Differentially expressed non-coding RNAs and their regulatory networks in liver cancer

Abstract

The vast majority of human transcriptome is represented by various types of small RNAs with little or no protein-coding capability referred to as non-coding RNAs (ncRNAs). Functional ncRNAs include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), which are expressed at very low, but stable and reproducible levels in a variety of cell types. ncRNAs regulate gene expression due to miRNA capability of complementary base pairing with mRNAs, whereas lncRNAs and circRNAs can sponge miRNAs off their target mRNAs to act as competitive endogenous RNAs (ceRNAs). Each miRNA can target multiple mRNAs and a single mRNA can interact with several miRNAs, thereby creating miRNA-mRNA, lncRNA-miRNA-mRNA, and circRNA-miRNA-mRNA regulatory networks. Over the past few years, a variety of differentially expressed miRNAs, lncRNAs, and circRNAs (DEMs, DELs, and DECs, respectively) have been linked to cancer pathogenesis. They can exert both oncogenic and tumor suppressor roles. In this review, we discuss the recent advancements in uncovering the roles of DEMs, DELs, and DECs and their networks in aberrant cell signaling, cell cycle, transcription, angiogenesis, and apoptosis, as well as tumor microenvironment remodeling and metabolic reprogramming during hepatocarcinogenesis. We highlight the potential and challenges in the use of differentially expressed ncRNAs as biomarkers for liver cancer diagnosis and prognosis.

Keywords: Hepatocellular carcinoma; Intrahepatic cholangiocarcinoma; Regulatory networks; circRNA; lncRNA; miRNA.

Fig. 1

Cellular processes regulated by DEC-DEG axes in liver cancer. Differentially expressed miRNAs: upregulated (in red), downregulated (in green), and with uncertain expression (in blue). The expression of the following miRNAs is upregulated: miR-10b-5p, miR-30e-5p, miR-147b, miR-18a, miR-548a-5p, miR-210-3p, miR-494-3p [30,31,40,43,52,55,56]. The expression of the following miRNAs is downregulated: miR-26a, miR-15a-3p, miR-4651, miR-30b-5p, miR-504, miR-542-3, miR-199a-5p, miR-302a, miR-98, miR-328-3p, miR-122, miR-195-5p, miR-5589-3p, miR-let-7c-3p, miR-126-3p, and miR-98-5p [[25], [26], [27], [28], [29],36,39,[41], [42], [43], [44], [45],[51], [52], [53], [54]]. Cellular effects (in purple) are determined by functions of genes targeted by a definite miRNA and influence on cancer growth is dependent on the miRNA expression level.

Fig. 2

The involvement of DEL-DEM-DEG and DEC-DEM-DEG networks in signaling pathways, transcriptional activity, and cell cycle progression in liver cancer cells. MAPK-mediated, PI3K/Akt-mediated, canonical Wnt/β-catenin-mediated, TGF-β-mediated, and integrin-mediated signaling as well as cell cycle progression pathways are regulated by DEL-DEM-DEG and DEC-DEM-DEG axes during hepatocarcinogenesis. MiRNAs are shown in red, lncRNAs in dark green, and circRNAs in blue colors. In human HCC HepG2 cells, miR-26a are upregulated to act via PI3K/Akt-mediated signaling [26,27], while miR-98 inhibits Bcl2 expression [39] and miR-98-5p represses NF-κB in HBV-related HCC MHCC97H-HBV cells [53]. In several human liver cancer lines, lncRNA-based KTN1-AS1/miR-23c/ERBB2IP axis activates MAPK/ERK1/2 pathway [85], whereas HULC/miR-15a/PTEN [95], UBE2R2/miR-302b/EGFR and ZEB1-AS1/miR-302b/EGFR axes activate PI3K/PKB(Akt) pathway [96,97], and LINC00662/miR-15a/β-catenin axis activates Wnt/β-catenin signaling [102], SBF2-AS1/miR-140-5p/TGFBR1 activates TGFβ-signaling [103]. In HCC tissues and cell lines such as SNU-387 and Huh7, circRNA-based circEIF3I/miR-526b-5p/HGF/c-Met and circ_0015756/miR-610/FGFR1 as well as circ_0015756/miR-7/FAK axes are identified [131,132,138]. Also, hsa_circ_0016788/hsa_circ_0016788/CDK4/6 axis regulates cell cycle [135].

Fig. 3

The Venn diagrams of cellular processes implicated in molecular mechanisms underlying the effects of (A) lncRNA and (B) circRNA during hepatocarcinogenesis. Quantities of genes in each category and ncRNA types involved in their regulation are shown. Several ncRNAs are implicated in two or three cellular processes. (A) lncRNAs implicated in cell signaling [63,64,70,74,85,[95], [96], [97], [98], [99], [100], [101], [102], [103], [104]], metabolic reprogramming [108,111], epithelial-mesenchymal transition/morphogenesis [81,82,86,89], tumor microenvironment remodeling [88], cell cycle [107], and apoptosis [84,87,103,106]. (B) CircRNAs implicated in cell signaling [132,133], cell cycle [108,118,134,135], transcriptional regulation [136,137,154], metabolic reprogramming [[145], [146], [147]], epithelial-mesenchymal transition [[139], [140], [141], [142]], immune response [144,149,150], and angiogenesis [129,131].