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SNHG9 promotes Hepatoblastoma Tumorigenesis via miR-23a-5p/Wnt3a Axis.

ABSTRACT: Background: Hepatoblastoma is a common hepatic tumor occurring in children between 0-5 years. Accumulating studies have shown lncRNA's potential role in distinct cancer progression and development, including hepatoblastoma. SnoRNA host gene 9 (SNHG9) is associated with the progression of distinct human cancers, but, its specific molecular mechanisms in hepatoblastoma is not unknown. Methods: In this study, we estimated SNHG9 expression in hepatoblastoma tissue and cell lines by quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). Next, we downregulated and upregulated SNHG9 expression in hepatoblastoma cell lines and then determined cell proliferation (CCK-8), colony formation, and cellular apoptosis activity. The dual luciferase reporter activity, RNA immunoprecipitation (RIP), biotin RNA pull down and Spemann's Pearson correlation coefficient assay were performed to establish the interaction between SNHG9, WNt3a and miR- 23a-5p. A xenograft in-vivo tumorgenicity test was performed to elucidate the role of SNHG9 hepatoblastoma in tumorigenesis. SNHG9 role in Cisplatin drug resistance in hepatoblastoma was also determined. Results: SNHG9 was significantly upregulated in hepatoblastoma tissue and cell lines. SNHG9 overexpression on HUH6 & HepG2 resulted in a significant increase in cell proliferation and clonogenic activity while SNHG9 knock down resulted in a sustained inhibition of cell proliferation and clonogenic activity. Dual luciferase activity, RNA immunoprecipitation and biotin pull down confirmed the direct interaction of miR-23a-5p with SNHG9. The xenograft tumorgenicity test showed SNHG9 downregulation significantly inhibited the tumor growth in BALB/c mice. ROC and Kaplan-Meier analysis showed potential prognostic and diagnostic importance of SNHG9 in hepatoblastoma. Conclusion: We concluded that SNHG9/miR-23a-5p/Wnt3a axis promotes the progression hepatoblastoma tumor.

SUBMITTER: Feng SG

PROVIDER: S-EPMC8425203 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, and radiotherapy is currently one of the main treatments. Long non-coding RNAs (lncRNAs) are associated with the radiosensitivity and tumorigenesis of HCC. However, the role and molecular mechanism of potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) in HCC are still unclear. The relative expression of KCNQ1OT1, microRNA-146a-5p (miR-146a-5p) and alkaline ceramidase 3 (ACER3) was quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Clonogenic assay was used to assess the radiosensitivity of cells. Cell apoptosis and metastasis were evaluated by flow cytometry and transwell assays, respectively. The protein levels of apoptosis markers, metastasis markers and ACER3 were detected by western blot (WB) analysis. The relationship between miR-146a-5p and KCNQ1OT1 or ACER3 was determined by dual-luciferase reporter assay. Additionally, animal experiments were carried out to explore the effect of KCNQ1OT1 silencing on HCC tumor growth in vivo. KCNQ1OT1 was highly expressed in HCC, and its knockdown hindered the proliferation and metastasis, while increased the radiosensitivity and apoptosis of HCC cells. MiR-146a-5p could interact with KCNQ1OT1, and its inhibition reversed the effects of silenced-KCNQ1OT1 on the radiosensitivity and tumorigenesis of HCC cells. Besides, ACER3 was a target of miR-146a-5p, and its overexpression inversed the effects of miR-146a-5p mimic on the radiosensitivity and tumorigenesis of HCC cells. The expression of ACER3 was regulated by KCNQ1OT1 and miR-146a-5p. Furthermore, KCNQ1OT1 also could reduce the growth of HCC by regulating the miR-146a-5p/ACER3 axis in vivo. Our study suggested that KCNQ1OT1 improved ACER3 expression to regulate the radiosensitivity and tumorigenesis of HCC through sponging miR-146a-5p, indicating that KCNQ1OT1 might be a new therapeutic target for HCC.

Project description:BackgroundRecently, multiple lines of evidence have demonstrated that linc00662 serves as an oncogene in various cancers. However, the exact mechanism of oncogenesis mediated by linc00662 in colorectal cancer (CRC) remains unknown. In this study, we aimed to explore the biological role of linc00662 in the regulation of CRC progression.MethodsBoth gene expression omnibus (GEO) and the cancer genome atlas (TCGA) datasets were used to evaluate the expression of linc00662. RT-qPCR was used to analyze the expression of linc00662, miR-497-5p, and AVL9 in CRC clinical samples and cell lines. Cell Counting Kit-8 (CCK-8), flow cytometry, transwell assay, and xenograft model were used to investigate the effect of linc00662 on CRC cell proliferation, cell cycle, and metastasis. Western blot analysis was used to analyze the expression of the epithelial-mesenchymal transition (EMT)-associated markers. Furthermore, bioinformatics analysis and mechanism assays were used to elucidate the underlying mechanism. Dual-luciferase reporter assays were used to analyze the regulatory relationships among linc00662, miR-497-5p, and AVL9.ResultsIn this study, we found that the expression of linc00662 was significantly upregulated in CRC tissues compared to normal tissues and positively correlated with tissue differentiation, T stage, and lymphatic metastasis. Further, our data showed that the expression of linc00662 was positively associated with lymph node metastasis, TMN stage, and poor-moderate differentiation. Patients with higher linc00662 expression level were more likely to have poorer overall survival. Knockdown of linc00662 inhibited CRC cell growth, induced cell apoptosis, triggered cell cycle arrest at G2/M phase, and suppressed cell migration and invasion through regulating the EMT pathway. Further, mechanistic studies revealed that knockdown of linc00662 significantly reduced the expression of AVL9, a direct target of miR-497-5p.ConclusionsLinc00662 was significantly upregulated in CRC, and mediated CRC progression and metastasis by competing with miR-497-5p to modulate the expression of AVL9. Therefore, our result sheds light on the potential application of linc00662 in CRC diagnosis and therapy.

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SNHG9 promotes Hepatoblastoma Tumorigenesis via miR-23a-5p/Wnt3a Axis.

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