ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis

Abstract

Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3′ UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients.

Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy

“…Wei et al analyzed and reported that with the removal of FIP200 in human breast cancer mouse models, tumor initiation and progression was suppressed [ 89 ]. The analysis of multiple cancers showed the overexpression of ATG5 in gastric [ 90 ] and prostate [ 91 ] cancers while overexpression of ATG7 was seen in bladder cancer [ 92 ]. In contrast, mice with systemic mosaic deletion of Atg5 or Atg7 developed benign liver adenomas that do not progress to adenocarcinoma or metastasize [ 93 ].…”

lncRNA SNHG1 Promotes Basal Bladder Cancer Invasion via Interaction with PP2A Catalytic Subunit and Induction of Autophagy

“…Their results, together with our other most recent findings showing that SNHG1 overexpression promotes normal urothelial cell transformation and growth, reveal our discovery that SNHG1 could completely mimic the biological effects of bladder carcinogen BBN exposure in terms of induction of urothelial cell transformation, invasion, and autophagy, as well as upregulation of ATG7 and MMP2 in human BC cells. 48 , 49 The results also showed that SNHG1 was significantly upregulated in human basal BC cells, and mechanistic studies showed that SNHG1 increased MMP2 expression via increases in the latter’s mRNA transcription and stability.…”

Tenascin-C Modulates Cell Cycle Progression to Enhance Tumour Cell Proliferation through AKT/FOXO1 Signalling in Pancreatic Cancer

“…Moreover, A previous study has shown that FOXO1 acts downstream of active AKT to downregulate p27 Kip1 , p21 Waf1 and Bim at the transcriptional level 15 , 25 , 26 . We observed that TNC/AKT caused a remarkable pFOXO1 activity and cytoplasm translocation, which indicates that TNC inhibited FOXO1 transcriptional activity.…”