Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR.
Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR.
复制标题
环状RNA circDLC1通过与HuR相互作用抑制MMP1介导的肝癌进展
作者：
Liu H;Lan T;Li H;Xu L;Chen X;Liao H;Chen X;Du J;Cai Y;Wang J;Li X;Huang J;Yuan K;Zeng Y
理由：环状 RNA (circRNA) 已被证明在癌症进展中发挥着至关重要的作用。 KIAA1429 是 m6A 甲基转移酶复合物的关键成分，最近有报道称其通过调节 m6A 甲基化来促进肝细胞癌 (HCC) 进展。本研究的目的是研究环状 RNA 在 KIAA1429 介导的 HCC 进展中的作用。方法：利用RNA测序（RNA-seq）和甲基化RNA免疫沉淀测序（m6A-seq）来鉴定KIAA1429调节的circRNA。体外和体内研究了circDLC1对肝癌细胞增殖和转移的影响。 RT-qPCR用于检测HCC组织和肝癌细胞中circDLC1的表达。 RNA FISH、RIP 测定和生物素标记的 RNA Pull-down 用于研究 circDLC1 的下游效应子。使用 RNA-seq 鉴定了 circDLC1 的下游靶标。结果：我们的数据表明，circDLC1 在 HCC 组织中表达下调，与良好的预后密切相关。 circDLC1的过表达在体外和体内抑制肝癌细胞的增殖和运动，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和MMP1 mRNA之间的相互作用，从而抑制MMP1的表达，最终有助于抑制HCC进展。结论：我们的工作表明，KIAA1429 的下游靶点 circDLC1 是 HCC 患者有希望的预后标志物，并且 circDLC1-HuR-MMP1 轴可能作为 HCC 治疗的潜在治疗靶点。
Rationale: 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. Methods: 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 in vitro and in vivo. 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. Results: 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 in vitro and in vivo, 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. Conclusion: 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.