Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai, 200001, China.
Oncogene. 2019 Apr;38(15):2844-2859. doi: 10.1038/s41388-018-0619-z. Epub 2018 Dec 13.
Hepatocellular carcinoma (HCC), the major form of liver cancer, has shown increasing incidence and poor prognosis. Adipose tissue is known to function in energy storage and metabolism regulation by the secretion of adipokines. Circular RNAs (circRNAs), a novel type of noncoding RNA, have recently been recognized as key factors in tumor development, but the role of exosome circRNAs derived from adipose tissues has not been defined yet. Here, adipose-secreted circRNAs were found to regulate deubiquitination in HCC, thus facilitating cell growth. It was observed that exosome circ-deubiquitination (circ-DB) is upregulated in HCC patients with higher body fat ratios. Moreover, in vitro and in vivo studies showed that exo-circ-DB promotes HCC growth and reduces DNA damage via the suppression of miR-34a and the activation of deubiquitination-related USP7. Finally, the results showed that the effects of adipose exosomes on HCC cells can be reversed by knockdown of circ-DB. These results indicate that exosome circRNAs secreted from adipocytes promote tumor growth and reduce DNA damage by suppressing miR-34a and activating the USP7/Cyclin A2 signaling pathway.
肝细胞癌（HCC）是肝癌的主要形式，其发病率和预后均较差。脂肪组织通过分泌脂肪因子来调节能量储存和代谢。环状 RNA（circRNA）是一种新型非编码 RNA，最近被认为是肿瘤发展的关键因素，但脂肪组织来源的外泌体 circRNA 的作用尚未确定。在这里，发现脂肪组织分泌的 circRNA 调节 HCC 中的去泛素化作用，从而促进细胞生长。观察到在体脂比更高的 HCC 患者中，外泌体 circ-DB 上调。此外，体外和体内研究表明，外泌体 circ-DB 通过抑制 miR-34a 和激活去泛素化相关 USP7 来促进 HCC 生长和减少 DNA 损伤。最后，结果表明，通过敲低 circ-DB 可以逆转脂肪外泌体对 HCC 细胞的作用。这些结果表明，脂肪细胞分泌的外泌体 circRNA 通过抑制 miR-34a 和激活 USP7/Cyclin A2 信号通路促进肿瘤生长并减少 DNA 损伤。
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