Abstract
BackgroundHepatoblastoma (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 studyPresent study was designed to study the circular RNA (circRNA) STAT3 in HB.MethodsGel 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.ResultsCirc_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.ConclusionGli2-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.
Highlights
Hepatoblastoma (HB) is a common liver malignancy in children
Circ_0043800 was up-regulated in HB tissues and cells We firstly detected relative expression of 14 circRNAs which are derived from Signal transducer and activator of transcription 3 (STAT3) in HepG2 and HuH-6 cells normalized to control cells
Convergent primers were used to amplify STAT3 while divergent primers were used for circSTAT3 with cDNA and gDNA as the templates. It was revealed in Quantitative realtime PCR (qRT-PCR) that circ-STAT3 was amplified by divergent primers only in cDNA while STAT3 was amplified by convergent primers in both cDNA and gDNA (Fig. 1d)
Summary
Hepatoblastoma (HB) is a common liver malignancy in children. Hepatoblastoma (HB) is a highly invasive malignancy in children and takes up around 50% in pediatric liver cancers [1]. 20% of HB patients are confronted with metastasis when firstly diagnosed [2]. The annual morbidity of HB is 1.5 cases per million, which represents around 1% in childhood cancers [3], and its incidence has risen by 2.7% each year in the last decades [4]. Patients with lower risk have a 5-year survival rate of 80% while after relapse this number declines to 30– 40% [5]. Despite HB control has got advanced due to adjuvant chemotherapy, surgical resection, and liver transplantation, the prognosis for patients with advanced HB remains disappointing [6]. It is in need to identify effective biomarkers for early diagnosis of HB
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