open access

https://hdl.handle.net/2115/86755

Hsa_circ_0000098 is a novel therapeutic target that promotes hepatocellular carcinoma development and resistance to doxorubicin

英語

Drug resistance

2022-09-07

BioMed Central

Journal of Experimental & Clinical Cancer Research

41(1)

267

Background:Circular RNA (circRNA) is crucial to the progression of hepatocellular cancer (HCC). In addition, Mito-chondrial 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 prolifera-tion 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 intracellu-lar 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.

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Creative Commons Attribution 4.0 International

1756-9966