Junlong Zhao1, Huichen Li2, Shoujie Zhao3, Enxin Wang4, Jun Zhu2, Dayun Feng5, Yejing Zhu3, Weijia Dou4, Qingling Fan4, Jie Hu4, Lintao Jia6, Lei Liu7,8. 1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Development Biology, Fourth Military Medical University, Xi'an, 710032, China. 2. 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. 3. Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China. 4. Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China. 5. Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710038, China. 6. 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. jialth@fmmu.edu.cn. 7. Department of Gastroenterology, Tangdu Hospital of the Fourth Military Medical University, No.569 Xinsi Road, Xi'an, 710038, China. liulei84207@163.com. 8. Department of Cell Biology, Fourth Military Medical University, No.169 Changlexi Road, Xi'an, 710032, China. liulei84207@163.com.
Abstract
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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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. METHODS: 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. RESULTS: The miR-144/miR-451acluster was downregulated in HCC and predicted a better HCCpatient 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-451acluster 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. CONCLUSIONS: Our study revealed novel mechanisms underlying miR-144/miR-451acluster deregulation and the crosstalk between malignant cells and tumor-associated macrophages (TAMs) in HCC, providing new insights into HCC pathogenesis and diagnostic strategies.
Authors: Kavitha Yaddanapudi; Kalyani Putty; Beatriz E Rendon; Gwyneth J Lamont; Jonathan D Faughn; Abhay Satoskar; Amanda Lasnik; John W Eaton; Robert A Mitchell Journal: J Immunol Date: 2013-02-06 Impact factor: 5.422