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J Cancer 2018; 9(14):2549-2558. doi:10.7150/jca.24560 This issue Cite

Review

The emergence of long non-coding RNAs in hepatocellular carcinoma: an update

Li Peng ^1,2*, Xiao-Qing Yuan^3,4*, Chao-Yang Zhang¹, Jiang-Yun Peng², Ya-Qin Zhang¹, Xi Pan⁵, Guan-Cheng Li¹

1. Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha 410078, P.R. China; Cancer Research Institute, Central South University, Changsha 410078, P.R. China.
2. Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China.
3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
4. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
5. Department of Oncology, the third Xiangya Hospital, Central South University, Changsha 410013, P.R. China.
^* Li Peng and Xiao-Qing Yuan are equally contributed to this work.

✉ Corresponding author: Prof. Guan-Cheng Li, Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University; Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, P.R. China. Tel: +86 731 84805445; Fax: +86 731 82355042; E-mail: ligc61edu.cn (G.-C. Li) More

Abstract

Hepatocellular carcinoma (HCC) accounting for roughly 90% of all primary liver neoplasms is the sixth most frequent neoplasm and the second prominent reason of tumor fatality worldwide. As regulators of diverse biological processes, long non-coding RNAs (lncRNAs) are involved in onset and development of neoplasms. With the continuous booming of well-featured lncRNAs in HCC from 2016 to now, we reviewed the newly-presented comprehension about the relationship between lncRNAs and HCC in this study. To be specific, we summarized the overview function and study tools of lncRNAs, elaborated the roles of lncRNAs in HCC, and sketched the molecule mechanisms of lncRNAs in HCC. In addition, the application of lncRNAs serving as biomarkers in early diagnosis and outcome prediction of HCC patients was highlighted.

Keywords: long non-coding RNAs, hepatocellular carcinoma, function, mechanism, diagnosis, prognostic biomarker

Introduction

Hepatocellular carcinoma (HCC) accounts for roughly 90% of all primary liver neoplasms, and is the sixth most frequent neoplasm and the second prominent reason of tumor fatality worldwide [1]. The highest morbidity of HCC has been found in China and the Asia-Pacific area, which accounts for >50% of HCC cases in the world [2]. Meanwhile, liver cancer is fatal in both developed and developing countries, with the 5-year overall survival rate generally lower than 20% [3]. HCC is the sole solid neoplasm that could be cured by liver transplant which can simultaneously heal the neoplasm and latent cirrhosis, and which is not influenced by the extent of liver function impairment [4]. However, the extreme shortage of liver donors results in procrastination before transplantation, and increasing the risk of tumor progression, and transplantation failure during this period [5]. These suggested that HCC is a devastating disease with disappointing outcomes and limited therapeutic options. Similar to other cancers, HCC is characterized by the gradual accumulation of genetic and epigenetic changes [6-8]. Among these alterations, long non-coding RNAs (lncRNAs) play crucial roles in the initiation and progression of HCC.

LncRNAs are transcripts with more than 200 bp in length, and have incrementally been recognized as the emerging star in neoplasm study as their essential function in tumor biology [9-11]. These transcripts are lack of the protein-coding potential in general and are particularly ubiquitous in almost whole livings [9]. LncRNAs have emerged as regulators in diverse biological processes [12-14] containing cellular proliferation, differentiation, motility, invasiveness, survival and so on [15-17]. Mounting evidences have demonstrated that lncRNAs are involved in tumor onset and development [18, 19], and their expression is frequently deregulated in cancers [20-27]. LncRNAs are strikingly cell type-specificity and cancer type-specificity in expression which are relatively stable [18, 28]. Therefore, lncRNAs stand a chance to serve as a kind of desired indicators with underlying utilizations in neoplasm divination, early-discovery, classification and treatment.

With the continuous booming of well-featured lncRNAs in HCC from 2016 to now, a great quantity of newly-presented researches is coming into being on the relationship between lncRNAs and HCC. Here, we reviewed the present comprehension of lncRNAs in HCC. To be specific, we summarized the overview function and study tools of lncRNAs, elaborated the roles of lncRNAs in HCC, and sketched the molecule mechanisms of lncRNAs in HCC. Meanwhile, the utilization of lncRNAs as markers in HCC early-diagnosis and outcome prediction was also highlighted.

Tools for the research of lncRNAs

A mounting number of databases about lncRNAs are developed to assist in the research of lncRNAs that include the functions of lncRNAs under the physiological state and pathological conditions. Over twenty databases touching upon the biological properties of lncRNAs are outlined in Table 1. These databases will dramatically facilitate a better understanding of lncRNAs which are essential members of epigenetic regulation, and their interaction with other RNAs.

Dysregulation and roles of lncRNAs in HCC

Tumor progression and recurrence

HCC is a complicated disease referred to multiple factors. A growing body of evidence suggested that lncRNAs involved in the occurrence and development of diverse neoplasm containing HCC. Importantly, some could affect the features of neoplasm, including proliferation, apoptosis, motility, invasiveness and angiogenesis. As an example, HOTAIR expression levels increased in both HCC tumor tissues and HepG2 cells, which promoted HCC progression [29] and were bound up with earlier relapse [30, 31]. Those showed the importance of HOTAIR in the evolvement and the relapse of HCC. Furthermore, lncRNAs could be involved in tumor progression and had potential to serve as an attractive target for precision therapy in HCC.

Invasiveness and metastasis

It is well known that invasiveness is an origin in worse disease prognosis and higher recurrence of neoplasm patients [32], which was partly correlated with certain behaviors of cancerous cells. Studies have showed that lncRNAs were related to vital growth-boosting properties and their deregulation dedicated to the survival of cancerous cells. LINC00052 [33], ZEB1-AS1 [34] and LINC01225 [35] was showed to accelerate cellular motility and invasiveness. In short, these lncRNAs could function as oncogenes via facilitating invasion and metastasis of HCC cells. Inversely, it was indicated that CPS1-IT1 [36], lncRNA XIST [37] and lncRNA FTX [38] were down-regulated in HCC samples and inhibited the relapse and metastasis of HCC cells. These lncRNAs act as tumor suppressor genes via restraining invasion and metastasis in HCC.

Proliferation and apoptosis

A flood of literatures have mirrored that lncRNAs participated in the development of HCC via modulating cell proliferation and apoptosis. On the one aspect, some lncRNAs could accelerate cell proliferation while inhibit cell apoptosis in HCC. It was demonstrated that the expression of XIST [39], lncRNA HOST2 [40], HOXA-AS2 [41], CCHE1 [42] and AFAP1-AS1 [43] was significantly elevated in HCC tumor tissues and/or cell lines, which promoted cell proliferation while protected cells from apoptosis in HCC. Conversely, lncRNA AK058003 [44], lincRNA-p21 [45] and lncRNA XIST [37] were revealed to decrease in HCC tumors, and act as a tumor suppressor, suppressing HCC cellular multiplication and clonality while accelerating cellular apoptosis. These results suggested that lncRNAs played important roles in proliferation and apoptosis of HCC and may serve as latent therapeutic targets of HCC.

Chemo-sensitivity and radio-resistance

LncRNAs have also been reported to function in chemo-sensitivity or radio-resistance through arrest of cell cycle, suppression of apoptosis as well as strengthening of DNA injury repair [46, 47]. For instance, lncRNA TUC338 [48] and MALAT1 [49] was involved in HCC evolution and drug-resistance (such as sorafenib). These suggested that lncRNAs have the potential to serve as new targets for exploiting novel strategies of chemotherapy and radiotherapy in HCC patients.

Angiogenesis

Coupling with the increase of neoplasm sizes, angiogenesis is required. In order to supply nutrient substances and O₂, angiogenesis permits neoplasm to handle its metabolism waste with following access to blood metastasis process. Frequently, neoplasm cell leads to induction of pro-angiogenic signs or blockage of anti-angiogenic markers, which could open an “on-off” of angiogenesis. LncRNAs are mirrored to serve as a key player in the regulation of angiogenesis. LncRNAs contributed to abnormal hypervascularity of HCC and afforded a novel landscape into the mechanism of neoplasm angiogenesis.

Molecular mechanisms of lncRNAs in HCC

Epigenetic regulatory lncRNAs

LncRNAs have been shown to excert regulatory roles at nearly all stages of gene expression [50], from targeting epigenetic modification, transcriptional regulation, interactions of lncRNAs-proteins, lncRNAs-miRNAs-mRNAs, lncRNA-lncRNA, autophagy as well as signaling pathway to modulation of mRNA stabilization. LncRNA GIHCG promoted HCC progression through epigenetically upregulating H3K27me3 levels and DNA methylation contents [51]. LncRNA ZNFX1-AS1 suppressed HCC cell growth through modulating miR-9 methylation [52]. Linc00441 promoted HCC tumorigenesis in a H3K27 modification-dependent manner [53].

Transcriptional regulatory lncRNAs

Several lncRNAs could serve as transcriptional regulators. It was reported that CCAT2 [54] and HOTAIR [55] accelerated EMT process mediated by transcription factor (TF) Slug and Snail in HCC, respectively. LncRNA ZEB1-AS1 promoted neoplasm invasiveness and indicated an adverse clinical outcome via positively regulating the ZEB1 expression in HCC [34]. Meanwhile, lncRNA CPS1-IT1 suppressed HCC aggressivity via controlling HIF-1α activity [36]. LncRNA uc.338 was found to promote cellular growth via modulating of CDKN1A transcription in HCC [56].

LncRNAs-proteins interactions

LncRNA HNF1A-AS1 repressed NKD1 and p21 expression via interacting with EZH2, and then promoted HCC cell proliferation [57]. LncRNA NEAT1 modulated hnRNP-A2 level to facilitate cellular multiplication and invasiveness in HCC cell lines [58]. LncRNA TUC338 targeted RASAL1 to be involved in sorafenib-sensitized HCC cells [48]. LncRNA BANCR elevated the protein level of VIM while lowered the protein content of E-cad to cripple cellular malignant degree [59]. The lncRNA EGFR-AS1, a target of GHR, up-regulated the expression of EGFR in HCC [60]. To summarize, lncRNAs-proteins interactions functioned as a vital mechanism of lncRNAs in HCC.

LncRNAs-miRNAs-mRNAs interactions

It has been demonstrated that microRNAs (miRNAs) functioned crucially in many caners, including HCC [61-63]. LncRNAs could share miRNA recognition elements (MREs) with mRNAs and modulate the function of mRNAs with miRNAs-mediated mechanisms, where lncRNAs were called competing endogenous RNAs (ceRNAs) [64-66]. For instance, lncRNA SNHG12 - miR-199a/b-5p - MLK3 - NF-κB signaling [67] accelerated tumorigenesis and metastasis in HCC. LncRNA UCA1 - miR-203 - Slug axis [68] and lncRNA Ftx - miR-545 - RIG-I network [69] were involvement in HCC progression. The HIF-2α - MALAT1 - miR-216b axis regulated multi-drug resistance of HCC cells [49]. Overall, lncRNAs could serve as “miRNA sponges” to share the same MREs with mRNAs.

Others

LncRNAs - lncRNAs interactions

LncRNAs functioned vitally in a variety of biology processes. Frequently, the occurrence and development of neoplasm frequently was attributed to the interaction effects of some lncRNAs. LncRNA-lncRNA synergistic networks were beneficial to explore clinically related lncRNAs in neoplasm [70]. Reports suggested that LncRNA HULC cooperated with MALAT1 to promote CSCs proliferation in HCC [71]. And the overexpression of HULC along with MALAT1 increased the binding of RNA pol II, P300, CREPT to TRF2, which triggered the upregulation, phosphorylation and SUMOylation of TRF2 [71]. Indeed, lncRNAs could interact with other lncRNAs.

Autophagy

Autophagy is a cellular degradation pathway that is essential to maintain cell physiology progress, and its disruption leads to multiple diseases in humans [72]. Recently, macro-autophagy/autophagy has emerged as a promising therapeutic target in various types of solid tumor treatment [73]. LncRNAs exerted crucial roles in the regulation of autophagy lately, which made them act as potential biomarkers of disease phenotypes [74]. LncRNA HULC could induce a protective autophagy [75]. LncRNA HNF1A-AS1 served as a autophagic accelerator in HCC [76]. And the lncRNA HOTAIR activated autophagy [30]. These studies indicated that the lncRNAs-autophagy networks are likely to supply additional insights into treatment interventions and markers evaluation in human diseases, especially in cancers.

Signaling pathway

As we all know, signaling pathways functioned considerably in the development of HCC and presented some therapeutic strategies based on in vivo and in vitro findings. LncRNA T-UCR severed as a potential growth driver gene modulated by the Wnt/β-catenin signaling in hepatobiliary carcinogenesis [77, 164]. LncRNA MEG3 could activate ER stress and p53 signaling related to NF-κB pathway, which followed by suppressing cell multiplication and promoting apoptosis [78]. Lnc-DILC was downregulated in liver cancer stem cells and mediated intrahepatic inflammation via governing the cross-linking of TNF-α - NF-κB pathway with IL-6 - STAT3 pathway [79].

mRNA stabilization

Transcription activity and post-transcription mechanisms involved in lncRNAs could modulate ribonucleotide reductase followed by altering the stability of message RNAs [80]. In turn, mRNA steady state levels could directly influence their expression [80]. The lncRNA MALAT1 accelerated arsenite-induced glycolysis, which was mediated via HIF-1α mRNA stabilization in human liver L-02 cell lines [81]. LncRNA AK058003 could reduce the expression of mRNA stabilizing protein HuR and act as a precursor of miR-15a to suppress γ-synuclein-mediated cell proliferation and the metastasis of HCC [44]. In addition, lncRNA HULC triggered autophagy via stabilizing Sirt1 and attenuated the chemosensitivity of HCC cells [75]. These studies suggested that some lncRNAs participating biological processes may be mediated by selective stabilization of mRNAs.

Potential clinical application of lncRNAs in HCC

LncRNAs for diagnosis of HCC

A growing amount of evidence supports that benefiting from their attractive characteristics, lncRNAs are potential indicators for human diseases including HCC. The majority of lncRNAs displayed the trait of strict tissue-specific and neoplasm-specific expression. Frequently, distinct upregulation or downregulation of lncRNA was found in neoplasm tissues in comparison with normal samples. Meanwhile, a few lncRNAs were declared to be existed in urine, blood and other body fluids, which could be easily acquired through the non-invasive way as much as possible. What's more, utilizing lncRNAs as indicators of neoplasm states was superior to protein-coding RNAs, due to the more representative expression of lncRNAs [82]. Compared with current varying greatly biomarkers in protein coding genes, lncRNAs are likely to be advantageous indicators on the strength of their specificity and easy acquirement.

The pooled sensitivity and specificity of HCC patients predicted by lncRNAs were showed as Table 2. These lncRNAs are likely to act as valuable indicators for neoplasm diagnosis and have potential application value for clinic diagnosis of HCC patients.

LncRNAs as prognostic biomarkers for HCC

Accumulating reports declared that lncRNAs have potential to serve as prognostic predictors in neoplasms containing HCC patients. A variety of lncRNAs were demonstrated to exhibit abnormal expression in HCC, which were significantly correlated with the survival time and were independent outcome predictors in HCC patients (Table 3). Therefore, lncRNAs might be acted as potential and useful prognostic indicators in HCC.

Conclusion and future prospective

In a nutshell, lncRNAs have the potential to serve as promising biomarkers for tumor progression and recurrence (lncRNA HOTAIR, SNHG1, HULC, MALAT1, CRNDE, GIHCG, UCA1, lncSox4 and lncBRM), as well as for invasion and metastasis (SNHG20, CCAT2, HOST2, Linc-cdh4-2, LINC00052, AFAP1-AS1, ZEB1-AS1, ZEB2-AS1, LINC01225, UC001kfo, SPRY4-IT1, Unigene56159, HULC, plncRNA-1, SchLAH, lncRNA-AK058003, CPS1-IT1, XIST, FTX, TUSC7 and GAS5). Besides, lncRNAs are involved in HCC through affecting on cell proliferation and apoptosis (UC001kfo, SPRY4-IT1, ZEB2-AS1, RBMY2FP, uc.338, UCA1, XIST, HOST2, HOXA-AS2, CCHE1, CCAT2, SNHG1, HNF1A-AS1, PCAT-1, AFAP1-AS1, HULC, MALAT1, lncCAMTA1, lnc-DILC, lncRNA-AK058003, ZNFX1-AS1, lincRNA-p21, XIST, FTX and GAS5), as well as angiogenesis (lncRNA TUG1 and HULC). Additionally, lncRNAs serve as a conceivable indicator for chemo-sensitivity and radio-resistance (HULC, RP11-134G8.8, RP11-363E7.4, RP1-193H18.2, TUC338 and MALAT1; Figure 1, Table S1). Meanwhile, lncRNAs exerted their efficient and effective actions in mechanisms of interaction with proteins/ miRNAs/ mRNAs/ lncRNAs, in epigenetic regulation/transcriptional regulation, as well as in regulation of autophagy, signaling pathway and mRNA stabilization in HCC on the horizon of the current studies (Figure 1, Table S1). Furthermore, these lncRNAs might be promising indicators for disease diagnosis (Table 2), prognosis and recurrence prediction (Table 3), and even be new up-and-coming targets for therapeutic intervention of HCC.

Yet, the precise biological function and molecule mechanisms of lncRNAs in HCC remained uncharacterized. Thus, further exploration and validation researches are required for illuminating the intricate mechanisms (especially in epigenetic and transcriptional modulation of lncRNAs) as well as the clinical utilizations of lncRNAs in HCC.

 Figure 1 

Dysregulation and functional roles of lncRNAs in hepatocellular carcinoma.

Supplementary Material

Supplementary table.

Acknowledgements

This work was supported by the Open-End Fund for the Valuable and Precision Instruments of Central South University (CSUZC201746 for Li Peng), Hunan Provincial Innovation Foundation for Postgraduates (CX2016B056 for Li Peng), Fundamental Research Funds for the Central Universities of Central South University (2015zzts096 for Li Peng), and the Science and Technology Department Research Foundation of Hunan province (12JJ2052 for Guan-Cheng Li).

Authors' contributions

LP collected the references and drafted the manuscript. GCL and XQY participated in the design of the review and helped to draft the manuscript. CYZ, JYP, YQZ and XP revised critically the manuscript. All authors read and approved the final manuscript.

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding author: Prof. Guan-Cheng Li, Key Laboratory of Carcinogenesis of the Chinese Ministry of Health and the Key Laboratory of Carcinogenesis and Cancer Invasion of Chinese Ministry of Education, Xiangya Hospital, Central South University; Cancer Research Institute, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, P.R. China. Tel: +86 731 84805445; Fax: +86 731 82355042; E-mail: ligc61edu.cn (G.-C. Li)

Received 2017-12-25
Accepted 2018-3-31
Published 2018-6-22

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