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KIAA1429 promotes osteosarcoma progression by promoting stem cell properties and is regulated by miR-143-3p.

ABSTRACT: Background: Osteosarcoma (OS) is the most common primary bone malignancy, it has a dismal prognosis and mainly affects the children and adolescents. Previous reports have demonstrated that aberrantly expressed KIAA1429 plays crucial roles in the carcinogenesis of several cancers, but its expression status and functional role in the progression of OS have not previously been investigated.Methods: Immunohistochemistry (IHC) and western blotting were conducted to determine KIAA1429 expression status in OS. The relationship between KIAA1429 expression and OS prognosis was analyzed based on public database and tissue microarray (TMA). Cell proliferation ability was evaluated by CCK8, EdU and colony formation assays, and Transwell and wound healing potential were also assessed in vitro. Xenograft nude mouse model was performed to elucidate the tumor growth in vivo. The main specific miRNA targeting KIAA1429 in OS cells was identified.Results: KIAA1429 expression is markedly overexpressed in OS, and elevated KIAA1429 expression is significantly associated with an unfavorable prognosis. Functional investigations demonstrate that KIAA1429 silencing could attenuate proliferation, migration and invasion abilities of OS in vitro, as well as tumor growth in vivo. Mechanistically, microRNA-143-3p (miR-143-3p) was identified as the crucial specific mediator of KIAA1429 expression in OS cells. Furthermore, restoring KIAA1429 expression could partially reverse miR-143-3p mediated tumor-inhibition effects. Additionally, we found that knockdown of KIAA1429 or ectopic overexpression of miR-143-3p could repress stemness cell properties and the inhibition could be partly abolished by overexpression of KIAA1429.Conclusions: In summary, this study establishes miR-143-3p/KIAA1429 axis as promising therapeutic target for OS patients.

SUBMITTER: Han Q

PROVIDER: S-EPMC7217356 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Osteosarcoma (OS) is the most common bone tumor. Many studies have reported that circular RNAs (circRNAs) play an important role in the development of a variety of human cancers. However, the underlying mechanism of circ_0001721 in regulating osteosarcoma progression remains unknown. Materials and Methods:Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of circ_0001721, miR-372-3p, and mitogen-activated protein kinase 7 (MAPK7) in osteosarcoma tissues and cells. Besides, glycolysis was investigated by glucose consumption, lactate production and hexokinase II (HK2) protein level. Cell proliferation and apoptosis were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and flow cytometry, separately. Cell migration and invasion were determined by transwell assay. Moreover, the protein levels of HK2 and epithelial-to-mesenchymal transition (EMT) markers were determined by Western blot analysis. The relationship between miR-372-3p and circ_0001721 or MAPK7 was predicated by starbase v3.0 and confirmed by dual-luciferase reporter assay or RNA binding protein immunoprecipitation (RIP) assay. Murine xenograft model was established to investigate the role of circ_0001721 in vivo. Results:The levels of circ_0001721 and MAPK7 were upregulated in osteosarcoma tissues and cells, while miR-372-3p was downregulated. Knockdown of circ_0001721 inhibited glycolysis, cell proliferation, cell migration, invasion and epithelial-to-mesenchymal transition (EMT), and promoted apoptosis. Circ_0001721 was validated as a sponge of miR-372-3p and mediated glycolysis, cell proliferation, apoptosis, migration, invasion, and EMT of osteosarcoma cells through miR-372-3p. MAPK7 was a target of miR-372-3p and overexpression of MAPK7 attenuated anti-cancer role of miR-372-3p in OS cells. Further studies revealed that circ_0001721 regulates MAPK7 expression via sponging miR-372-3-p. Finally, knockdown of circ_0001721 inhibited tumor progression in vivo. Conclusion:Circ_0001721 promoted osteosarcoma development through the miR-372-3p/MAPK7 axis.

Project description:BackgroundLong noncoding RNAs (lncRNAs) have critical regulatory functions in biological and pathological activities during osteosarcoma progression. It is important to elucidate the expression pattern and reveal the underlying mechanisms of the newly identified lncRNAs.MethodsHerein, we screened the differentially expressed lncRNAs in osteosarcoma tumors and cell lines using lncRNA microarray. The candidate lncRNA was further verified by qRT-PCR, and the association of gene expression with clinicopathological features was evaluated by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The targeting miRNA was identified using starBase analysis, and the competing endogenous RNA (ceRNA) network was established by STRING. Overexpression and silence of RNA were detected by qRT-PCR. Osteosarcoma cell proliferation was measured with CCK-8 assay, and the migration and invasion were evaluated with Transwell assay. Colony formation assay was observed. Flow cytometry evaluated the cell cycle. Western blot was performed to detect the mitotic markers and apoptosis-related proteins. A nude mouse tumor formation experiment was used to evaluate osteosarcoma progression in vivo. Cooverexpressing miR-34b-3p with RAD51 reversed the miR-34b-3p-induced changes in proliferation, the cell cycle, the expression of H2A.X, and that of apoptosis-related proteins.ResultsHCG9 was identified as osteosarcoma-associated lncRNA. Osteosarcoma tissues and cell lines expressed higher levels of HCG9 as compared to normal tissues and osteoblasts, and high expression of HCG9 was further proved to be related to metastasis and the grade of osteosarcoma in clinical cases. Knockdown of HCG9 inhibited the proliferation, migration, and invasion of osteosarcoma cells. miR-34b-3p was identified as the target of HCG9, and RAD51 acted as a potential target of miR-34b-3p. Cooverexpressing miR-34b-3p with HCG9 partially suppressed the HCG9-stimulated proliferation, migration, and invasion of osteosarcoma cells in vitro and delayed the tumor progression in vivo.ConclusionWe discovered that lncRNA HCG9 promoted the proliferation of osteosarcoma cells via suppressing miR-34b-3p. Our study provides novel biomarkers and potential therapeutic targets for osteosarcoma treatment.

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KIAA1429 promotes osteosarcoma progression by promoting stem cell properties and is regulated by miR-143-3p.

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