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LncRNA EBLN3P promotes the progression of osteosarcoma through modifying the miR-224-5p/Rab10 signaling axis.

ABSTRACT: The treatment of patients with advanced-stage osteosarcoma represents a major challenge, with very few treatments currently approved. Although accumulating evidence has demonstrated the importance of lncRNAs in osteosarcoma, the current knowledge on the functional roles and molecular mechanisms of lncRNA endogenous born avirus-like nucleoprotein (EBLN3P) is limited. At present, the expressions of EBLN3P and miR-224-5p in osteosarcoma tissues were quantified by reverse transcription-quantitative PCR assay, and the expression of Ras-related protein 10 (Rab10) in osteosarcoma tissues was quantified by immunohistochemistry and western-blotting. The bioinformatics prediction software ENCORI was used to predict the putative binding sites of EBLN3P, Rab10 and miR-224-5p. The regulatory role of EBLN3P or miR-224-5p on cell proliferation, migration and invasion ability were verified by Cell Counting Kit-8, wound healing and Transwell assays, respectively. The interaction among EBLN3P, miR-224-5p and Rab10 were testified by luciferase. The increased expression of EBLN3P and Rab10 and decreased expression of miR-224-5p were observed in osteosarcoma tissues and cell lines. Besides, the overexpression of EBLN3P or knockdown of miR-224-5p were revealed to promote the proliferation, migration and invasion of osteosarcoma cells. Bioinformatics analysis and luciferase assay revealed that EBLN3P could directly interacted with miR-224-5p to attenuate miR-224-5p binding to the Rab10 3'-untranslated region. Furthermore, the mechanistic investigations revealed activation of the miR-224-5p/Rab10 regulatory loop by knockdown of miR-372-3p or overexpression of Rab10, thereby confirming the in vitro role of EBLN3P in promoting osteosarcoma cell proliferation, migration and invasion. To the best of our knowledge, the present study is the first to demonstrate that EBLN3P may act as a competitive endogenous RNA to modulate Rab10 expression by competitive sponging to miR-224-5p, leading to the regulation of osteosarcoma progression, which indicates a possible new approach to osteosarcoma diagnosis and treatment.

SUBMITTER: Dai S

PROVIDER: S-EPMC7820338 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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LncRNA EBLN3P promotes the progression of osteosarcoma through modifying the miR-224-5p/Rab10 signaling axis.

Dai Shuhong S Li Ning N Zhou Ming M Yuan Yue Y Yue Ding D Li Tao T Zhang Xiaowei X

Scientific reports 20210121 1

The treatment of patients with advanced-stage osteosarcoma represents a major challenge, with very few treatments currently approved. Although accumulating evidence has demonstrated the importance of lncRNAs in osteosarcoma, the current knowledge on the functional roles and molecular mechanisms of lncRNA endogenous born avirus-like nucleoprotein (EBLN3P) is limited. At present, the expressions of EBLN3P and miR-224-5p in osteosarcoma tissues were quantified by reverse transcription-quantitative ...[more]

PMID: 33479458

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Project description:BackgroundOsteosarcoma (OS) is the most common primary malignant bone tumor in young people. Tumor-associated macrophages (TAMs) have been reported to play an important role in the development of osteosarcoma. However, the detailed molecular mechanisms remain largely unknown and need to be elucidated. Recently, exosomes have been reported as the crucial mediator between tumor cells and the tumor microenvironment. And a lot of lncRNAs have been reported to act as either oncogenes or tumor suppressors in osteosarcoma. In this research, we aim to explore the role of macrophages-derived exosomal lncRNA in osteosarcoma development and further elucidated the potential molecular mechanisms involved.MethodsTAMs were differentiated from human mononuclear cells THP-1, and a high-throughput microarray assay was used to analyze the dysregulated lncRNAs and miRNAs in osteosarcoma cells co-cultured with macrophages-derived exosomes. Western blot, qRT-PCR assays, and Dual-luciferase reporter assay were used to verify the interaction among LIFR-AS1, miR-29a, and NFIA. Cck-8, EdU, colony formation assay, wound-healing, and transwell assay were performed to explore the characterize the proliferation and metastasis ability of OS cells. And qPCR, Western blots, immunohistochemistry, and cell immunofluorescence were used to detect the expression of relative genes or proteins.ResultsIn this study, we found that THP-1-induced macrophage-derived exosomes could facilitate osteosarcoma cell progression both in vitro and in vivo. Then, the results of the high-throughput microarray assay showed that LIFR-AS1 was highly expressed and miR-29a was lowly expressed. Furthermore, LIFR-AS1 was identified as a miR-29a sponge, and NFIA was validated as a direct target of miR-29a. Functional assays demonstrated that knockdown of exosomal LIFR-AS1 could attenuate the promotion effects of macrophages-derived exosomes on osteosarcoma cell progression and miR-29a inhibition could reserve the effect of LIFR-AS1-knockdown exosomes. Correspondingly, NFIA-knockdown could partially reverse the tumor inhibition effect of miR-29a on osteosarcoma cells.ConclusionsTaken together, macrophages-derived exosomal lncRNA LIFR-AS1 can promote osteosarcoma cell proliferation, invasion, and restrain cell apoptosis via miR-29a/NFIA axis, which can act as a potential novel therapeutic target for osteosarcoma therapy.

Dataset Information

LncRNA EBLN3P promotes the progression of osteosarcoma through modifying the miR-224-5p/Rab10 signaling axis.

Publications

LncRNA EBLN3P promotes the progression of osteosarcoma through modifying the miR-224-5p/Rab10 signaling axis.

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