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

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. Present study was designed to study the circular RNA (circRNA) STAT3 in HB. 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. 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. 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.