STIL Promotes Tumorigenesis of Bladder Cancer by Activating PI3K/AKT/mTOR Signaling Pathway and Targeting C-Myc.

Content Provider	Europe PMC
Author	Yu, Hua Chen, Liang Wang, Xia Tang, Feng Wan, Ziyu Wang, Hao Fu, Qiqi Chen, Zhizhuang Shi, Jiageng Hu, Xuan Zuhaer, Yisha Aersi, Madanyeti Liu, Tao Tao, Huangheng Peng, Jianping
Editor	Morrione, Andrea
Copyright Year	2022
Abstract	Simple SummaryCurrently; there are no reports on the role of STIL in bladder cancer. Using public databases; we observed that STIL is highly expressed in bladder cancer and is closely related to the cell cycle. The results of tumor formation experiments on UMUC3 and T24 bladder cancer cell lines indicate that STIL promotes the growth of bladder cancer cells in vivo and in vitro. Mechanistically, the cell cycle after STIL knockout was arrested in the G0/G1 phase; and cell cycle-related proteins (cyclin D1 and CDK2/4/6) were also reduced. RNA-seq results and immunoblotting experiments confirmed that STIL enhanced the PI3K/AKT/mTOR pathway, resulting in increased c-myc expression which ultimately promoted the occurrence and progression of bladder cancer. Our results suggest that STIL may be a promising potential therapeutic target for bladder cancer.AbstractSCL/TAL1 interrupting locus (STIL) regulates centriole replication and causes chromosome instability, which is closely related to malignant tumors. The purpose of our study was to investigate the role of STIL in bladder cancer (BC) tumorigenesis for the first time. The public database indicated that STIL is highly expressed and correlated with the cell cycle in BC. Immunohistochemistry staining showed that STIL expression is significantly elevated in BC tissues compared with paracancer tissues. CRISPR-Cas9 gene editing technology was used to induce BC cells to express STIL-specific sgRNA, revealing a significantly delayed growth rate in STIL knockout BC cells. Moreover, cell cycle arrest in the G0/G1 phase was triggered by decreasing STIL, which led to delayed BC cell growth in vitro and in vivo. Mechanically, STIL knockout inhibited the PI3K/AKT/mTOR pathway and down-regulated the expression of c-myc. Furthermore, SC79 (AKT activating agent) partially reversed the inhibitory effects of STIL knockout on the proliferation and migration of BC cells. In conclusion, STIL enhanced the PI3K/AKT/mTOR pathway, resulting in increased expression of c-myc, ultimately promoting BC occurrence and progression. These results indicate that STIL might be a potential target for BC patients.
Journal	Cancers
Volume Number	14
PubMed Central reference number	PMC9739707
Issue Number	23
PubMed reference number	36497260
e-ISSN	20726694
DOI	10.3390/cancers14235777
Language	English
Publisher	MDPI
Publisher Date	2022-11-24
Access Restriction	Open
Rights License	Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). © 2022 by the authors.
Subject Keyword	STIL bladder cancer PI3K/AKT/mTOR pathway c-myc cell cycle
Content Type	Text
Resource Type	Article
Subject	Oncology Cancer Research