The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment

Abstract

Hepatocellular carcinoma (HCC) is a common liver malignancy with high morbidity and poor prognosis. Long non-coding RNAs (lncRNAs) are involved in crucial biological processes of tumorigenesis and progression, and play four major regulatory roles, namely signal, decoy, guide, and scaffold, to regulate gene expression. Through these processes, lncRNAs can target microRNAs (miRNAs) to form lncRNA and miRNA networks, which regulate cancer cell proliferation, metastasis, drug resistance, and the tumor microenvironment. Here, we summarize the multifaceted functions of lncRNA and miRNA networks in the pathogenesis of HCC, the potential use of diagnostic or prognostic biomarkers, and novel therapeutic targets in HCC. This review also highlights the regulatory effects of lncRNA and miRNA networks in the tumor microenvironment of HCC.

The Mechanism Underlying the ncRNA Dysregulation Pattern in Hepatocellular Carcinoma and Its Tumor Microenvironment

“…LncRNAs can sponge miRNAs, which affects the expression of miRNA-targeted genes (69). A growing body of evidence shows that lncRNAs acting as ceRNAs play a significant role in regulating tumor cell proliferation, migration, invasion, apoptosis, immune evasion and drug treatment response (70)(71)(72)(73). For instance, lncRNA LNC00667 plays an oncogenic role by binding to miR-130a-3p, thereby attenuating the inhibition of AR expression and promoting the HCC cell malignant phenotype (71).…”

“…A growing body of evidence shows that lncRNAs acting as ceRNAs play a significant role in regulating tumor cell proliferation, migration, invasion, apoptosis, immune evasion and drug treatment response (70)(71)(72)(73). For instance, lncRNA LNC00667 plays an oncogenic role by binding to miR-130a-3p, thereby attenuating the inhibition of AR expression and promoting the HCC cell malignant phenotype (71). LncRNA PICSAR is upregulated in tissues, and gain-and loss-of-function experiments indicated that lncRNA PICSAR enhances cell proliferation and cell cycle progression, inhibits apoptosis by sponging miR-194-5p and subsequently upregulates eukaryotic initiation factor 6 (EIF6) expression in HCC (74).…”

Wnt/β-Catenin Signaling as a Driver of Stemness and Metabolic Reprogramming in Hepatocellular Carcinoma

“…It has been suggested that microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are critical regulators associated with various tumors, in which they are negatively regulated [ 45 ]. Dysregulation of miRNAs and lncRNAs could lead to tumorigenesis in HCC.…”

“…Dysregulation of miRNAs and lncRNAs could lead to tumorigenesis in HCC. LncRNA-miRNA binding yields a complete endogenous RNA (ceRNA) that can avoid messenger RNA (mRNA) recognition and further silencing effects, known as the “sponge effect” [ 45 ]. Mounting evidence suggests that miRNA sponges are involved in Wnt/β-catenin signaling and are associated with HCC progression ( Table 1 ).…”

Long noncoding RNA LINC01124 activates hepatocellular carcinoma cell proliferation, migration, and invasion by absorbing microRNA-1247-5p and overexpressing FOXO3

“…MicroRNAs (miRNAs) are approximately 17-24nucleotides-long RNA molecules that are not translated into proteins [16]. miRNAs directly bind to the 3′-untranslated region of their target genes through complementary base pairing and exert a negative regulatory effect on target gene expression, resulting in mRNA degradation and/or translation inhibition [17,18] MiRNAs are important gene expression regulators that contribute to the tumorigenesis and progression of HCC by influencing the malignant phenotype of tumors [19,20]. Recent evidence has revealed a crosslink between miRNAs and lncRNAs, known as the competing endogenous RNA (ceRNA) theory [21][22][23].…”