Gli2 诱导的 circ-STAT3 转录激活通过作为 miR-29a/b/c-3p 的海绵体来上调 STAT3/Gli2，促进肝母细胞瘤的进展。
Transcription activation of circ-STAT3 induced by Gli2 promotes the progression of hepatoblastoma via acting as a sponge for miR-29a/b/c-3p to upregulate STAT3/Gli2.
机构信息
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, No.107 Wenhuaxi Road, Jinan, 250012, Shandong Province, China.
Department of General Surgery, 96602 Military Hospital, No.462 Chuanjin Road, Kunming, 650224, Yunnan Province, China.
出版信息
J Exp Clin Cancer Res. 2020 Jun 3;39(1):101. doi: 10.1186/s13046-020-01598-8.
BACKGROUND
Hepatoblastoma (HB) is a common liver malignancy in children. Our previous study has disclosed the crucial role of STAT3 (signal transducer and activator of transcription 3) in HB.
AIM OF THE STUDY
Present study was designed to study the circular RNA (circRNA) STAT3 in HB.
METHODS
Gel electrophoresis revealed the circular characteristics of circ-STAT3. Function assays like EdU, transwell and sphere formation assay disclosed the function of circ-STAT3 in HB cells. Mechanism assays including ChIP, RIP, RNA pull down assay demonstrated the macular mechanism underlying circ-STAT3.
RESULTS
Circ_0043800, which was originated from STAT3, was up-regulated in HB tissues and cells. More importantly, silencing of circ-STAT3 led to the inhibition on HB cell growth, migration and stem-cell characteristics. Circ_0043800 was predominantly located in the cytoplasm of HB cells. Then, circ_0043800 was found to up-regulate STAT3 via sponging miR-29a/b/c-3p. Besides, we identified that STAT3 overexpression partially rescued silenced circ_0043800, while miR-29a/b/c-3p inhibition completely rescued silenced circ_0043800 on HB cellular biological behaviors. Subsequently, Gli2 (GLI family zinc finger 2) was identified as another target of miR-29a/b/c-3p. Circ_0043800 served as a competing endogenous RNA (ceRNA) to up-regulate both Gli2 and STAT3 via sponging miR-29a/b/c-3p. Moreover, we figured out that Gli2 overexpression completely rescued silenced circ_0043800 on HB cell malignant behaviors. After that, we discovered that Gli2 transcriptionally activated circ_0043800. The in-vivo assays further revealed that circ_0043800 promoted HB tumor growth by up-regulation of Gli2 and STAT3.
CONCLUSION
Gli2-induced circ_0043800 served as the ceRNA to promote HB by up-regulation of STAT3 and Gli2 at a miR-29a/b/c-3p dependent manner.
背景
肝母细胞瘤（HB）是儿童常见的肝脏恶性肿瘤。我们之前的研究揭示了 STAT3（信号转导和转录激活因子 3）在 HB 中的关键作用。
目的
本研究旨在研究 HB 中的环状 RNA（circRNA）STAT3。
方法
凝胶电泳显示 circ-STAT3 的环状特征。EdU、transwell 和球体形成实验等功能测定揭示了 circ-STAT3 在 HB 细胞中的功能。包括 ChIP、RIP 和 RNA 下拉实验在内的机制测定证明了 circ-STAT3 背后的关键机制。
结果
来源于 STAT3 的 circ_0043800 在 HB 组织和细胞中上调。更重要的是，沉默 circ-STAT3 导致 HB 细胞生长、迁移和干细胞特性的抑制。circ_0043800 主要位于 HB 细胞的细胞质中。然后，circ_0043800 通过海绵吸附 miR-29a/b/c-3p 来上调 STAT3。此外，我们发现 STAT3 的过表达部分挽救了沉默的 circ_0043800，而 miR-29a/b/c-3p 的抑制完全挽救了沉默的 circ_0043800 对 HB 细胞生物学行为的影响。随后，鉴定出 Gli2（GLI 家族锌指蛋白 2）是 miR-29a/b/c-3p 的另一个靶标。circ_0043800 作为竞争性内源性 RNA（ceRNA），通过海绵吸附 miR-29a/b/c-3p 上调 Gli2 和 STAT3。此外，我们发现 Gli2 的过表达完全挽救了沉默的 circ_0043800 对 HB 细胞恶性行为的影响。之后，我们发现 Gli2 转录激活了 circ_0043800。体内实验进一步表明，circ_0043800 通过上调 Gli2 和 STAT3 促进 HB 肿瘤生长。
结论
Gli2 诱导的 circ_0043800 通过依赖于 miR-29a/b/c-3p 的方式上调 STAT3 和 Gli2 作为 ceRNA 促进 HB。
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