Abstract 3310: Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo

Abstract

Abstract Autophagy is the basic catabolic mechanism regulating degradation of unnecessary or dysfunctional cellular components and is regulated by the autophagy-related gene 7 (Atg7). Since invasive bladder cancer (BC) can progress to life threatening metastases, understanding the molecular mechanisms underlying BC invasion is of tremendous importance for potentially reducing the mortality of this disease. In the present study, we for the first time found that the Atg7 was remarkably upregulated in human BC cell lines and the BBN-induced mouse invasive BCs, which is consistent with our most recent finding in human BCs. The knockdown of Atg7 in human BC cells dramatically inhibited cancer cell invasion, suggesting that Atg7 is a key player in regulation of BC invasion. Mechanistic studies revealed that Atg7 overexpression was mediated by miR-190, which was highly upregulated at transcriptional level in BC tissues and cell lines, and was able to bind to 3’-UTR of atg7 mRNA for its stabilization. Moreover, Atg7-mediated autophagic mechanism could remove AUF1 protein and in turn reduced AUF1 interaction with rhogdi2 mRNA, resulting in elevation of rhogdi2 mRNA stability, and subsequently leading to BC cell invasion. Remarkably, inhibition of Atg7-mediated autophagy led to AUF1 protein accumulation, RhoGDI2 downregulation and BC cell invasion attenuation. Collectively, our results demonstrate that overexpressed Atg7 mediates BC cell autophagy, which removes AUF1 protein, thereby reducing its binding with rhogdi2 mRNA and subsequently leading to elevation of rhogdi2 mRNA stability and protein expression, further promoting BC invasion. The identification of miR-190/Atg7 autophagic mechanism regulating AUF1/RhoGDI2 expression provides a significant insight into understanding the nature of BC invasion, and is also highly potential for developing autophagy-based-specific therapeutic strategy for treatment of human BC patients. Citation Format: Junlan Zhu, Yang Li, Chuanshu Huang, Haishan Huang. Atg7 overexpression promotes bladder cancer invasion via autophagic removal of AUF1 protein and subsequently increased RhoGDI2 mRNA stability in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3310. doi:10.1158/1538-7445.AM2017-3310