Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
Theranostics. 2021 Jan 1;11(3):1396-1411. doi: 10.7150/thno.53227. eCollection 2021.
circular RNAs (circRNAs) have been demonstrated to play a crucial role in cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. The aim of present study is to investigate the role of circular RNAs in KIAA1429-mediated HCC progression. RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (m6A-seq) were utilized to identify KIAA1429-regulated circRNAs. The effects of circDLC1 on proliferation and metastasis of hepatoma cells were examined and . RT-qPCR was used to measure the expression of circDLC1 in HCC tissues and hepatoma cells. RNA FISH, RIP assays and biotin-labeled RNA pull-down were used to investigate the downstream effector of circDLC1. The downstream targets of circDLC1 were identified using RNA-seq. Our data demonstrated that circDLC1 was downregulated in HCC tissues and closely relevant to favorable prognosis. Overexpression of circDLC1 inhibited the proliferation and motility of hepatoma cells and while silencing of circDLC1 played the opposite role. Mechanistic investigations revealed that circDLC1 could bind to RNA-binding protein HuR, which subsequently reduced the interaction between HuR and MMP1 mRNAs, and thus inhibited the expression of MMP1, ultimately contributing to inhibition of HCC progression. Our work suggests that circDLC1, a downstream target of KIAA1429, is a promising prognostic marker for HCC patients, and the circDLC1-HuR-MMP1 axis may serve as a potential therapeutic target for HCC treatment.
环状 RNA（circRNAs）已被证明在癌症进展中发挥关键作用。KIAA1429 是 m6A 甲基转移酶复合物的关键组成部分，最近有报道称其通过调节 m6A 甲基化促进肝细胞癌（HCC）的进展。本研究旨在探讨环状 RNA 在 KIAA1429 介导的 HCC 进展中的作用。利用 RNA 测序（RNA-seq）和 m6A 甲基化 RNA 免疫沉淀测序（m6A-seq）鉴定 KIAA1429 调控的环状 RNA。通过检测增殖和转移实验来检测 circDLC1 对肝癌细胞的影响。利用 RT-qPCR 检测 HCC 组织和肝癌细胞中 circDLC1 的表达。采用 RNA FISH、RIP 实验和生物素标记 RNA 下拉实验来研究 circDLC1 的下游效应器。通过 RNA-seq 鉴定 circDLC1 的下游靶点。我们的数据表明，circDLC1 在 HCC 组织中下调，与良好的预后密切相关。circDLC1 的过表达抑制肝癌细胞的增殖和迁移，而 circDLC1 的沉默则起到相反的作用。机制研究表明，circDLC1 可以与 RNA 结合蛋白 HuR 结合，从而减少 HuR 与 MMP1 mRNA 之间的相互作用，抑制 MMP1 的表达，最终抑制 HCC 的进展。我们的工作表明，circDLC1 是 KIAA1429 的下游靶点，是 HCC 患者有前途的预后标志物，circDLC1-HuR-MMP1 轴可能成为 HCC 治疗的潜在治疗靶点。
