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Long noncoding RNA CASC11 promotes osteosarcoma metastasis by suppressing degradation of snail mRNA.

ABSTRACT: Osteosarcoma (OS) is the most common primary bone tumor in adolescents. Dysregulation of long noncoding RNAs (lncRNAs) is associated with the cancer progression, of which cancer susceptibility candidate 11 (CASC11) has been indicated as an oncogene in several human cancers. However, the underlying mechanisms by which CASC11 contributes to OS metastasis remain undetermined. Here, we found that CASC11 expression in OS tissues was markedly higher than that in noncancerous tissues. Clinical association analysis revealed that high CASC11 expression correlated with clinical stage, distant metastasis and poor prognosis of OS patients. Gain- and loss-of-function assays demonstrated that CASC11 promoted migration, invasion, epithelial-mesenchymal transition (EMT) and metastasis of OS cells in vitro and in vivo. CASC11 associated with the EMT inducer Snail mRNA and increased its stability. Association of CASC11 with Snail mRNA blocked the repressing effect of miR-122, miR-145, miR-211, miR-34a and miR-137 on Snail. Moreover, CASC11-specific siRNAs significantly inhibit tumor metastasis in vivo. Taken together, our findings suggest that CASC11 may be a candidate prognostic biomarker and a novel therapeutic target for OS.

SUBMITTER: Song K

PROVIDER: S-EPMC6405980 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGrowing evidences have been revealing that long noncoding RNAs are vital factors in oncogenesis and tumor development. Among them, cancer susceptibility candidate 11 (CASC11) has displayed an impressively essential role in various kinds of cancers including hepatocellular carcinoma (HCC). Nevertheless, its role and potential mechanism in HCC still remain to be fully investigated.MethodsCASC11 expression level was evaluated by real-time polymerase chain reaction, western blotting, and in situ hybridization staining in HCC patients, and its prognostic effect was analyzed. The role of CASC11 in HCC tumorigenesis and progression was investigated by cell proliferation assay, transwell assay, extracellular acidification rate, western blotting, flow cytometry, and an in vivo xenograft model. The interactions among CASC11, E2F transcription factor 1 (E2F1), and eukaryotic translation initiation factor 4A3 (EIF4A3) were explored by using quantitative reverse transcriptase polymerase chain reaction, western blotting, RNA-binding protein immunoprecipitation assay, and chromatin immunoprecipitation assays.ResultsUpregulation of CASC11 was confirmed in HCC tissues and associated with poor prognosis. Loss of function assays showed inhibition of CASC11 expression suppressed HCC cells proliferation, mobility, and glucose metabolism and promoted apoptosis. E2F1 expression significantly decreased after inhibition of CASC11. Rescue experiments illustrated that E2F1 overexpression alleviated the suppression of CASC11 inhibition on HCC progression in vitro and in vivo. Mechanistically, CASC11 recruited EIF4A3 to enhance the stability of E2F1 mRNA. CASC11 and E2F1 impacted the activation of the NF-κB signaling and PI3K/AKT/mTOR pathway and further regulated the expression PD-L1 that is an important target of immunotherapy. In addition, we identified YY1 could modulate CASC11 expression by binding to its promoter.ConclusionsOur data revealed that CASC11 promoted the progression of HCC by means of EIF4A3-mediated E2F1 upregulation, indicating CASC11 is a promising diagnostic biomarker and therapeutic target for HCC.

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Long noncoding RNA CASC11 promotes osteosarcoma metastasis by suppressing degradation of snail mRNA.

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