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

Abstract

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.

Nanoparticles Mediated circROBO1 Silencing to Inhibit Hepatocellular Carcinoma Progression by Modulating miR-130a-5p/CCNT2 Axis

“…Accumulating studies indicate that circRNAs are differentially expressed in HCC, and these differentially expressed circRNAs may play the role of biomarkers in cancer diagnosis and prognosis. 37 , 38 However, the molecular mechanisms for circRNAs in HCC are still largely elusive. Hence, we investigated the function and underlying mechanism of the upregulated circROBO1 expression in HCC by screening the differentially expressed circRNAs (DECs) between HCC tissues and paired nontumor liver tissues.…”

Exosomes and circular RNAs: promising partners in hepatocellular carcinoma from bench to bedside

“…Li et al[ 35 ] showed the potential diagnostic value of circ_0000098 in HCC, with an area of 0.829 under the receiver operating characteristic (ROC) curve. Further in vivo and in vitro experiments showed that circ_0000098 could play an oncogenic role by regulating mitochondrial calcium uniporter regulatory factor 1 expression by sequestering miR-383 [ 35 ].…”

“…Li et al[ 35 ] showed the potential diagnostic value of circ_0000098 in HCC, with an area of 0.829 under the receiver operating characteristic (ROC) curve. Further in vivo and in vitro experiments showed that circ_0000098 could play an oncogenic role by regulating mitochondrial calcium uniporter regulatory factor 1 expression by sequestering miR-383 [ 35 ]. Inhibiting the expression of circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing the levels of intracellular ATP and the expression of the ATP-dependent drug efflux protein P-glycoprotein (P-gp) [ 35 ].…”

“…Further in vivo and in vitro experiments showed that circ_0000098 could play an oncogenic role by regulating mitochondrial calcium uniporter regulatory factor 1 expression by sequestering miR-383 [ 35 ]. Inhibiting the expression of circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing the levels of intracellular ATP and the expression of the ATP-dependent drug efflux protein P-glycoprotein (P-gp) [ 35 ]. Based on this finding, DOX and a short hairpin RNA against circ_0000098 (referred to as sh-1) were encapsulated into platelets, named DOX/sh-1@PLT, which could reverse DOX resistance [ 35 ].…”

“…Inhibiting the expression of circ_0000098 in HCC cells could diminish doxorubicin (DOX) resistance by decreasing the levels of intracellular ATP and the expression of the ATP-dependent drug efflux protein P-glycoprotein (P-gp) [ 35 ]. Based on this finding, DOX and a short hairpin RNA against circ_0000098 (referred to as sh-1) were encapsulated into platelets, named DOX/sh-1@PLT, which could reverse DOX resistance [ 35 ]. Wang's team confirmed that circCDYL was related to the expression of Ki-67 and alpha-fetoprotein (AFP), suggesting that circCDYL promoted the proliferation of HCC cells [ 36 ].…”