<p>Circular RNA hsa_circ_0003496 Contributes to Tumorigenesis and Chemoresistance in Osteosarcoma Through Targeting (microRNA) miR-370/Krüppel-Like Factor 12 Axis</p>

Abstract

Background Osteosarcoma (OS) is the most common primary malignancy of bone with a high incidence in children. Circular RNAs (circRNAs) play crucial roles in the carcinogenesis and chemoresistance of OS. In the current work, we focused on the function and mechanism of hsa_circ_0003496 (circ_0003496) in OS progression and chemoresistance. Materials and Methods The expression levels of circ_0003496, miR-370 and Krüppel-like factor 12 (KLF12) mRNA were measured by quantitative real-time polymerase chain reaction (qRT-PCR). The Cell Counting Kit-8 (CCK-8) assay was used to assess the 50% inhibitory concentration (IC50) value and cell proliferation. Cell migration, invasion and apoptosis were detected by transwell assay and flow cytometry, respectively. Western blot analysis was performed to assess the protein level. Targeted relationships among circ_0003496, miR-370 and KLF12 were validated by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Animal studies were carried out to observe the role of circ_0003496 in vivo. Results Our results indicated that circ_0003496 up-regulation was associated with doxorubicin (DXR) resistance of OS. Circ_0003496 knockdown repressed DXR-resistant OS cell proliferation, migration and invasion, and enhanced apoptosis and DXR sensitivity. Circ_0003496 functioned as a sponge of miR-370, and miR-370 mediated the regulatory effect of circ_0003496 depletion on DXR-resistant OS cell progression and DXR sensitivity. KLF12 was a direct target of miR-370, and miR-370 overexpression suppressed cell progression and enhanced DXR sensitivity by KLF12. Moreover, circ_0003496 protected against KLF12 repression through sponging miR-370. Additionally, circ_0003496 knockdown hampered tumor growth and promoted DXR sensitivity in vivo. Conclusion Our present work suggested that the knockdown of circ_0003496 suppressed OS progression and enhanced DXR sensitivity at least partially through modulating KLF12 expression via functioning as a miR-370 sponge, highlighting new opportunities for OS management.

circ_0000467 promotes the proliferation, metastasis, and angiogenesis in colorectal cancer cells through regulating KLF12 expression by sponging miR-4766-5p

“…Chen et al declared that circNEIL3 sponged miR-137 to promote the level of KLF12, thus accelerating cell proliferation in cervical cancer [ 32 ]. Also, circ_0003496 enhanced tumorigenesis and chemoresistance in osteosarcoma by regulating KLF12 via absorbing miR-370 [ 33 ]. Therefore, we concluded that the effect of circ_0000467 on CRC progression was partly associated with the KLF12 level via targeting miR-4766-5p.…”

Decreased circUBAP2 Expression Is Associated with Preeclampsia by Limiting Trophoblast Cell Proliferation and Migration

“…In this study, we focused on a new circRNA, circUBAP2 (hsa_circ_0003496), that functions in the trophoblast cell line HTR-8/SVneo and choriocarcinoma cell line JEG-3. circRNAs originate from the UBAP2 (ubiquitin-associated protein 2) gene, which includes hsa_circ_0003496 and has been reported to be upregulated in a variety of tumors [17][18][19]. However, it has not been reported in pregnancy-related diseases.…”

CircPRDM2 Contributes to Doxorubicin Resistance of Osteosarcoma by Elevating EZH2 via Sponging miR-760

“…Diverse circRNAs, such as circ_001569, 22 circ_0004674, 23 circ_0003074 24 and circ_0003496, 10 have been reported to play vital roles in the drug resistance of OS. Previous research indicated that circ_0005986 suppressed the malignancy of hepatocellular carcinoma by sponging miR-129-5p.…”

“…For example, circ_0003496 promoted the DXR resistance and malignancy of OS by decoying miR-370 and elevating KLF12. 10 Circ_0000073 enhanced OS cell growth and motility and improved methotrexate resistance of OS by the modulation of miR-145-5p/NRAS axis or miR-151-3p/NRAS axis. 11 Hierarchical cluster analysis and heat map analysis showed that circRNA PR/SET domain 2 (circPRDM2) (also named as circ_0005986) level was elevated in OS tissues, indicating the potential role of circPRDM2 in OS development.…”