Diversity of Dysregulated Long Non-Coding RNAs in HBV-Related Hepatocellular Carcinoma

Abstract

Infection with the hepatitis B virus (HBV) continues to pose a major threat to public health as approximately 292 million people worldwide are currently living with the chronic form of the disease, for which treatment is non-curative. Chronic HBV infections often progress to hepatocellular carcinoma (HCC) which is one of the world's leading causes of cancer-related deaths. Although the process of hepatocarcinogenesis is multifaceted and has yet to be fully elucidated, several studies have implicated numerous long non-coding RNAs (lncRNAs) as contributors to the development of HCC. These host-derived lncRNAs, which are often dysregulated as a consequence of viral infection, have been shown to function as signals, decoys, guides, or scaffolds, to modulate gene expression at epigenetic, transcriptional, post-transcriptional and even post-translational levels. These lncRNAs mainly function to promote HBV replication and oncogene expression or downregulate tumor suppressors. Very few lncRNAs are known to suppress tumorigenesis and these are often downregulated in HCC. In this review, we describe the mechanisms by which lncRNA dysregulation in HBV-related HCC promotes tumorigenesis and cancer progression.

Keywords: HBV-related HCC; ceRNA; epigenetic regulation; lncRNA; miRNA precursor processing; protein interactions; transcriptional regulation.

Figure 1

Epigenetic modification of chromatin by lncRNAs. (1) LncRNAs HEIH, UCA1 and Linc00152 recruit the repressive chromatin modifying complex, PRC2, to specific sites on the human genome to catalyze H3K27 trimethylation. This results in chromatin compaction and transcriptional repression of tumor suppressor genes. (2) LncRNAs PVT1 and HOTAIR inhibit formation of the PRC2 complex whereas DLEU2 displaces PRC2 from chromatin to prevent H3K27 methylation, allowing transcription of oncogenic host genes. HOTTIP recruits the activating chromatin-modifying complex WDR2/MKK to mediate H3K4 methylation of chromatin enabling the transcription of HOXA13 which suppresses HBV replication. (3) DLEU2 and HOTAIR can also inhibit PRC2 recruitment to HBV cccDNA, alleviating epigenetic silencing and promoting HBV replication. Color coding of names indicate a functional relationship between the lncRNA and its target. Created with BioRender.com.

Figure 2

LncRNA modulation of promoter activity. (1) LncRNAs linc00152 and linc01152 have enhancer-like properties and interact with the promoters of the EpCAM and IL23 genes respectively. EpCAM positive cells display enhanced stemness and metastatic potential, and increased levels of IL23 promote proliferation. (2) LncRNA HULC interacts with the promoter of the tumor suppressor p18 to inhibit its transcription and promote cell proliferation. (3) Certain lncRNAs can guide transcription factors to the promoters of specific genes to enhance transcription. MALAT1 recruits the transcription factor Sp1 to the promoter of the LTBP3 gene on the host genome resulting in metastasis. HULC and HOTAIR recruit the transcription factors STAT3 and Sp1 to host and viral genomes respectively to enhance transcription of viral genes thus promoting HBV replication. Created with BioRender.com.

Figure 3

Alternative splicing by lncRNA ZEB2-AS1. The antisense lncRNA ZEB2-AS1 binds to the 5’ UTR donor splice site of mRNA encoding ZEB2, a transcriptional repressor of E-cadherin. This prevents the spliceosome from eliminating this region of the transcript, which contains an IRES that is necessary for translation. ZEB2 is subsequently translated, and its increased levels promote EMT. Created with BioRender.com.

Figure 4

LncRNAs act as ceRNAs to sequester complementary miRNAs. LncRNAs harbor MREs which allow them to bind to miRNAs with complementary sequences. H19, n335586 and Unigene56159 promotes EMT by sequestering miR-22, miR-924 and miR-140-5p, respectively. HBx-LINE1 and WEE2-AS1 promotes EMT and cell proliferation by sponging miR-122 and miR-214, respectively. DBH-AS1 increases cell proliferation by sequestering miR-138. PCNAP1 sponges miR-340-5p and miR-154 to promote cell proliferation and HBV replication, respectively. HULC sequesters miR-372, thereby maintaining its upregulation. Created with BioRender.com.

Figure 5

LncRNAs interact with proteins and alter their stability or functionality. (1) DREH and LncRNA-6195 are downregulated in HBV-related HCCs. The lack of interaction between DREH and the protein vimentin promotes EMT. Deficient binding of LncRNA-6195 to ENO1 promotes EMT and cell proliferation. (2) HUR1, SAMD12-AS1 and MVIH are upregulated in HBV-related HCCs. HUR1 and SAMD12-AS1 enhance cell proliferation by inhibiting p53 and NPM1, respectively. MVIH interacts with PGK1 to prevent its secretion thereby promoting angiogenesis. Created with BioRender.com.

Figure 6

LncRNAs are precursors of miRNAs. The Ftx and H19 genes transcribe lncRNAs Ftx and H19, respectively. LncRNA Ftx encodes the miR-545/374a cluster, which subsequently promotes EMT and cell proliferation. LncRNA H19 transcribes miR-675 which enhances cell proliferation. Created with BioRender.com.