Abstract
Hepatocellular carcinoma (HCC) is one of the leading lethal malignancies and a hypervascular tumor. Although some long non-coding RNAs (lncRNAs) have been revealed to be involved in HCC. The contributions of lncRNAs to HCC progression and angiogenesis are still largely unknown. In this study, we identified a HCC-related lncRNA, CMB9-22P13.1, which was highly expressed and correlated with advanced stage, vascular invasion, and poor survival in HCC. We named this lncRNA Progression and Angiogenesis Associated RNA in HCC (PAARH). Gain- and loss-of function assays revealed that PAARH facilitated HCC cellular growth, migration, and invasion, repressed HCC cellular apoptosis, and promoted HCC tumor growth and angiogenesis in vivo. PAARH functioned as a competing endogenous RNA to upregulate HOTTIP via sponging miR-6760-5p, miR-6512-3p, miR-1298-5p, miR-6720-5p, miR-4516, and miR-6782-5p. The expression of PAARH was significantly positively associated with HOTTIP in HCC tissues. Functional rescue assays verified that HOTTIP was a critical mediator of the roles of PAARH in modulating HCC cellular growth, apoptosis, migration, and invasion. Furthermore, PAARH was found to physically bind hypoxia inducible factor-1 subunit alpha (HIF-1α), facilitate the recruitment of HIF-1α to VEGF promoter, and activate VEGF expression under hypoxia, which was responsible for the roles of PAARH in promoting angiogenesis. The expression of PAARH was positively associated with VEGF expression and microvessel density in HCC tissues. In conclusion, these findings demonstrated that PAARH promoted HCC progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. PAARH represents a potential prognostic biomarker and therapeutic target for HCC.
Highlights
Hepatocellular carcinoma (HCC), the major primary liver cancer, is one of the most common malignancies and leading cause of cancer-related death [1]
Depletion of HOTTIP largely reversed the roles of Progression and Angiogenesis Associated RNA in HCC (PAARH) in modulating HCC cellular growth, apoptosis, migration, and invasion Given that HOTTIP was identified as a downstream target of PAARH, we further investigated whether HOTTIP is a critical mediator of the oncogenic roles of PAARH in HCC
PAARH facilitated angiogenesis via upregulating VEGF Given that PAARH expression was positively correlated with vascular invasion in HCC tissues and PAARH promoted angiogenesis in xenografts (Fig. 4g, h), we further explored the influences of PAARH on angiogenesis and the underlying mechanism
Summary
Hepatocellular carcinoma (HCC), the major primary liver cancer, is one of the most common malignancies and leading cause of cancer-related death [1]. HIF-1α activates the expression of its targeted genes, such as VEGF, which induces angiogenesis [15, 16]. Repressive roles of miRNAs on their targets These lncRNAs were classed as competing endogenous RNA (ceRNA). We further investigated the expression, roles, and mechanism of action of this lncRNA in HCC. Our findings revealed that this lncRNA enhanced malignant phenotypes of HCC cells, and promoted angiogenesis. We named this lncRNA Progression and Angiogenesis Associated RNA. The PCR products were cloned into the Hind III and BamH I sites of pcDNA3.1(+) (Invitrogen) to generate PAARH in HCC (PAARH). The PCR products were cloned into the Hind III and BamH I sites of pSPT19 (Roche, Basel, Switzerland) to generate PAARH in vitro transcription plasmid pSPT19-PAARH
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