Hsa_circ_0000098 是一个促进肝癌发展和多柔比星耐药的新型治疗靶点。
Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin.
机构信息
Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
Department of Hepatology Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, 226006, China.
出版信息
J Exp Clin Cancer Res. 2022 Sep 7;41(1):267. doi: 10.1186/s13046-022-02482-3.
BACKGROUND
Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mitochondrial calcium uniporter regulatory factor 1 (MCUR1) is commonly overexpressed in HCC to increase cellular ATP levels. Due to the highly aggressive characteristics of HCC, it is essential to identify new diagnostic biomarkers and therapeutic targets that may facilitate the diagnosis of HCC and the development of effective anti-HCC treatments.
METHODS
A series of in vitro and in vivo experiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC.
RESULTS
The expression of circ_0000098 was higher in HCC tissues compared to paired adjacent tissues. According to the receiver-operating characteristic curves, circ_0000098 functioned as a potential diagnostic tumor marker in HCC. Our experiments indicated that circ_0000098 served as a key oncogenic circRNA to increase HCC cell proliferation and invasion in vitro and HCC progression in vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3'-UTR of MCUR1, circ_0000098 positively regulated MCUR1 expression in HCC cells and finally promoted HCC progression. On the other hand, inhibiting circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing P-glycoprotein (P-gp, MDR1) expression and intracellular ATP levels. Either downregulation of MCUR1 or overexpression of miR-383 improved DOX sensitivity in HCC cells. Subsequently, a short hairpin RNA targeting circ_0000098 (referred to as sh-1) and doxorubicin (DOX) were encapsulated into platelets (PLTs), referred to as DOX/sh-1@PLT. Activated DOX/sh-1@PLT through HCC cells resulted in the creation of platelet-derived particles that were capable of delivering the DOX/sh-1 combination into HCC cells and promoting intracellular DOX accumulation. Furthermore, our in vivo experiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance.
CONCLUSIONS
Our results demonstrated that circ_0000098 is an oncogenic circRNA that promotes HCC development through the miR-383/MCUR1 axis and targeting circ_0000098 with DOX/sh-1@PLT may be a promising and practical therapeutic strategy for preventing DOX resistance in HCC.
背景
环状 RNA（circRNA）对肝细胞癌（HCC）的进展至关重要。此外，线粒体钙单向转运体调节因子 1（MCUR1）在 HCC 中普遍过表达，以增加细胞内 ATP 水平。由于 HCC 具有高度侵袭性的特征，因此识别新的诊断生物标志物和治疗靶点对于促进 HCC 的诊断和开发有效的抗 HCC 治疗方法至关重要。
方法
进行了一系列的体外和体内实验，以研究 circ_0000098 在 HCC 中的生物学重要性及其潜在机制。
结果
与配对的相邻组织相比，HCC 组织中 circ_0000098 的表达更高。根据接受者操作特征曲线，circ_0000098 可作为 HCC 的潜在诊断肿瘤标志物。我们的实验表明，circ_0000098 作为一种关键的致癌 circRNA，可在体外增加 HCC 细胞的增殖和侵袭，并在体内促进 HCC 的进展。此外，机制研究表明，circ_0000098 通过与 MCUR1 的 3'-UTR 结合来隔离 miR-383，从而正向调节 HCC 细胞中的 MCUR1 表达，最终促进 HCC 的进展。另一方面，抑制 HCC 细胞中的 circ_0000098 可以通过降低 P-糖蛋白（P-gp，MDR1）表达和细胞内 ATP 水平来减少多柔比星（DOX）耐药性。下调 MCUR1 或过表达 miR-383 均可提高 HCC 细胞对 DOX 的敏感性。随后，靶向 circ_0000098 的短发夹 RNA（称为 sh-1）和多柔比星（DOX）被包被到血小板（PLT）中，称为 DOX/sh-1@PLT。通过 HCC 细胞激活 DOX/sh-1@PLT 会导致形成能够将 DOX/sh-1 组合递送至 HCC 细胞并促进细胞内 DOX 积累的血小板衍生颗粒。此外，我们的体内实验表明，DOX/sh-1@PLT 可有效降低 P-gp 表达，促进 DOX 积累，并逆转 DOX 耐药性。
结论
我们的研究结果表明，circ_0000098 是一种致癌性 circRNA，通过 miR-383/MCUR1 轴促进 HCC 发展，用 DOX/sh-1@PLT 靶向 circ_0000098 可能是预防 HCC 中 DOX 耐药的一种有前途且实用的治疗策略。
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