Background. Hepatocellular carcinoma (HCC) is the most frequently occurring cancer and contributes to the largest number of cancer-associated deaths worldwide. Recent evidence suggests that circular RNAs (circRNAs), which are critical for HCC etiology and metastasis, are distinctly modulated in HCC. Nevertheless, the underlying mechanism of circRNA-mediated sorafenib resistance (SOR) in HCC is yet to be determined. Methods. The hsa_circ_0006988, IGF1, and miR-15a-5p contents were quantified via ELISA and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. Cell Counting Kit-8 (CCK-8) was used for the IC50 evaluation. Lastly, associations among hsa_circ_0006988, IGF1, and miR-15a-5p were validated through dual-luciferase reporter (DLR) and RNA immunoprecipitation (RIP) assays. Results. Herein, a new circRNA, hsa_circ_0006988, was identified, and its levels were markedly enhanced in SOR-resistant (SOR-R) HCC tissues. Functionally, hsa_circ_0006988 strongly suppressed SOR toxicity in vitro. Our examination of the signaling pathway revealed that hsa_circ_0006988 sequestered miR-15a-5p, a negative modulator of IGF1, thus suggesting that hsa_circ_0006988 deficiency diminished SOR resistance of HCC, and this action utilized the release of excess miR-15a-5p, which suppressed IGF1 levels. Moreover, miR-15a-5p overexpression reversed the hsa_circ_0006988-mediated SOR-R and enhanced IGF1 levels in HCC cells. Conclusion. Hsa_circ_0006988 partly promoted the SOR-R of HCC cells through miR-15a-5p sequestering and upregulation of IGF1 levels.

中文翻译：

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Hsa_circ_0006988 通过使用 miR-15a-5p 调节 IGF1 促进肝细胞癌索拉非尼耐药

背景。肝细胞癌 (HCC) 是最常见的癌症，也是全球癌症相关死亡人数最多的癌症。最近的证据表明，对于 HCC 病因和转移至关重要的环状 RNA (circRNA) 在 HCC 中受到明显调节。然而，HCC 中 circRNA 介导的索拉非尼耐药（SOR）的潜在机制尚未确定。方法。分别通过 ELISA 和定量实时聚合酶链反应 (qRT-PCR) 定量 hsa_circ_0006988、IGF1 和 miR-15a-5p 含量。使用 Cell Counting Kit-8 (CCK-8) 进行 IC50 评估。最后，通过双荧光素酶报告基因 (DLR) 和 RNA 免疫沉淀 (RIP) 测定验证了 hsa_circ_0006988、IGF1 和 miR-15a-5p 之间的关联。结果。在此，鉴定了一种新的circRNA hsa_circ_0006988，其水平在SOR抵抗（SOR-R）HCC组织中显着增强。在功能上，hsa_circ_0006988 强烈抑制体外SOR 毒性。我们对信号通路的检查表明，hsa_circ_0006988 隔离了 miR-15a-5p（IGF1 的负调节剂），因此表明 hsa_circ_0006988 缺陷降低了 HCC 的 SOR 抵抗力，并且这一作用利用了过量 miR-15a-5p 的释放，从而抑制了 IGF1水平。此外，miR-15a-5p过表达逆转了hsa_circ_0006988介导的SOR-R并增强了HCC细胞中的IGF1水平。结论。Hsa_circ_0006988 通过 miR-15a-5p 隔离和 IGF1 水平上调部分促进 HCC 细胞的 SOR-R。