Non-Coding RNAs in Hepatocellular Carcinoma Progression: Comparison
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Please note this is a comparison between Version 2 by Wendy Huang and Version 1 by Mario Romeo.

Hepatocellular carcinoma (HCC) is a predominant malignancy with increasing incidences and mortalities worldwide. In Western countries, the progressive affirmation of Non-alcoholic Fatty Liver Disease (NAFLD) as the main chronic liver disorder in which HCC occurrence is appreciable even in non-cirrhotic stages, constitutes a real health emergency. In light of this, a further comprehension of molecular pathways supporting HCC onset and progression represents a current research challenge to achieve more tailored prognostic models and appropriate therapeutic approaches. RNA non-coding transcripts (ncRNAs) are involved in the regulation of several cancer-related processes, including HCC. When dysregulated, these molecules, conventionally classified as “small ncRNAs” (sncRNAs) and “long ncRNAs” (lncRNAs) have been reported to markedly influence HCC-related progression mechanisms. 

  • non-coding RNAs
  • liver cancer
  • sncRNAs
  • lncRNAs
  • transcription
  • dysregulation
  • circular RNAs

1. Introduction

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and a predominant malignancy with increasing incidences and mortalities worldwide [1]. In parallel with the chronic Hepatitis C virus (HCV), Hepatitis B virus (HBV) infection, alcohol consumption [Alcoholic Fatty Liver Disease (AFLD)], and aflatoxin B1 exposure [1], the progressive increase of Non-alcoholic Fatty Liver Disease (NAFLD) incidence has fueled HCC occurrence even in non-cirrhotic contexts [1,2][1][2]. In light of this, the full comprehension of the molecular pathways supporting HCC onset and progression is urgently needed to design more tailored prognostic models and appropriate therapeutic approaches.
A wide inter- and intra-individual molecular diversity, as well as the crucial role of genetics in the clinical outcome for HCC patients, has been reported [3]. The accumulation of several genetic (and epigenetic) alterations is considered the key driver of liver carcinogenesis, a multi-step process where the acquisition of a malignant phenotype represents only the beginning of a dramatic cascade of events [4].
For this purpose, a plethora of early gene-sequencing studies focused mainly on protein-coding genes, profiled the HCC-associated mutations, and subsequently defined the related pathobiological pathways, confirming a heterogeneous tumor microenvironment where various clusters of neoplastic cells showing different molecular gene signatures [3,5][3][5]. Hereafter, further findings have progressively shown that, at the hepatic level, as well as in other organs, a large number of pro-carcinogenic and anti-carcinogenic mechanisms are regulated also by RNA non-coding transcripts known as non-coding RNAs (ncRNAs) [6,7,8][6][7][8].
Conventionally, ncRNAs are classified in terms of their molecular size: ncRNAs shorter than 200 nucleotides are defined as small ncRNAs (sncRNAs), whereas longer ncRNAs are considered long ncRNAs (lncRNAs) [7]. However, beyond genetics, the systemic and local immune system status (both innate and acquired immune dysfunction [9]), and the gut microbiota composition (HCC-related dysbiosis “signature” [10]) represent equally relevant emerging, mutually influenced, and incompletely explored pathogenic frontiers composing the complex network of the still-not-fully clarified HCC pathogenesis.
Unlike sncRNAs, linear lncRNAs are transcripts longer than 200 nucleotides and share several common features with mRNAs, such as the transcription by RNA polymerase II, the 5′capping, the splicing, and the polyadenylation. lncRNAs are less expressed than mRNAs and they have tissue and developmental-stage-specific expression profiles [83][11]. In detail, lncRNAs constitute a heterogeneous large group of ncRNAs subdivisible, according to their genomic biogenesis, into five categories: (a) intronic lncRNAs, which originate from intronic regions within protein-coding genes; (b) intergenic lncRNAs, whose transcription occurs at the intergenic region level, between two protein-coding genes; (c) enhancer lncRNAs, whose transcription occurs in the enhancer sites of the genome; (d) bidirectional lncRNAs, which are transcribed bidirectionally in the promoter-regions of protein-coding genes; and (e) antisense lncRNAs, which originate from overlapping protein-coding genes and from which they are transcribed following the antisense direction [83][11]. Consistently with their heterogeneous biogenesis, the linear lncRNAs, whose heterogeneity appears to mirror their crucial regulatory functions in cancerogenesis processes, are very heterogeneous [83][11]. In this sense, linear lncRNAs can guide, after selectively binding, specific proteins on the cellular surface, and drive the release of the substance in the opportune target cell (“guide lncRNAs”). Moreover, they can act as molecular decoys to bind and facilitate the degradation of targeted proteins or other RNAs (“decoy lncRNAs”). Furthermore, they can serve as scaffolds (“scaffold lncRNAs”) functioning as a pivotal platform to assemble different molecular components (other RNAs and proteins). Lastly, by interacting with transcription factors or chromatin-modifying enzymes, they can tissue-specifically regulate the expression of targeted genes [83][11]. A particular emerging class of ncRNAs with a specific morphology is represented by the circular RNAs (CircRNAs), covalently closed RNA molecules modulating gene expression by acting as transcriptional regulators, miRNA sponges, and protein templates [84][12]. Due to their pleiotropic modes of action, circRNAs have been proposed as diagnostic and prognostic HCC markers and their potential role is reported in detail in the dedicated subsection of this paragraph.

2. Role of Linear Long Non-Coding RNA Dysregulation in Hepatocellular Carcinoma Progression

In recent years, it has been shown that lncRNAs can modulate different stages of liver diseases, affecting immune responses, liver regeneration, and redox signaling [85,86][13][14]. The dysregulation of lncRNA patterns promotes the worsening of liver pathologies, liver outgrowth, and oxidative stress, which eventually result in the initiation and progression of HCC through different signaling pathways [86][14]. Multiple lncRNA profiling studies on whole-genome transcriptome sequencing platforms have highlighted the altered expression pattern of lncRNAs in human HCC, suggesting a significant difference in the global expression profile between tumors and nontumor cells [86][14]. Abnormal cell proliferation is identified by cell cycle disturbances that result in uncontrolled cell division. lncRNAs are involved in different phases of the cell cycle by directly and indirectly influencing the activities of several Cyclin-dependent kinases (CDK) [87][15]. For instance, the interaction of Lnc-UCID with DHX9 (DExH-Box Helicase 9) determines CDK6 enhanced expression, the promotion of G0/G1 to S phase transition, and, ultimately, HCC cell proliferation [88][16]. A central regulator of cell cycle progression is the E2F transcription factor family, whose expression and functions are tightly linked with the occurrence and development of various malignant tumors [89][17]. In this regard, many lncRNAs exhibit involvement in HCC progression due to the regulation of E2F family members, like E2F1 and E2F2. For instance, lncRNA CASC11 enhances the stability of E2F1 mRNA by recruiting EIF4A3, which leads to the upregulation of E2F1 and, ultimately, promotes hepatocarcinogenesis and sponging mir-296–5p in HCC cells. It consequently activates the Wnt/β-catenin pathway by enhancing SOX12 and promoting HCC cell proliferation and progression [90][18]. Among scaffold lncRNAs, HULC lncRNA has been well-characterized as an oncogenic molecule, singularly upregulated in human HCC [91][19]. HULC lncRNA is implicated in HCC progression mainly by functioning as a molecular decoy of miR-107, which usually represses the E2F1 transcription factor [92][20]. Lu and colleagues demonstrated HULC’s capability to disable miR-107 functioning in the HCC microenvironment and, consequently, promote the activation of spongiosine kinase 1 with the stimulation of angiogenesis metastatic cell dissemination processes [92][20]. Consistent with this, Zhu and colleagues reported the capability of HULC to downregulate miR-29, whose TS-miRNA properties have already been described in Section 2.1.1 above [93]. HOTAIR displays its role in hepatoma cells at the epigenetic level. Indeed, it was shown to be able to interact and guide polycomb group complex 2 (PRC2) in the repression of specific target genes via the installation of transcriptional repressive histone 3 lysine 27 trimethylation (H3K27me3) [94][21]. It has been described by Fu and others that HOTAIR epigenetically silences miR-218-2 on chromosome 5, with the intervention of PRC2 to suppress P14 and P16 (tumor suppressor genes) signaling in the HepG2 cell line [95][22].

3. Etiology-Specific Dysregulated Linear lncRNAs in Hepatocellular Carcinoma Progression

Recently, several findings supporting the implication of lncRNAs in the pathogenesis of NAFLD-related HCC were published. As mentioned in Section 2.2 above, tThe dysregulation of miR-155 expression represents a relevant pathogenetic moment, contributing to the onset of HCC in the early stage of cancerogenesis in the NAFLD context [72,73][23][24]. In line with this, Yuan et al. revealed miR-155 as a target of the lncRNA CASC2: in particular, CASC2 was found to be downregulated in HCC tissue samples and was revealed to act as a molecular sponge inhibiting the expression of miR-155 [96][25]. Moreover, Wang et al. reported that the overexpression of lncRNA NEAT1 was positively correlated with the upregulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), both involved in NAFLD pathogenesis [97][26]. Conversely, treatment with si-NEAT1 lentivirus reduced the triglyceride and cholesterol levels in the animal model, further supporting the involvement of NEAT1 in NAFLD progression. Additionally, in 2019, Si-si Jin and colleagues demonstrated how NEAT1 affects miR-506 expression in BRL3A cells treated with free fatty acids (FFA) [98][27]. Hence, NEAT1 was upregulated while miR-506 was downregulated in the progression of NAFLD; furthermore, NEAT1 and miR-506 were proven to regulate fibrosis, inflammatory response, and lipid metabolism [98][27]. Another lncRNA that seems to exert a critical role in NAFLD-related HCC is MALAT1, whose expression was found to be elevated in liver tissue of NAFLD patients and HepG2 cells treated with 1 mM of FFA as an NAFLD in vitro model [99][28]. The knockdown of MALAT1 upregulated the expression of PPAR and reduced CD36 levels, thus reversing fatty-acid-induced lipid accumulation in HepG2 cells [99][28]. MALAT1 is also a crucial oncogene involved in the upregulation of Serine/arginine-rich splicing factor 1 (SRSF1) and the activation of the Wnt pathway, thus promoting HCC growth and development in liver tumors of the HCC mouse model [100][29]. Altogether, these findings highlighted a possible involvement of MALAT1 as a new potential therapeutic target. LncRNAs also exhibit a crucial role in infection-related HCC. For instance, the integration of HBV into a normally silenced region of chromosome 8p11.21 produces a novel chimeric HBx-LINE1 lncRNA, which exerts its function HBx-LINE1 by activating the Wnt signaling pathway and promoting hepatic injury by acting as a decoy to sequester liver-specific miR-122 [101][30]. Finally, high levels of HBx-LINE1 have been found in HBV-related HCCs, showing the importance of HBx-LINE1 as an independent prognostic factor in this context [101][30]. Moreover, HBV protein X (HBx) is highly carcinogenic, and 90% of HBx transgenic mice develop HCC [102][31]. HBx proteins seem to be implicated in the activation of several lncRNAs in HBV-related HCCs, such as DBH-AS1, lncRNA-UCA1, and HULC in HCC cell lines [103][32]. A profiling expression study by Zhang et al. demonstrated an altered lncRNA expression in a series of patients with different stages of HCV-associated liver disease [104][33]. Linc01419 was found to be highly expressed in early-stage HCCs compared with pre-malignant dysplastic nodules [104][33]. In addition, another lncRNA, K021443, was found to be overexpressed in advanced HCC [104][33]. Additionally, Linc01152 overexpression determines an increased HCC cell proliferation and tumor formation in nude mice, probably due to the activation of the transcription of IL-23 (interleukin 23), which induces the STAT3 pathway. Strikingly, linc01152 is described as being downregulated in all viral-hepatitis-related HCC through an unknown mechanism [104,105][33][34].

4. Circular RNAs in Liver Cancer Progression: Novel Diagnostic/Prognostic Markers?

In the following parallel-natured pathogenetic–clinical section, by focusing particularly on circRNAs correlated with HCC genesis and progression, we present an overview of ncRNAs that represent potentially useful novel tools in the diagnosis of HCC, as well as ncRNAs that can predict individual outcomes. In the last decade, also considering their well-demonstrated key regulator role in cancer-related molecular pathways, the world of circRNAs has been deeply investigated. In terms of downregulation or overexpression, a growing number of emerging studies provide evidence of several dysregulated circRNAs creating a complex pathomolecular network in the HCC context. Preliminary observational research revealed higher has_circ_0005075 expression levels in HCC tissues compared with corresponding nontumorous counterparts. In addition, has_circ_0005075 expression was significantly upregulated in tumoral specimens, and, relevantly, the correlation analysis including several clinicopathological parameters of HCC patients demonstrated the relationship between has_circ_0005075 expression levels and HCC tumor size. However, despite these interesting results, its function remains to be clarified [106][35]. For this purpose, a subsequent brilliant in vitro study by Li et al. showed the association of has_circ_0005075 HCC overexpression with increased numbers of proliferative, migrated, and invasive SMMC-7721 cells, as well as the capability of this circRNA to promote HCC progression through the downregulation of miR-431 [107][36]. Consistent with this, Pan et al., by evaluating miR-431 expression levels in 95 HCC cases, highlighted that this miRNA was markedly downregulated in the HCC samples compared with corresponding adjacent nontumoral tissues [108][37]. However, even though the correlation analysis provided evidence for the relationship of miR-431 downexpression with multiple malignant characteristics, including lymph node metastasis, the HCC diagnostic accuracy of the assessment of miR-431 expression levels appeared not likewise elevated [Area under the Receiving Operator (ROC) Curve (AUC): 0.66] [108][37]. Moreover, in a recent in vitro–in vivo study, Sun et al. brilliantly investigated the function and regulation of circ_0038718 in HCC, suggesting its crucial role in fueling liver cancer progression [109][38]. The reseauthorchers highlighted high expression levels of circ_0038718 in cell lines and HCC specimens and correlated this result with worsened prognosis in HCC patients. In vitro, circ_0038718 knockdown reduced HCC advancement mechanisms as cancer cell proliferation and cellular invasion [109][38]. Mechanistically, this molecule may act as the sponge of TS miR-139-3p, and, in support of this, the inhibition of miR-139-3p abrogated the regulatory effect of circ-0038718 in HCC cells, suggesting miR139 as a circ_0038718-specific target [109][38]. In the same vein, a group of researchers had previously tried to identify differentially expressed human miRNAs between HCC and normal liver tissues by evaluating the miRNA expression profiles of 375 HCC and 50 normal liver tissues. The reseauthorchers shed light on has-miR-139-5p as a potential discriminant marker, and, further, the ROC curve analysis suggested that the survival prediction model developed based on tumor stage and hsa-miR-139-5p expression levels exhibited good performance in predicting the 3-year overall survival (OS) of HCC patients. By combining these findings, the encouraging results proposed circ_0038718 and miR-139 as crucial regulators of liver cancer progression and promising reciprocally influenced prognostic indicators, while also providing potential therapeutic targets for HCC treatment [97,109][26][38]. Despite the progressively increasing evidence on circRNA- and miRNA-related implicated in the progression of HCC, some circRNAs continue to be “orphans” of specific miRNAs, and vice versa, suggesting that several molecular mechanisms have yet to be elucidated. For instance, although the TS miR-122 represents the most frequently detected miRNA in the liver and its crucial role in cancer suppression has been largely demonstrated, circRNAs specifically targeting and regulating this molecule expression and functioning have not been identified [15][39]. Of relevance, miR-122 appears also closely related to the prognosis of HCC: decreased miR-122 levels have been associated with cell proliferation, invasion, and metastasis mechanisms, and several targets of miR-122 have been implicated in tumorigenesis, including ADAM10, cyclin G1, SRF, Wnt1, and IGF1R [110][40]. Conversely, circ_0128298 represents a circRNA orphan for relative-targeted miRNAs. Due to its capability of promoting proliferation and metastasis by not-fully clarified molecular pathways, and considering its significant upregulation in liver cancer samples compared with those of peritumorous tissues, this molecule has been proposed as another relevant circRNA associated with HCC progression [111][41]. If on one side, it has been demonstrated to have only a moderate HCC diagnostic accuracy [AUC: 0.66; sensitivity: 0.71; specificity: 0.81], on the other, this circRNA tissue expression relevantly correlated with the OS [111][41]. However, the current goal in this context appears to approach circRNA biological effects by identifying specific circRNA signatures. In this sense, a recently published meta-analysis including a total of eight studies highlighted, through adequate ROC curve analysis, an elevated diagnostic accuracy [AUC: 0.86; sensitivity: 0.78; specificity:0.80] for the specific circRNAs expression profile [downregulated circRNAs: hsa_circ_0003570, circZKSCAN1, hsa_circ_0001649, hsa_circ_0004018 tissue levels, and hsa_circ_0001445 serum levels; overexpressed circRNAs: hsa_circ_0005075, hsa_circ_0091582, and hsa_circ_0128298 tissue levels] in confirming HCC [112][42]. In addition to the potential diagnostic role, survival analyses also revealed a relevant prognostic implication by showing that abnormally expressed circRNAs were intimately associated with tumor size, serum alpha fetal protein level, differentiation grade, microvascular invasion, and metastasis in patients with HCC, as well as that the downregulated circRNA expression signature correlated perfectly with HCC survival [hazard ratio (HR): 0.42], whereas the HCC cases with high circRNA levels had significantly poorer prognoses than those of patients with low circRNA levels (HR: 2.22). In the same vein, J. Cao et al. more recently explored lncRNA expression levels in HCC and para-carcinoma tissue to filter out 19 specific differentially expressed lncRNAs, demonstrating for this 19-lncRNA signature a good diagnostic accuracy in diagnosis and prognosis prediction in patients with HCC (AUC > 0.70) [113][43]. Altogether, these encouraging findings suggest that ncRNA expression signatures could be considered a potential tool for the diagnosis and prognosis determination of HCC.

5. Etiology-Specific Dysregulated Circular RNAs in Hepatocellular Carcinoma Progression

In addition to the above-presented evidence composing a clinical–pathogenetic heterogeneous background, identifying an association between definite ncRNAs and specific etiological HCC agents, in the optic of HCC-patient-tailored management, constitutes a current research challenge and would certainly represent a medical breakthrough. In the context of viral hepatitis, the detailed molecular mechanisms by which HBV contributes to the development of HCC remain largely unknown, and specific aberrantly expressed circRNAs might be involved in the pathogenesis of HBV-associated liver cancer by regulating several tumor-related molecules or pathways [114][44]. In this regard, a total of 13,124 circRNAs were recently found dysregulated in HBV-related HCC, and notably, the circRNA–miRNA interaction network analysis revealed that 6020 circRNAs were predicted to target 1654 miRNAs [114][44]. In particular, the downregulation of circRNA_10156 has been demonstrated to suppress liver cancer cell proliferation, suggesting this molecule is a pro-tumorigenic element [114][44]. In the same study, the reseauthorchers clarified the pathogenetic role of this ncRNA and the relatively targeted miRNA, highlighting that circRNA_10156 may act as a molecular sponge of the oncomiR miR-149-3p, which serves a crucial role in tumor development [114][44]. Consistently, they demonstrated that the depletion of circRNA_10156 upregulated miR-149-3p, reduced Akt1 serine/threonine-protein kinase expression, and suppressed liver cancer cell proliferation [114][44]. In the last few years, in parallel to viral hepatitis scenarios, given also the epidemiological data, NAFLD-related HCC represents, likewise, a research field where the role of circRNAs has been intensively investigated [115][45]. In this regard, circRNA CDR1-AS has been shown to be upregulated in HCC tissues with simultaneous downregulation of miR-7. This circRNA has been proposed to act as a molecular sponge of TS miR-7; consistently, CDR1-AS-determined decreased miR-7 expression promotes HCC progression facilitating the invasion/proliferation mechanisms of cancer cells [115,116,117][45][46][47]. In the same vein, circRNA_0067934 can promote progression events associated with HCC worsening as the invasion and metastasis-related mechanisms via the β-catenin/Wnt signaling pathway in the NAFLD setting. In support of this, the enhanced expression of this molecule has been found in HCC tissues compared with peritumoral healthy specimens and its inhibition suppresses the invasion and metastasis of liver cancer [115,118][45][48]. In contrast with circRNA_CDR1-AS and circRNA_0067934, circRNA MTO1, by acting as the oncomiR miR-9 sponge, has been associated with anti-cancer advancement mechanisms and its upregulation was proposed to negatively regulate HCC progression [115,119][45][49]. All these findings demonstrate how a better understanding of the molecular etiological-specific mechanisms of HCC carcinogenesis would contribute to the development of more effective molecular targeted interventions for the primary prevention and treatment of HCC. Table 1 summarizes lncRNA dysregulated pathways influencing etiologically specific HCC progression mechanisms.
Table 1. Major long non-coding RNAs associated with hepatocellular carcinoma (HCC) progression in Non-alcoholic Fatty Liver and viral hepatitis with relative mechanisms of action.
    Molecules’ Name Biogenesis/

Expression

Status		 Influence on Molecular Pathways Promoting HCC Progression Mechanisms microRNA(s) Targeted
Non-alcoholic

Fatty Liver Disease

(NAFLD)—HCC-related context		 Linear

Long Non-coding

RNAs		 NEAT1 Overexpression

[97,98][26][27]		 Promotion of NAFLD-related fibrosis worsening and HCC cell proliferation by sponging miR-506 [normally down-regulating acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) expression] [97][26]. miR-506 [98][27]
MALAT1 Overexpression [99][28] Upregulation of the splicing factor “SRSF1” and activation of the β-catenin/Wnt pathway [99][28]. Undefined/NA in this context
CASC2 Downregulation [96][25] Regulation of cell proliferation and dysregulation by sponging the oncoMiR miR-155 [96][25] miR-155

[96][25]
Circular

Long-Non-coding

RNAs		 circRNA CDR1-AS Overexpression

[117][47]		 Promotion of invasion/proliferation mechanisms of liver cancer cells by sponging miR-7 (normally inhibiting spindle checkpoint protein “SPC24”) [117][47]. miR-7 [116][46]
circRNA_0067934 Overexpression

[118][48]		 Promotion of invasion and metastasis-related mechanisms by sponging miR-1234 (normally regulating the β-catenin/Wnt signaling pathway) [118][48]. miR-1234 [118][48]
circRNA MTO1 Downregulation

[119][49]		 Promotion of HCC progression by sponging the oncomiRNA “miR-9” [119][49]. miR-9

[119][49]
Viral-hepatitis—HCC-related context   HBx-LINE1 lncRNA Integration of HBV DNA in ch.8p11.21 [102][31] In HBV context: activation of the Wnt signaling pathway; acting as a decoy to sequester miR-122 [101,102][30][31]. miR-122

[101][30]
HULC Overexpression induced by HBx protein [91,103][19][32] In HBV context: activation of sphingosine-kinase-1-mediated angiogenesis, functioning as a molecular decoy of miR-107 (normally repressing the expression of the transcription factor E2F1) [103][32]. miR-107

[92][20]
Linear

Long Non-coding

RNAs		 Linc01419 Overexpression

[104][33]		 In HCV context:
○
Promotion of cell proliferation and metastasis by sponging miR-485-5p (normally downregulating “LSM4” expression) [120][50].
○
Promotion of cell proliferation and metastasis by enhancing NDRG1 promoter activity [121][51].
○
Promotion of cell proliferation by recruiting XRCC5 and regulating its phosphorylation to repair DNA damage [122][52].
○
Promotion of proliferation by targeting EZH2-regulated RECK expression [123][53].
 miR-485-5p

[120][50]
LncAK021443 Overexpression

[124][54]		 In HCV context: promotion of cell proliferation, invasion, and metastasis by repressing epithelial-mesenchymal transition (EMT) [104,125][33][55] Unidentified/NA in this context
Linc01152 Overexpression

[126][56]		 In HBV context: increases cell proliferation by activating the STAT3 pathway [126][56]. Unidentified
Viral-hepatitis—HCC-related context Circular

Long-Non-coding

RNAs		 circRNA_10156 Overexpression

[114][44]		 In HBV context: promotes cell proliferation by sponging miR-149-3p (usually down-regulating the AKT1/mTOR pathway) [114][44]. miR-149-3p [114][44]
circ-RNF13 [circ_0067717] Downregulation

[127][57]		 In HBV context: promotes HCC progression by sponging miR-424-5p (usually regulating TGFβ-induced factor homeobox 2 (TGIF2) [127][57]. miR-424-5p

[127][57]
circ_0027089 Overexpression

[128][58]		 In HBV contexts: acts as an oncogene and promotes the development of HBV-related HCC by regulating nucleus accumbens associated protein 1 (NACC1) via competitively targeting miR-136-5p [129][59]. miR-136-5p [129][59]
HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; NA: not-applicable; NDRG1: N-Myc Downstream Regulated 1; XRCC5: X-ray Repair Cross Complementing 5; EZH2: Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit.

References

  1. Kulik, L.; El-Serag, H.B. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology 2019, 156, 477–491.e471.
  2. Younossi, Z.M.; Otgonsuren, M.; Henry, L.; Venkatesan, C.; Mishra, A.; Erario, M.; Hunt, S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology 2015, 62, 1723–1730.
  3. Li, L.; Wang, H. Heterogeneity of liver cancer and personalized therapy. Cancer Lett. 2016, 379, 191–197.
  4. Wong, C.M.; Ng, I.O. Molecular pathogenesis of hepatocellular carcinoma. Liver Int. 2008, 28, 160–174.
  5. Losic, B.; Craig, A.J.; Villacorta-Martin, C.; Martins-Filho, S.N.; Akers, N.; Chen, X.; Ahsen, M.E.; von Felden, J.; Labgaa, I.; DʹAvola, D.; et al. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat. Commun. 2020, 11, 291.
  6. Saw, P.E.; Xu, X.; Chen, J.; Song, E.W. Non-coding RNAs: The new central dogma of cancer biology. Sci. China. Life Sci. 2021, 64, 22–50.
  7. Hombach, S.; Kretz, M. Non-coding RNAs: Classification, Biology and Functioning. Adv. Exp. Med. Biol. 2016, 937, 3–17.
  8. Slack, F.J.; Chinnaiyan, A.M. The Role of Non-coding RNAs in Oncology. Cell 2019, 179, 1033–1055.
  9. Giraud, J.; Chalopin, D.; Blanc, J.F.; Saleh, M. Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies. Front. Immunol. 2021, 12, 655697.
  10. Schwabe, R.F.; Greten, T.F. Gut microbiome in HCC—Mechanisms, diagnosis and therapy. J. Hepatol. 2020, 72, 230–238.
  11. Quinn, J.J.; Chang, H.Y. Unique features of long non-coding RNA biogenesis and function. Nat. Rev. Genet. 2016, 17, 47–62.
  12. Zhou, W.Y.; Cai, Z.R.; Liu, J.; Wang, D.S.; Ju, H.Q.; Xu, R.H. Circular RNA: Metabolism, functions and interactions with proteins. Mol. Cancer 2020, 19, 172.
  13. Wen, S.; Wei, Y.; Zen, C.; Xiong, W.; Niu, Y.; Zhao, Y. Long non-coding RNA NEAT1 promotes bone metastasis of prostate cancer through N6-methyladenosine. Mol. Cancer 2020, 19, 171.
  14. Wong, C.M.; Tsang, F.H.; Ng, I.O. Non-coding RNAs in hepatocellular carcinoma: Molecular functions and pathological implications. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 137–151.
  15. Liang, W.; Shi, C.; Hong, W.; Li, P.; Zhou, X.; Fu, W.; Lin, L.; Zhang, J. Super-enhancer-driven lncRNA-DAW promotes liver cancer cell proliferation through activation of Wnt/β-catenin pathway. Mol. Therapy. Nucleic Acids 2021, 26, 1351–1363.
  16. Wang, Y.L.; Liu, J.Y.; Yang, J.E.; Yu, X.M.; Chen, Z.L.; Chen, Y.J.; Kuang, M.; Zhu, Y.; Zhuang, S.M. Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation. Hepatology 2019, 70, 259–275.
  17. Chen, H.Z.; Tsai, S.Y.; Leone, G. Emerging roles of E2Fs in cancer: An exit from cell cycle control. Nat. Rev. Cancer 2009, 9, 785–797.
  18. Song, H.; Liu, Y.; Li, X.; Chen, S.; Xie, R.; Chen, D.; Gao, H.; Wang, G.; Cai, B.; Yang, X. Long noncoding RNA CASC11 promotes hepatocarcinogenesis and HCC progression through EIF4A3-mediated E2F1 activation. Clin. Transl. Med. 2020, 10, e220.
  19. Panzitt, K.; Tschernatsch, M.M.; Guelly, C.; Moustafa, T.; Stradner, M.; Strohmaier, H.M.; Buck, C.R.; Denk, H.; Schroeder, R.; Trauner, M.; et al. Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA. Gastroenterology 2007, 132, 330–342.
  20. Lu, Z.; Xiao, Z.; Liu, F.; Cui, M.; Li, W.; Yang, Z.; Li, J.; Ye, L.; Zhang, X. Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1). Oncotarget 2016, 7, 241–254.
  21. Rinn, J.L.; Kertesz, M.; Wang, J.K.; Squazzo, S.L.; Xu, X.; Brugmann, S.A.; Goodnough, L.H.; Helms, J.A.; Farnham, P.J.; Segal, E.; et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 2007, 129, 1311–1323.
  22. Fu, W.M.; Zhu, X.; Wang, W.M.; Lu, Y.F.; Hu, B.G.; Wang, H.; Liang, W.C.; Wang, S.S.; Ko, C.H.; Waye, M.M.; et al. Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling. J. Hepatol. 2015, 63, 886–895.
  23. Oura, K.; Morishita, A.; Masaki, T. Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma-A Review. Int. J. Mol. Sci. 2020, 21, 8362.
  24. Torres, J.L.; Novo-Veleiro, I.; Manzanedo, L.; Alvela-Suárez, L.; Macías, R.; Laso, F.J.; Marcos, M. Role of microRNAs in alcohol-induced liver disorders and non-alcoholic fatty liver disease. World J. Gastroenterol. 2018, 24, 4104–4118.
  25. Yuan, Y.; Ye, J.; Zhang, X.; Liu, Z. LncRNA CASC2 Regulate Cell Proliferation and Invasion by Targeting miR-155/SOCS1 Axis in Hepatocellular Carcinoma. J. Oncol. 2023, 2023, 8457112.
  26. Wang, X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway. J. Cell. Biochem. 2018, 119, 1567–1574.
  27. Jin, S.S.; Lin, X.F.; Zheng, J.Z.; Wang, Q.; Guan, H.Q. lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3. Eur. Cytokine Netw. 2019, 30, 98–106.
  28. Xiang, J.; Deng, Y.Y.; Liu, H.X.; Pu, Y. LncRNA MALAT1 Promotes PPARα/CD36-Mediated Hepatic Lipogenesis in Nonalcoholic Fatty Liver Disease by Modulating miR-206/ARNT Axis. Front. Bioeng. Biotechnol. 2022, 10, 858558.
  29. Malakar, P.; Shilo, A.; Mogilevsky, A.; Stein, I.; Pikarsky, E.; Nevo, Y.; Benyamini, H.; Elgavish, S.; Zong, X.; Prasanth, K.V.; et al. Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation. Cancer Res. 2017, 77, 1155–1167.
  30. Liang, H.W.; Wang, N.; Wang, Y.; Wang, F.; Fu, Z.; Yan, X.; Zhu, H.; Diao, W.; Ding, Y.; Chen, X.; et al. Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122. J. Hepatol. 2016, 64, 278–291.
  31. Lau, C.C.; Sun, T.; Ching, A.K.; He, M.; Li, J.W.; Wong, A.M.; Co, N.N.; Chan, A.W.; Li, P.S.; Lung, R.W.; et al. Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell 2014, 25, 335–349.
  32. Du, Y.; Kong, G.; You, X.; Zhang, S.; Zhang, T.; Gao, Y.; Ye, L.; Zhang, X. Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J. Biol. Chem. 2012, 287, 26302–26311.
  33. Zhang, H.; Zhu, C.; Zhao, Y.; Li, M.; Wu, L.; Yang, X.; Wan, X.; Wang, A.; Zhang, M.Q.; Sang, X.; et al. Long non-coding RNA expression profiles of hepatitis C virus-related dysplasia and hepatocellular carcinoma. Oncotarget 2015, 6, 43770–43778.
  34. Fang, S.; Zhang, L.; Guo, J.; Niu, Y.; Wu, Y.; Li, H.; Zhao, L.; Li, X.; Teng, X.; Sun, X.; et al. NONCODEV5: A comprehensive annotation database for long non-coding RNAs. Nucleic Acids Res. 2018, 46, D308–D314.
  35. Shang, X.; Li, G.; Liu, H.; Li, T.; Liu, J.; Zhao, Q.; Wang, C. Comprehensive Circular RNA Profiling Reveals That hsa_circ_0005075, a New Circular RNA Biomarker, Is Involved in Hepatocellular Crcinoma Development. Medicine 2016, 95, e3811.
  36. Li, M.F.; Li, Y.H.; He, Y.H.; Wang, Q.; Zhang, Y.; Li, X.F.; Meng, X.M.; Huang, C.; Li, J. Emerging roles of hsa_circ_0005075 targeting miR-431 in the progress of HCC. Biomed. Pharmacother. Biomed. Pharmacother. 2018, 99, 848–858.
  37. Pan, L.; Ren, F.; Rong, M.; Dang, Y.; Luo, Y.; Luo, D.; Chen, G. Correlation between down-expression of miR-431 and clinicopathological significance in HCC tissues. Clin. Transl. Oncol. 2015, 17, 557–563.
  38. Sun, R.; Li, H.; Li, J.; Shen, S.; Cui, G.; Dong, G. CircRNA circ-0038718 promotes hepatocellular carcinoma progression through sponging miR-139-3p. Biochem. Biophys. Res. Commun. 2020, 533, 845–852.
  39. Thakral, S.; Ghoshal, K. miR-122 is a unique molecule with great potential in diagnosis, prognosis of liver disease, and therapy both as miRNA mimic and antimir. Curr. Gene Ther. 2015, 15, 142–150.
  40. Yang, G.; Zhang, M.; Zhao, Y.; Pan, Y.; Kan, M.; Li, J.; He, K.; Zhang, X. HNF-4α inhibits hepatocellular carcinoma cell proliferation through mir-122-adam17 pathway. PLoS ONE 2020, 15, e0230450.
  41. Chen, D.; Zhang, C.; Lin, J.; Song, X.; Wang, H. Screening differential circular RNA expression profiles reveal that hsa_circ_0128298 is a biomarker in the diagnosis and prognosis of hepatocellular carcinoma. Cancer Manag. Res. 2018, 10, 1275–1283.
  42. Jiang, Y.L.; Shang, M.M.; Dong, S.Z.; Chang, Y.C. Abnormally expressed circular RNAs as novel non-invasive biomarkers for hepatocellular carcinoma: A meta-analysis. World J. Gastrointest. Oncol. 2019, 11, 909–924.
  43. Cao, J.; Wu, L.; Lei, X.; Shi, K.; Shi, L.; Shi, Y. Long non-coding RNA-based signature for predicting prognosis of hepatocellular carcinoma. Bioengineered 2021, 12, 673–681.
  44. Wang, M.; Gu, B.; Yao, G.; Li, P.; Wang, K. Circular RNA Expression Profiles and the Pro-tumorigenic Function of CircRNA_10156 in Hepatitis B Virus-Related Liver Cancer. Int. J. Med. Sci. 2020, 17, 1351–1365.
  45. Chien, Y.; Tsai, P.H.; Lai, Y.H.; Lu, K.H.; Liu, C.Y.; Lin, H.F.; Huang, C.S.; Wu, W.W.; Wang, C.Y. CircularRNA as novel biomarkers in liver diseases. J. Chin. Med. Assoc. JCMA 2020, 83, 15–17.
  46. Yu, L.; Gong, X.; Sun, L.; Zhou, Q.; Lu, B.; Zhu, L. The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression. PLoS ONE 2016, 11, e0158347.
  47. Xu, L.; Zhang, M.; Zheng, X.; Yi, P.; Lan, C.; Xu, M. The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 2017, 143, 17–27.
  48. Zhu, Q.; Lu, G.; Luo, Z.; Gui, F.; Wu, J.; Zhang, D.; Ni, Y. CircRNA circ_0067934 promotes tumor growth and metastasis in hepatocellular carcinoma through regulation of miR-1324/FZD5/Wnt/β-catenin axis. Biochem. Biophys. Res. Commun. 2018, 497, 626–632.
  49. Han, D.; Li, J.; Wang, H.; Su, X.; Hou, J.; Gu, Y.; Qian, C.; Lin, Y.; Liu, X.; Huang, M.; et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology 2017, 66, 1151–1164.
  50. Sun, Z.P.; Tan, Z.G.; Peng, C. Long noncoding RNA LINC01419 promotes hepatocellular carcinoma malignancy by mediating miR-485-5p/LSM4 axis. Kaohsiung J. Med. Sci. 2022, 38, 826–838.
  51. Dang, H.; Chen, L.; Tang, P.; Cai, X.; Zhang, W.; Zhang, R.; Huang, A.; Tang, H. LINC01419 promotes cell proliferation and metastasis in hepatocellular carcinoma by enhancing NDRG1 promoter activity. Cell. Oncol. 2020, 43, 931–947.
  52. Liu, P.; Zhang, X.; Fu, Q.; Liu, C.; Luo, Q.; Yu, P.; Chen, S.; Zhang, H.; Qin, T. LINC01419 Promotes the Proliferation of Hepatoma Cells by Recruiting XRCC5 and Regulating Its Phosphorylation to Repair DNA Damage. Dis. Markers 2022, 2022, 9313680.
  53. Zhang, G.; Chen, X.; Ma, L.; Ding, R.; Zhao, L.; Ma, F.; Deng, X. LINC01419 facilitates hepatocellular carcinoma growth and metastasis through targeting EZH2-regulated RECK. Aging 2020, 12, 11071–11084.
  54. Li, Y.C.; Wang, D.; Zhu, G.Y. Increased expression of long noncoding RNA AK021443 predicts worse clinical outcome in hepatocellular carcinoma. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 4855–4860.
  55. Yang, J.; Li, J.; Liu, B.; Zhang, R.; Gu, F.; Zhao, J.; Cheng, S. Long Noncoding RNA AK021443 Promotes Cell Proliferation and Migration by Regulating Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells. DNA Cell Biol. 2018, 37, 481–490.
  56. Chen, T.; Pei, J.; Wang, J.; Luo, R.; Liu, L.; Wang, L.; Jia, H. HBx-related long non-coding RNA 01152 promotes cell proliferation and survival by IL-23 in hepatocellular carcinoma. Biomed. Pharmacother. Biomed. Pharmacother. 2019, 115, 108877.
  57. Chen, Y.; Li, S.; Wei, Y.; Xu, Z.; Wu, X. Circ-RNF13, as an oncogene, regulates malignant progression of HBV-associated hepatocellular carcinoma cells and HBV infection through ceRNA pathway of circ-RNF13/miR-424-5p/TGIF2. Bosn. J. Basic Med. Sci. 2021, 21, 555–568.
  58. Zhu, K.; Zhan, H.; Peng, Y.; Yang, L.; Gao, Q.; Jia, H.; Dai, Z.; Tang, Z.; Fan, J.; Zhou, J. Plasma hsa_circ_0027089 is a diagnostic biomarker for hepatitis B virus-related hepatocellular carcinoma. Carcinogenesis 2020, 41, 296–302.
  59. He, W.; Zhu, X.; Tang, X.; Xiang, X.; Yu, J.; Sun, H. Circ_0027089 regulates NACC1 by targeting miR-136-5p to aggravate the development of hepatitis B virus-related hepatocellular carcinoma. Anti-Cancer Drugs 2022, 33, e336–e348.
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