Angiomotin promotes renal epithelial and carcinoma cell proliferation by retaining the nuclear YAP.

Meng Lv,Xin Wang,Peijun Liu,Yanwei Shen,Shuting Li,Xiaoman Zhang,Yanxia Sui,Changqin Luo,Jiao Yang,Fan Wang,Jin Yang

doi:10.18632/oncotarget.7161

Abstract

Renal cell carcinoma (RCC) is one of the common tumors in the urinary system without effective therapies. Angiomotin (Amot) can interact with Yes-associated protein (YAP) to either stimulate or inhibit YAP activity, playing a potential role in cell proliferation. However, the role of Amot in regulating the proliferation of renal epithelial and RCC cells is unknown. Here, we show that Amot is expressed predominantly in the nucleus of RCC cells and tissues, and in the cytoplasm and nucleus of renal epithelial cells and paracancerous tissues. Furthermore, Amot silencing inhibited proliferation of HK-2 and 786-O cells while Amot upregulation promoted proliferation of ACHN cells. Interestingly, the location of Amot and YAP in RCC clinical samples and cells was similar. Amot interacted with YAP in HK-2 and 786-O cells, particularly in the nucleus. Moreover, Amot silencing mitigated the levels of nuclear YAP in HK-2 and 786-O cells and reduced YAP-related CTGF and Cyr61 expression in 786-O cells. Amot upregulation slightly increased the nuclear YAP and YAP-related gene expression in ACHN cells. Finally, enhanced YAP expression restored proliferation of Amot-silencing 786-O cells. Together, these data indicate that Amot is crucial for the maintenance of nuclear YAP to promote renal epithelial and RCC proliferation.

Highlights

Renal cell carcinoma (RCC) is one of the common malignant tumors in the urinary system [1]
While the Amot family members can inhibit the proliferation of non-tumor kidney epithelial MDCK cells and human embryonic kidney (HEK) 293 cells by inhibiting Yesassociated protein (YAP) [17,18], other studies indicate that Amot can act as a co-activator of YAP to promote the growth of hepatocarcinoma cells and breast cancer [19,21]
In other RCC (5/52) and paracancerous tissues (19/45), Amot was detected in the nucleus and cytoplasm

Summary

Introduction

Renal cell carcinoma (RCC) is one of the common malignant tumors in the urinary system [1]. Yesassociated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), two key downstream transcription co-activators, can bind to several transcription factors, such as TEADs, and promote tumor cell proliferation [6,7]. Angiomotin (Amot) is a member of the motin family of angiostatin binding proteins and contains conservative coiled-coil domains and C-terminal PDZ binding motifs, regulating the migration, angiogenesis and endothelial cell function [12,13,14]. While the Amot family members can inhibit the proliferation of non-tumor kidney epithelial MDCK cells and human embryonic kidney (HEK) 293 cells by inhibiting YAP [17,18], other studies indicate that Amot can act as a co-activator of YAP to promote the growth of hepatocarcinoma cells and breast cancer [19,21]. The role of Amot/YAP in regulating RCC proliferation has not been explored

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