Abstract
Background & AimsHepatocellular 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Hepatocellular carcinoma (HCC) is among the most common malignant tumors of the digestive system and has a poor prognosis and rising mortality rate [1]
The miR-144/miR-451a cluster suppresses HCC development and predicts better HCC prognosis MicroRNAs, which mature from the primary transcript after sequential processing by the ribonucleases Drosha and Dicer, are well documented regulators of carcinogenesis [22]
In line with the aforementioned analysis based on published datasets, we found that both miRNAs were associated with early tumor staging and better prognosis of tested HCC patients (Fig. 1e, f)
Summary
Hepatocellular carcinoma (HCC) is among the most common malignant tumors of the digestive system and has a poor prognosis and rising mortality rate [1]. Tumor-associated macrophages (TAMs), which are broadly considered the M2-polarized subtype and suppress antitumor immunity, are involved in the initiation, progression and metastasis of different kinds of HCC [5, 6]. Direct cell contact modulates macrophage development and functions through cell membrane ligands and integrin signaling, accumulated evidence has demonstrated that paracrine factors from HCC cells represent major contributors to immune microenvironment remodeling. It is important to dissect the molecular mechanisms underlying the crosstalk between HCC and TAMs in terms of earlier diagnosis and more efficient intervention. Aberrant epigenetic paradigms, including deregulated microRNAs (miRNAs), exert profound impacts on hepatocyte transformation and tumor microenvironment remodeling; the underlying mechanisms are largely uncharacterized
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