Li Dong, Wang Wujie, Liu Bin, Jin Die, Wang Yang, He Guanghui, Guo Lei, Liu Wen, Li Yuliang
Department of Interventional Medicine, The Second Hospital of Shandong University, Jinan, China.
Institute of Interventional Oncology, Shandong University, Jinan, China.
Cell Death Discov. 2023 Aug 10;9(1):294. doi: 10.1038/s41420-023-01593-w.
Iodine-125 (I-125) radioactive seed implantation is used for the local treatment of hepatocellular carcinoma (HCC), but the molecular mechanisms regulating its anticancer effects remain incompletely understood. In this study, we report that hsa_circ_0000647 (circSEC11A) is highly expressed after I-125 treatment in HCC cell lines and tissues and is a key regulator of I-125-induced anticancer effects. CircSEC11A acts as a competing endogenous RNA (ceRNA) to sponge miR-3529-3p, promoting the expression of zinc fingers and homeoboxes 2 (ZHX2) and enhancing I-125-induced anticancer effects. Dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation, and fluorescence in situ hybridization were thereafter performed to verify the interaction among the molecules. Anticancer effects were detected using CCK-8, flow cytometry, TUNEL, EdU, transwell, and wound healing assays. Furthermore, ZHX2 transcriptionally inhibits GADD34, a negative regulator of endoplasmic reticulum stress (ERS), to enhance I-125- induced anticancer effects in vivo and in vitro. In conclusion, we characterized circSEC11A as a novel regulator of I-125-induced anticancer effects in HCC via miR-3529-3p/ZHX2/GADD34 axis-mediated ERS. Thus, circSEC11A may act as a potential therapeutic target for I-125 implantation in the clinic.
碘-125(I-125)放射性粒子植入术用于肝细胞癌(HCC)的局部治疗,但其抗癌作用的分子机制仍未完全明确。在本研究中,我们发现hsa_circ_0000647(circSEC11A)在I-125处理后的HCC细胞系和组织中高表达,是I-125诱导抗癌作用的关键调节因子。CircSEC11A作为竞争性内源性RNA(ceRNA),吸附miR-3529-3p,促进锌指同源框2(ZHX2)的表达,增强I-125诱导的抗癌作用。随后进行双荧光素酶报告基因检测、RNA下拉实验、RNA免疫沉淀实验和荧光原位杂交实验,以验证分子间的相互作用。采用CCK-8、流式细胞术、TUNEL、EdU、Transwell和伤口愈合实验检测抗癌效果。此外,ZHX2转录抑制内质网应激(ERS)的负调节因子GADD34,以增强I-125在体内外诱导的抗癌作用。总之,我们将circSEC11A鉴定为通过miR-3529-3p/ZHX2/GADD34轴介导的ERS在I-125诱导的HCC抗癌作用中的新型调节因子。因此,circSEC11A可能成为临床上I-125植入治疗的潜在靶点。