Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths, and its incidence is still high in China. This study aimed to investigate the circular RNAs (circRNAs) involved in the development of HCC and elucidate the mechanism. RNA sequencing found 72 downregulated circRNAs and 88 upregulated circRNAs in human HCC tissues, including hsa_circ_0098181, hsa_circ_0072309, hsa_circ_0000831, and hsa_circ_0000231. The reduction of hsa_circ_0098181 was confirmed in eight paired human HCC tissues, hepatoma cell lines, and CCL4/DEN-induced mouse HCC models by RT-qPCR. The FISH assay revealed that hsa_circ_0098181 is mainly located in the cytoplasm of hepatocytes in the paratumor tissues. Further log-rank analysis performed in 91 HCC patients demonstrated that low expression of hsa_circ_0098181 was related to poor prognosis. The plasmid and lentivirus overexpressing hsa_circ_0098181 were delivered into HCC cell lines. After hsa_circ_0098181 was upregulated, the proliferation, invasion, migration, and colony formation of HCC cell lines were inhibited, and the apoptosis was promoted. Moreover, exogenous hsa_circ_0098181 delivery mitigated the tumor formation ability of Huh7 in Balb/C nude mice. The dual-luciferase reporter assay and the RIP assay verified that hsa_circ_0098181 sponged miR-18a-3p to regulate PPARA. In addition, a rescue experiment found miR-18a-3p mimic partly reversed the suppression of hsa_circ_0098181 on proliferation, invasion, and migration of HCC cell lines. In conclusion, hsa_circ_0098181 can repress the development of HCC through sponging miR-18a-3p and promoting the expression of PPARA in vitro and in vivo, and hsa_circ_0098181 might be a therapeutic target for HCC.
Highlights
Primary liver cancer is one of the leading causes of death from cancer (Akinyemiju et al, 2017)
It was shown that 72 Circular RNA (circRNA) were less expressed and 88 circRNAs were up-regulated in human Hepatocellular carcinoma (HCC) tissues compared with their paratumor tissues (Figures 1A,B)
Considering the length, nd homogeneous and differential expression of circular RNA (Zheng et al, 2016), 4 circRNAs at about 500 nt length were selected for further verification
Summary
Primary liver cancer is one of the leading causes of death from cancer (Akinyemiju et al, 2017). Many risk factors, such as chronic hepatitis B, hepatitis C, alcohol, metabolic liver disease (especially nonalcoholic fatty liver), and chemical toxins, are involved in the development of liver cancer (Yang et al, 2019). Primary liver cancer can be divided into three types, including hepatocellular carcinoma (HCC, accounting for 75%), cholangiocarcinoma, and mixed types (Petrick et al, 2020). Circular RNA (circRNA) is a kind of non-coding RNA (ncRNA) which does not contain 5′ polarity and a 3′ polyadenylated tail, and has closed ring structures to ensure their stability (Chen and Yang, 2015). CircRNAs regulate translation, bind with proteins, and affect gene transcription in recent studies (Prats et al, 2020; Zhou et al, 2020)
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