State Key Laboratory of Cancer Biology, Department of Medical Genetics and Development Biology, Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, School of Basic Medicine, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China.
Mol Cancer. 2021 Mar 3;20(1):46. doi: 10.1186/s12943-021-01343-5.
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the malignancies with the highest mortality. The key regulators and their interactive network in HCC pathogenesis remain unclear. Along with genetic mutations, aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; however, the underlying mechanisms are largely uncharacterized.
We performed RNA sequencing on HCC specimens and bioinformatic analyses to identify tumor-associated miRNAs. The miRNA functional targets and their effects on tumor-infiltrating immune cells were investigated. The upstream events, particularly the epigenetic mechanisms responsible for miRNA deregulation in HCC, were explored.
The miR-144/miR-451a cluster was downregulated in HCC and predicted a better HCC patient prognosis. These miRNAs promoted macrophage M1 polarization and antitumor activity by targeting hepatocyte growth factor (HGF) and macrophage migration inhibitory factor (MIF). The miR-144/miR-451a cluster and EZH2, the catalytic subunit of polycomb repressive complex (PRC2), formed a feedback circuit in which miR-144 targeted EZH2 and PRC2 epigenetically repressed the miRNA genes via histone H3K27 methylation of the promoter. The miRNA cluster was coordinately silenced by distal enhancer hypermethylation, disrupting chromatin loop formation and enhancer-promoter interactions. Clinical examinations indicated that methylation of this chromatin region is a potential HCC biomarker.
Our study revealed novel mechanisms underlying miR-144/miR-451a cluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.
肝细胞癌（HCC）是死亡率最高的恶性肿瘤之一。HCC 发病机制中的关键调控因子及其相互作用网络仍不清楚。除了遗传突变，异常的表观遗传模式，包括失调的 microRNAs（miRNAs），对肝细胞转化和肿瘤微环境重塑有深远影响；然而，其潜在机制在很大程度上仍未被阐明。
我们对 HCC 标本进行了 RNA 测序和生物信息学分析，以鉴定肿瘤相关的 miRNAs。研究了 miRNA 的功能靶标及其对肿瘤浸润免疫细胞的影响。探讨了上游事件，特别是负责 HCC 中 miRNA 失调的表观遗传机制。
miR-144/miR-451a 簇在 HCC 中下调，预测 HCC 患者预后较好。这些 miRNA 通过靶向肝细胞生长因子（HGF）和巨噬细胞迁移抑制因子（MIF）促进巨噬细胞 M1 极化和抗肿瘤活性。miR-144/miR-451a 簇和 EZH2（多梳抑制复合物（PRC2）的催化亚基）形成了一个反馈回路，其中 miR-144 靶向 EZH2 和 PRC2，通过启动子上组蛋白 H3K27 的甲基化来表观遗传抑制 miRNA 基因。miRNA 簇通过远端增强子超甲基化被协调沉默，破坏染色质环形成和增强子-启动子相互作用。临床检查表明，该染色质区域的甲基化是 HCC 的一个潜在生物标志物。
本研究揭示了 miR-144/miR-451a 簇失调的新机制以及 HCC 中恶性细胞与肿瘤相关巨噬细胞（TAMs）之间的串扰，为 HCC 的发病机制和诊断策略提供了新的见解。
