Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin.
Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin.
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Hsa_circ_0000098是一种新的治疗靶点，可促进肝细胞癌的发展和对阿霉素的耐药性
DOI：
10.1186/s13046-022-02482-3
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发表时间：
2022-09-07
影响因子：
11.3
通讯作者：
Wang, Feng
中科院分区：
文献类型：
--
作者：
Li, Yi;Wu, Anqi;Chen, Lin;Cai, Aiting;Hu, Yuhao;Zhou, Zhou;Qi, Qianyi;Wu, Yixuan;Xia, Donglin;Dong, Peixin;Ju, Shaoqing;Wang, Feng
研究背景环状RNA（CircRNA）在肝细胞癌（HCC）的发生发展中起重要作用。此外，线粒体钙单向转运体调节因子1（MCUR 1）通常在HCC中过表达，以增加细胞ATP水平。由于HCC的高度侵袭性特征，方法采用体外和体内实验研究circ_0000098在肝癌中的生物学意义和作用机制。结果circ_0000098在肝癌组织中的表达明显高于对照组（P < 0.01），且circ_000098在肝癌组织中的表达水平明显高于对照组（P < 0.01）。0000098在HCC组织中的表达高于配对的相邻组织。根据受试者工作特征曲线，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作为一个关键的致癌circRNA，在体外增加肝癌细胞的增殖和侵袭，并在体内肝癌进展。进一步的机制研究表明，circ_0000098通过将miR-383从MCUR 1的3′-UTR中隔离，正调控HCC细胞中MCUR 1的表达，最终促进HCC的进展。另一方面，在HCC细胞中抑制circ_0000098可以通过降低P-糖蛋白（P-gp，MDR 1）表达和细胞内ATP水平来降低阿霉素（DOX）抗性。无论是MCUR 1的下调还是miR-383的过表达都能提高HCC细胞对DOX的敏感性。随后，将靶向circ_0000098（称为sh-1）和多柔比星（DOX）的短发夹RNA包封到血小板（PLT）中，称为DOX/sh-1@PLT。通过HCC细胞活化的DOX/sh-1@PLT导致产生血小板衍生颗粒，其能够将DOX/sh-1组合递送到HCC细胞中并促进细胞内DOX积累。此外，体内实验表明DOX/sh-1@PLT可有效降低P-gp表达，促进DOX蓄积，结论我们的结果表明，circ_0000098是一种致癌的circRNA，通过miR-383/MCUR 1轴促进HCC的发展，并以DOX/sh-1@ PLT可能是一个有前途的和实用的治疗策略，以防止阿霉素耐药的肝癌。
BackgroundCircular 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.MethodsA series ofin vitroandin vivoexperiments were undertaken to investigate the biological importance and underlying mechanisms of circ_0000098 in HCC.ResultsThe 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 invasionin vitroand HCC progressionin vivo. Furthermore, mechanistic investigation demonstrated that by sequestering miR-383 from the 3′-UTR ofMCUR1, 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, ourin vivoexperiments showed that DOX/sh-1@PLT can effectively reduce P-gp expression, promote DOX accumulation, and reverse DOX resistance.ConclusionsOur 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.
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影响因子：
4.7
作者：
Wang JQ;Wu ZX;Yang Y;Li JS;Yang DH;Fan YF;Chen ZS
通讯作者：
Chen ZS
影响因子：
5.2
作者：
Narayanan S;Fan YF;Gujarati NA;Teng QX;Wang JQ;Cai CY;Yang Y;Chintalapati AJ;Lei Y;Korlipara VL;Chen ZS
通讯作者：
Chen ZS
影响因子：
2.7
作者：
Zhong, Yanmei;Wang, Dan;Jiang, Bing
通讯作者：
Jiang, Bing
MCUR1通过线粒体钙依赖性ROS/Nrf2/Notch通路促进肝细胞癌上皮-间质转化和转移
DOI：
10.1186/s13046-019-1135-x
发表时间：
2019-03-25
影响因子：
11.3
作者：
Jin, Mingpeng;Wang, Jiaojiao;Xing, Jinliang
通讯作者：
Xing, Jinliang
影响因子：
12.4
作者：
Lyu M;Chen M;Liu L;Zhu D;Wu X;Li Y;Rao L;Bao Z
通讯作者：
Bao Z