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AATF silencing suppresses tumor progression by reprogramming the microenvironment in hepatocellular carcinoma

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. It is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) that promotes disease progression and therapeutic resistance. The TME plays a crucial role in the progression of HCC by regulating immune response, extracellular matrix remodeling, and angiogenesis. We previously elucidated that apoptosis antagonizing transcription factor (AATF) drives angiogenesis in HCC. However, its role in TME remains unexplored. Here, we studied the effect of AATF silencing in TME on HCC progression using an orthotopic xenograft model. Mice were injected with liver-specific AAV8 carrying siAATF or siControl and monitored for tumor growth. Whole transcriptomics and molecular analyses were carried out. AATF silencing reduced tumor growth and invasion. Species-specific transcriptomic analysis showed that the TME signatures like inflammation, immune response, angiogenesis, and ECM remodeling were altered in siAATF mice compared to the siControl. Mechanistically, TGF-β signaling was markedly suppressed in the TME affecting the cell cycle and metabolic activity of tumor cells, leading to tumor regression. These findings highlight AATF as a critical regulator of the TME, offering novel insights into potential therapeutic targets for HCC.

ORGANISM(S): Mus musculus

PROVIDER: GSE295864 | GEO | 2026/07/15

REPOSITORIES: GEO

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Project description:Abstract: Background & Aims: Unusual hypervascularity is a hallmark of human hepatocellular carcinoma (HCC). Although microRNA-214 (miR-214) is upregulated in other human cancers, it is downregulated in HCC. We elucidated the biological and clinical significance of miR-214 downregulation in HCC. Methods: MicroRNAs deregulated in HCC were identified using array-based MicroRNA profiling. A luciferase reporter assay confirmed target association between miR-214 and hepatoma-derived growth factor (HDGF). Tube formation and in vivo angiogenesis assays validated the roles of miR-214/HDGF in angiogenesis. Results: MiR-214 downregulation was associated with higher tumor recurrence and worse clinical outcomes. Ectopic expression of miR-214 suppressed xenograft tumor growth and microvascularity of the tumor and its surrounding tissues. The genes downregulated by ectopic expression of miR-214 were involved in the regulation of apoptosis, cell cycle, and angiogenesis. Integrated analysis disclosed HDGF as a downstream target of miR-214. Conditioned medium of HCC cells contained bioactivity to stimulate tube formation of human umbilical vein endothelial cells, which was abolished by pretreatment of the conditioned media with HDGF antibodies, silencing of HDGF expression or ectopic expression of miR-214 in the donor HCC cells. The angiogenic activity of the conditioned media lost by ectopic expression of miR-214 in the donor cells was restored by supplementation with recombinant HDGF. In vivo tumor angiogenesis assays showed significant suppression of tumor vascularity by ectopic expression of miR-214. Conclusions: A novel role of microRNA in tumrigenesis is identified. Downregulation of miR-214 contributes to unusual hypervascularity of HCC via activation of the HDGF paracrine pathway for tumor angiogenesis. To identify miRNAs that are deregulated in human HCC, 68 HCC and 21 non-tumor liver tissues were subjected to profiling of miRNA expression using miRNA arrays containing 739 human miRNA probes. Differentially expressed microRNAs were identified.

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AATF silencing suppresses tumor progression by reprogramming the microenvironment in hepatocellular carcinoma

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