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.
Highlights
Bladder cancer (BC) is a significant public health issue worldwide; it is the fourth most commonly diagnosed tumor and the second most common cause of death among genitourinary tumors.[1]
Our results demonstrate that ATG7 overexpression promotes miR-196b expression, which subsequently binds to the FOXO1 mRNA 30 UTR and leads to FOXO1 mRNA degradation and p27 transcription inhibition, in turn promoting human BC tumorigenic growth
The canonical pathway controlling autophagosome formation requires ATG7, which acts as an E1 enzyme and is responsible for the two ubiquitin-like systems required for transport from the cytoplasm to the vacuole and further leading to autophagy.[27,28]
Summary
Bladder cancer (BC) is a significant public health issue worldwide; it is the fourth most commonly diagnosed tumor and the second most common cause of death among genitourinary tumors.[1]. The advances in suitable therapies for increasing the survival rate of BC patients have been limited because of the poor understanding of the underlying mechanisms of tumorigenesis and cancer progression. ATG7 (autophagy-related gene 7) is an E1-like activating enzyme involved in the two ubiquitin-like systems required for autophagy.[2,3] It has been reported that the liver-specific deletion of ATG7 promotes spontaneous tumorigenesis by simultaneous deletion of p62.4 lung-specific ATG7 deficiency inhibits KrasG12D-driven lung tumor growth and reduction of lung tumor burden with dysfunctional mitochondria and proliferative arrest.[5] ATG7 deficiency produces an autophagy-deficient phenotype and inhibits PTEN (phosphatase and tensin homolog)-deficient prostate tumor progression through management of protein homeostasis under endoplasmic reticulum (ER) stress.[6] in our most recent studies, we have shown that ATG7 and its mediated autophagy were much higher in human BC cell lines and N-Butyl-N-(4-hydmoxybutyl)nitrosamine (BBN)treated UROtsa cells as well as in BBN-induced mouse invasive BCs, which play a promotive role in human BC invasion (J.Z., unpublished data). We elucidated the potential role and molecular mechanism of the essential autophagy gene ATG7 in promoting human BC tumorigenic growth in vitro and in vivo
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