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Overexpression of lncRNA MAGI2-AS3 Retards Tumor Progression and Angiogenesis by Regulating ACY1 via Interacting with Transcription Factor HEY1
34 Pages Posted: 11 Aug 2020
More...Abstract
Background: Clear cell renal cell carcinoma (ccRCC) is a high vascularized malignancy that is unresponsive to chemotherapy and resistant to radiotherapy. So far, it remains to be determined about the complexity of tumor vasculature in ccRCC. Long non-coding RNAs (lncRNAs) are recognized as regulators of gene expression in tumor development and angiogenesis, while their effects on metastasis and tumor vasculature of ccRCC are less understood. Here we functionally characterize a lncRNA MAGI2-AS3 as a regulator of tumor vasculature in ccRCC and detail the molecular mechanism of action.
Methods and Results: At first, we determined downregulated MAGI2-AS3 and ACY1 in tumor tissues compared to adjacent no-tumor tissues collected from 86 ccRCC patients. Low expression of MAGI2-AS3 was associated with poor patient survival. Gain- and loss-of-function studies demonstrated overexpression of MAGI2-AS3 was shown to retard ccRCC cell viability and migration, inhibit vessel-like tube formation of HUVECs in vitro, and repress tumor growth and angiogenesis in the xenograft ccRCC mouse model. Dual-luciferase reporter assay, RIP, and ChIP assays showed lncRNA MAGI2-AS3 bound with HEY1 and reduced the HEY1 enrichment at the ACY1 promoter region, thus increasing ACY1 gene transcription. For the rescue experiments, HEY1 knockdown or ACY1 overexpression resisting to MAGI2-AS3 knockdown was found in both in vivo and in vitro settings.
Conclusions: Taken together, the present study supports the MAGI2-AS3/HEY1/ACY1 pathway as a novel target for developing anti-angiogenesis therapy for ccRCC.
Funding Statement: None.
Declaration of Interests: The authors declare that they have no conflict of interest.
Ethics Approval Statement: Subjects were included using informed consent for a protocol approved by the Ethics committee of China-Japan Union Hospital of Jilin University. Animal studies were performed with the approval from the Institutional Animal Care and Use Committee of the China-Japan Union Hospital of Jilin University.
Keywords: Clear cell renal cell carcinoma; Long non-coding RNA; MAGI2-AS3; Angiogenesis; HEY1; ACY1
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