Soudeh Ghafouri-Fard
Mahdi Gholipour
Bashdar Mahmud Hussen3
Mohammad Taheri- 1Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 2Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- 3Pharmacognosy Department, College of Pharmacy, Hawler Medical University, Erbil, Iraq
- 4Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Hepatocellular carcinoma (HCC) is among the utmost deadly human malignancies. This type of cancer has been associated with several environmental, viral, and lifestyle risk factors. Among the epigenetic factors which contribute in the pathogenesis of HCC is dysregulation of long non-coding RNAs (lncRNAs). These transcripts modulate expression of several tumor suppressor genes and oncogenes and alter the activity of cancer-related signaling axes. Several lncRNAs such as NEAT1, MALAT1, ANRIL, and SNHG1 have been up-regulated in HCC samples. On the other hand, a number of so-called tumor suppressor lncRNAs namely CASS2 and MEG3 are down-regulated in HCC. The interaction between lncRNAs and miRNAs regulate expression of a number of mRNA coding genes which are involved in the pathogenesis of HCC. H19/miR-15b/CDC42, H19/miR-326/TWIST1, NEAT1/miR-485/STAT3, MALAT1/miR-124-3p/Slug, MALAT1/miR-195/EGFR, MALAT1/miR-22/SNAI1, and ANRIL/miR-144/PBX3 axes are among functional axes in the pathobiology of HCC. Some genetic polymorphisms within non-coding regions of the genome have been associated with risk of HCC in certain populations. In the current paper, we describe the recent finding about the impact of lncRNAs in HCC.
Introduction
Liver cancer is among the most lethal malignancies among both sexes. More than 8% of cancer-related mortalities are due to this type of cancer (1). Hepatocellular carcinoma (HCC) includes more than 75% of the primary liver neoplasms (1). Several factors have been related with elevated risk of HCC among them are chronic infection with hepatitis B virus (HBV) B or hepatitis C virus (HCV), dietary exposure with aflatoxin, excessive alcohol use, obesity, and smoking (2). The cirrhosis-induced carcinogenic alterations have been detected in 90% of HCC patients (3). High throughput sequencing methods have shown the occurrence of several genetic changes in the HCC samples (4) among the early events are inactivating mutations in insulin-like growth factor 2 receptor (5). Catenin Beta 1 (CTNNB1) and Tumor Protein P53 (TP53) are the utmost recurrently mutated oncogene and tumor suppressor gene in HCC, respectively (4). In addition to these somatic mutations, several epigenetic factors partake in the evolution of HCC. Such involvement is further highlighted by the fact that liver is an organs that is continuously adapting to extremely various environmental factors (6). Non-coding RNAs are among epigenetic elements that contribute in the pathogenesis of HCC. Long non-coding RNAs (lncRNAs) can affect expression of genes via diverse mechanisms including recruitment of regulatory protein complexes, acting as a decoy, changing genome organization and modulating the distribution of posttranslational modifications (7). These transcripts have sizes longer than 200 nucleotides and are comparable with mRNAs in the terms of chromatin state of genome loci, their transcription by RNA polymerase II, polyadenylation, 5’ capping and being spliced, yet they do not produce large-sized polypeptides (8). However, there are several reports demonstrating the presence of stable, functional micropeptides being translated from lncRNAs (9). Several lines of evidence indicates that these transcripts contribute in the pathophysiology of HCC (10). In the present manuscript, we review the current knowledge about the partake of lncRNAs in the pathogenesis of HCC.
Up-regulated lncRNAs in HCC
The LINC01138 is located in a frequently amplified region in HCC. This lncRNA transcript is stabilized by IGF2BP1/IGF2BP3. Over-expression of LINC01138 in HCC confers malignant characteristics and is associated with poor survival of patients. Mechanistically, this lncRNA interacts with arginine methyltransferase 5 and increases the stability of this protein through inhibiting ubiquitin-mediated degradation in proteasomes (11). Over-expression of the lnc-Epidermal Growth Factor Receptor (EGFR) regulatory T cells (Tregs) has been related with tumor size and levels of EGFR/Foxp3. Its over-expression has also been negatively correlated with the levels of interferon (IFN)-γ in HCC patients and animal models. This lncRNA promotes Treg differentiation, inhibits function of cytotoxic T cells and increases HCC growth. These effects are exerted through binding of lnc-EGFR with EGFR, increasing its stability and activation of the AP-1/NF-AT1 axis (12). The oncogenic lncRNA HULC has been shown to exert its effects via modulation of phosphorylation pattern of YB-1. Notably, up-regulation of this lncRNA in HCC has been correlated with pathological grade and patients’ outcome. HULC can also increase cell proliferation, migration, and invasion and suppress cisplatin-associated cell apoptosis (13). LncRNA-MUF is another over-expressed lncRNA in HCC tissues whose up-regulation has been correlated with poor clinical outcome. This lncRNA has an indispensable impact in epithelial-mesenchymal transition (EMT). Such effects have been exerted through binding with Annexin A2 and induction of the Wnt/β-catenin signaling. Mechanistically, lncRNA-MUF serves as a competing endogenous RNA (ceRNA) for miR-34a, resulting in up-regulation of Snail1 induction of EMT process (14). GHET1 over-expression in HCC sections has been associated with vascular invasion, cirrhosis, size of tumor, histological grade, and poor clinical outcome. GHET1 silencing has suppressed cell proliferation and prompted both cell cycle arrest and cell apoptosis. GHET1 can suppress expression of KLF2 in HCC cells through recruitment of PRC2 into its promoter (15). MALAT1 is another up-regulated lncRNA in HCC, which affect neoplastic transformation through several mechanisms among them is its role as a ceRNA. Figure 1 depicts this mechanism in HCC.
Figure 1 MALAT1 is an important oncogenic lncRNA in hepatocellular carcinoma (HCC). MALAT1 can sequester several miRNAs. For instance, MALAT1 can sequester miR-140. Through down-regulation of miR-140, MALAT1 enhances expression of VEGF-A and increases angiogenic potential. Moreover, via this route, MALAT1 enhances polarization of macrophage differentiation to M2. These macrophages facilitate tumor progression via modulation of tumor microenvironment (16). MALAT1 also reduces expression of miR-204 in HCC leading to upsurge in SIRT1 levels. SIRT1 up-regulation enhances expression of Vimentin and Twist and inhibits E-cadherin, thus facilitating epithelial-mesenchymal transition (EMT) (17). MALAT1 can also sequester miR-143-3p, thus up-regulating FGF1, N-cadherin, Vimentin, Snail, and Slug while down-regulating E-cadherin. These effects are associated with enhancement of EMT (18). Similarly, through down-regulation of miR-30a-5p, MALAT1 enhances Vimentin levels and EMT process (19). Via sequestering miR-200a, MALAT1 increases aspartate-β-hydroxylase (ASPH) levels, thus elevating expression of proteins which are involved in EMT or cell proliferation (20). MALAT1-mediated down-regulation of miR-124-3p leads to up-regulation of Slug, therefore increasing cell proliferation and EMT (21). MALAT1 can also sponge miR-195 resulting in over-expression of FGFR, activation of PI3K/AKT and enhancement of cell proliferation and invasion (22). Finally, MALAT1-mediated down-regulation of miR-22 increases Snail levels and facilitates EMT. Moreover, MALAT1 recruits EZH2 to the of promoter E-cadherin and miR-22 to decrease their expression (23). Table 1 enlists function of over-activated lncRNAs in HCC.
Table 1 Function of over-activated lncRNAs in HCC (ANT, adjacent non-cancerous tissue; HBS Ag, hepatitis B surface antigen).
Down-Regulated lncRNAs in HCC
Through a high throughput approach, Ni et al. have identified uc.134 as a novel lncRNA which is under-expressed in a highly aggressive HCC cell line. They further verified its down-regulation in clinical HCC samples compared with paired nearby tissues. Notably, down-regulation of uc.134 has been related with poor prognosis of HCC patients. Functionally, this lncRNA suppresses cell proliferation, invasion, and metastasis through binding with CUL4A suppressing its nuclear export. Besides, uc.134 suppresses the CUL4A-associted ubiquitination of LATS1 and enhances YAPS127 phosphorylation which results in down-regulation of YAP target genes of YAP (223). LncRNA-PRAL has been shown to suppress HCC growth and stimulate apoptosis via a p53-dependent route. Certain motifs at the 5’ end of this lncRNA have been identified that participate in competitive inhibition of MDM2-dependent p53 ubiquitination (224). Expression of the lncRNA-LET has been decreased in HCC. Further experiments have shown the role of hypoxia-induced histone deacetylase 3 in down-regulation of this lncRNA. Notably, repression of lncRNA-LET has been identified as an important step in the stabilization of nuclear factor 90 protein and subsequent hypoxia-associated tumor cell invasion. The association between down-regulation of lncRNA-LET and metastatic potential of HCC has also been verified in clinical samples (225). TSLNC8 is also down-regulated in HCC samples. Down-regulation of this lncRNA in HCC has been shown to confer malignant phenotype. TSLNC8 competitively interacts with transketolase and STAT3 and alters the phosphorylation patterns and transcriptional activity of STAT3 leading to suppression of the IL-6-STAT3 signaling (226). CASC2 is another down-regulated lncRNAs in HCC samples, particularly in the samples obtained patients with aggressive and recurrent forms of HCC. CASC2 suppresses migration and invasive properties of HCC cells and inhibits EMT program in these cells. Mechanistically, it serves as a competing endogenous RNA for miR-367 to increase expression of its target gene FBXW7. Notably, CASC2 down-regulation and miR-367 up-regulation have been associated with the metastasis-associated characteristics in the clinical samples (227). Table 2 displays the impact of down-regulated lncRNAs in HCC.
Table 2 List of under-expressed lncRNAs in HCC (ANT, adjacent non-cancerous tissue).
Diagnostic and Prognostic Impact of lncRNAs in HCC
Expression patterns of several lncRNAs have been related with overall survival or disease-free survival of patients with liver neoplasm. Oncogenic lncRNAs which decrease survival of HCC patients include NEAT1, PTTG3P, UBE2CP3, LINC00461, MALAT1, MNX1-AS1, MCM3AP-AS1, ANRIL, AWPPH, PVT1, SNHG1, ENST00000429227.1, LINC00665, CRNDE, FOXD2-AS1, HULC and some other lncRNAs. Instead, low expressions of several tumor suppressor lncRNAs namely PSTAR, CASC2, lnc-FTX, LINC00472, TSLNC8, miR503HG, MEG3, LIN00607, AOC4P, uc.134, GAS8-AS1, LINC00657, MAGI2-AS3, LINC01093, GAS5, SchLAH, and NKILA predict patients’ outcome. Univariate/multivariate cox regression analyses have confirmed the role of these lncRNAs in the determination of HCC prognosis. Table 3 lists the results of studies which evaluated the prognostic roles of lncRNAs in patients with HCC.
Table 3 Prognostic role of lncRNAs in HCC (ANT, adjacent non-cancerous tissue; OS, overall survival; RFS, relapse-free survival; DFS, disease-free survival; PFS, progression-free survival; TTR, time to tumor recurrence).
Table 4 Diagnostic role of lncRNAs in HCC.
Genomic Variants Within lncRNAs and Risk of HCC
Genetic polymorphisms include at least four type of variations namely, single nucleotide polymorphisms, small insertion/deletion polymorphisms, polymorphic repetitive elements and microsatellites. The importance of somatic copy number variations (SCNVs) loci in non-coding regions in the development of HCC has been assessed by Zhou et al. Such investigation has led to identification of recurrent deletion of lncRNA-PRAL in HCC samples in association with poor clinical outcome (224). The lncRNA TSLNC8 on 8p12 is another tumor suppressor lncRNA which is commonly deleted in HCC tissues (226). Table 5 shows the summarized results of studies which assessed association between lncRNAs insertion/deletion or tetranucleotide repeat polymorphisms and HCC.
Table 5 Association between lncRNAs polymorphisms and HCC.
Discussion
LncRNAs contribute in the pathogenesis of HCC through diverse mechanisms including modulation of oncogenes and tumor suppressor genes as well as modification of tumor microenvironment. The latter route of action has been best exemplified by the lnc-EGFR which enhances differentiation of Tregs therefore increasing immune evasion (12). Moreover, certain lncRNAs such as MUF and SNHG7 facilitate EMT process through modulation of Wnt/β-catenin signaling pathway (14, 114). Other lncRNAs can modulate EMT through sponging a number of miRNAs. MAPK, PI3K/AKT and JAK/STAT signaling pathways are other cancer-related pathways that are modulated by several lncRNAs in HCC. The interactions between lncRNAs, miRNAs and mRNAs have functional importance in the pathogenesis of HCC. Examples of such trios include H19/miR-15b/CDC42, H19/miR-326/TWIST1, NEAT1/miR-485/STAT3, MALAT1/miR-124-3p/Slug, MALAT1/miR-195/EGFR, MALAT1/miR-22/SNAI1 and ANRIL/miR-144/PBX3.
Functional roles of lncRNAs in HCC have been appraised in animal models. These models have facilitated identification of lncRNAs targets and related pathways (304), which can be used as therapeutic candidates in HCC. HCC-associated lncRNAs can affect gene expression via recruiting epigenetic factors (305), regulation of transcription factors (306), modulation of protein degradation (307) and alteration of phosphorylation of proteins (308).
Genomic alterations and polymorphisms within lncRNA-coding regions have been shown to confer risk of HCC. Such variations might also predict survival of these patients. However, the observed association between these variants and HCC should be verified in independent samples from different ethnic groups. Integration of the results of genome-wide association studies with high throughput sequencing data obtained from microarray and RNA seq experiments would help in discovery of HCC-related single nucleotide polymorphisms within lncRNAs.
The biomarker role of lncRNAs in HCC has been verified by several studies indicating their importance both in the diagnosis and in the prognosis of this cancer. Expression levels of lncRNAs can differentiate HCC patients from inactive HBs Ag carriers, patients with chronic hepatitis and those with liver cirrhosis. In addition, the high diagnostic power values of peripheral levels of a number of lncRNAs such as UCA1 and NEAT1 have potentiated them as methods for non-invasive diagnosis of HCC. Moreover, lncRNAs can be regarded as therapeutic targets in HCC. The importance of lncRNAs as therapeutic targets in HCC has been noted by several experiments in animal models of HCC. Yet, such experiments wait approval in clinical settings. In vivo delivery of a number of lncRNAs such as lncRNA-PRAN, uc.134 and TSLNC8 has been shown to attenuate tumor growth and enhance lifespan of xenograft models of HCC (223, 224, 226). Moreover, a number of lncRNAs such as HULC confer resistance to chemotherapeutic agents (13), indicating the potential of targeted therapies against these transcripts in enhancement of response of HCC patients to conventional therapeutic options. Antisense oligonucleotides and small interfering RNAs are putative methods for suppression of expression of lncRNAs (309, 310) whose efficacies have been verified in animal models and cell line experiments. Yet, this knowledge has not been translated into clinical practice.
Taken together, lncRNAs as important class of regulatory transcripts can influence pathogenesis of HCC from different aspects and can be used as suitable markers for differentiation of HCC from related pathogenic conditions.
Author Contributions
SG-F and MT wrote the draft and revised it. BH and MG designed the tables and figures. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Keywords: lncRNA, biomarker, hepatocellular carcinoma, expression, polymorphism
Citation: Ghafouri-Fard S, Gholipour M, Hussen BM and Taheri M (2021) The Impact of Long Non-Coding RNAs in the Pathogenesis of Hepatocellular Carcinoma. Front. Oncol. 11:649107. doi: 10.3389/fonc.2021.649107
Received: 03 January 2021; Accepted: 22 March 2021;
Published: 21 April 2021.
Edited by:
Xing-Xing He, Huazhong University of Science and Technology, ChinaReviewed by:
Ying Chang, Wuhan University, ChinaMin Wang, Huazhong University of Science and Technology, China
Copyright © 2021 Ghafouri-Fard, Gholipour, Hussen and Taheri. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohammad Taheri, mohammad_823@yahoo.com