interleukin 6 / Interleukin-6 - metabolism / Life Sciences / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - secondary / Mesenchyme / Metastases / Mice / Mice, Inbred BALB C / Mice, Nude / MicroRNAs - genetics / MicroRNAs - metabolism / mRNA / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Post-transcription / Signal transduction / Signal Transduction - genetics / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism / Transplantation, Heterologous / Tumorigenesis / Vascular Endothelial Growth Factor A - genetics / Vascular Endothelial Growth Factor A - metabolism