M1 极化巨噬细胞来源的外泌体 miR-628-5p 抑制 circFUT8 的 m6A 修饰从而抑制肝癌进展。

Exosomal miR-628-5p from M1 polarized macrophages hinders m6A modification of circFUT8 to suppress hepatocellular carcinoma progression.

机构信息

Digestive Department, Affiliated Hospital of Guilin Medical College, No.15 Lequn Road, Xiufeng District, Guilin, 541001, Guangxi, China.

出版信息

Cell Mol Biol Lett. 2022 Dec 6;27(1):106. doi: 10.1186/s11658-022-00406-9.

BACKGROUND

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. CircFUT8 has been shown to be upregulated in cancers, but its function in HCC remains unclear. Tumor-associated macrophages (TAMs) are one of the main components of the tumor microenvironment (TME), and M1 macrophages function as tumor suppressors in cancers. Exosomes exert an important role in the TME, and circRNAs can be modified by m6A. We investigated the function of circFUT8 in HCC and its interaction with exosomes, M1 macrophages, and m6A.

METHODS

CircFUT8 expression was detected in HCC cells, and its effects on HCC cell growth were verified through functional assays. Mechanism assays including RNA pull down, RNA-binding protein immunoprecipitation (RIP), and luciferase reporter assays were undertaken to verify how circFUT8 may interact with miR-628-5p, and how these molecules may modulate HCC cell malignancy via interacting with exosomes and macrophages.

RESULTS

CircFUT8 was upregulated in HCC cells and it accelerated HCC cell growth. Exosomes derived from M1 macrophages transferred miR-628-5p to HCC cells to inhibit human methyltransferase-like 14 (METTL14) expression. METTL14 promoted circFUT8 m6A modification and facilitated its nuclear export to the cytoplasm, where M1 macrophages regulated the circFUT8/miR-552-3p/CHMP4B pathway, thereby suppressing HCC progression.

CONCLUSION

M1 macrophages-derived exosomal miR-628-5p inhibited the m6A modification of circFUT8, inhibiting HCC development.

背景

肝细胞癌（HCC）是最常见的肝癌类型。已经表明环状 RNA FUT8（circFUT8）在癌症中上调，但它在 HCC 中的功能尚不清楚。肿瘤相关巨噬细胞（TAMs）是肿瘤微环境（TME）的主要组成部分之一，M1 巨噬细胞在癌症中作为肿瘤抑制因子发挥作用。外泌体在 TME 中发挥重要作用，circRNAs 可以被 m6A 修饰。我们研究了 circFUT8 在 HCC 中的功能及其与外泌体、M1 巨噬细胞和 m6A 的相互作用。

方法

检测 HCC 细胞中 circFUT8 的表达，并通过功能测定验证其对 HCC 细胞生长的影响。进行 RNA 下拉、RNA 结合蛋白免疫沉淀（RIP）和荧光素酶报告基因测定等机制测定，以验证 circFUT8 如何与 miR-628-5p 相互作用，以及这些分子如何通过与外泌体和巨噬细胞相互作用来调节 HCC 细胞恶性。

结果

circFUT8 在 HCC 细胞中上调，并加速 HCC 细胞生长。M1 巨噬细胞衍生的外泌体将 miR-628-5p 转移至 HCC 细胞，以抑制人甲基转移酶样蛋白 14（METTL14）的表达。METTL14 促进 circFUT8 m6A 修饰，并促进其核输出到细胞质，在细胞质中 M1 巨噬细胞调节 circFUT8/miR-552-3p/CHMP4B 通路，从而抑制 HCC 进展。