Role of ncRNAs in Hepatocellular CarcinomaView this Special Issue
Review Article | Open Access
A Systematic Review of Long Noncoding RNAs in Hepatocellular Carcinoma: Molecular Mechanism and Clinical Implications
Hepatocellular carcinoma (HCC) has the second highest mortality rate worldwide among all cancers. Previous studies have revealed the significant involvement of long noncoding RNAs (lncRNAs) in numerous human cancers including HCC. Both oncogenic and tumor repressive lncRNAs have been identified and implicated in the complex process of hepatocarcinogenesis. They can be further explored as prospective diagnostic, prognostic, and therapeutic markers for HCC. An in-depth understanding of lncRNAs’ mechanism in HCC is therefore required to fully explore their potential role. In the current review, we will concentrate on the underlying function, molecular mechanisms, and potential clinical implications of lncRNA in HCC.
Among all cancers, hepatocellular carcinoma (HCC) has the second highest mortality rate worldwide . The risk factors, including HBV or HCV infection, alcoholism, liver cirrhosis, and metabolic diseases, contribute to HCC . The molecular mechanism of hepatocarcinogenesis is highly complex and involves an interplay between dysregulated cell cycle, apoptosis, tumor cell invasion, and metastasis . Despite advances in diagnosis and therapy, the incidence and mortality of liver cancer continue to increase . It is vital therefore to illustrate the molecular mechanism of HCC in order to improve diagnosis, treatment, and overall prognosis.
With the development of human genome sequencing technology, about 20000 protein-coding genes have been identified, which account for less than 2% of the entire genome . In fact, greater than 90% of the human DNA would be converted into noncoding RNAs (ncRNAs), which, despite not being translated into proteins, are involved in several cellular functions [5, 6]. The long ncRNAs (lncRNAs) with more than 200 nucleotides play significant roles in cell growth and differentiation, chromatin organization, and regulation of gene expression [7, 8]. lncRNAs are classified into intronic, intergenic, sense, and antisense types based on their genomic location  and into signaling, decoy, guide, and scaffold lncRNAs on a functional basis . Signaling lncRNAs mainly act as transcription factors or as intermediates in various signaling pathways , and decoy lncRNAs act as “molecular sponges” by binding to and sequestering transcription factors away from their target genes . Guide lncRNAs can regulate gene expression through chromatin remodeling by recruiting chromatin-modifying enzymes . Finally, the scaffold lncRNAs act as recruiting platforms for multiple proteins and form lncRNA-ribonucleoprotein (lncRNA-RNP) complexes, which subsequently regulate downstream signaling .
Numerous lncRNAs have been identified recently with the help of high-throughput sequencing and microarrays. Most of them are aberrantly expressed in tumors like HCC, breast cancer, lung cancer, colorectal cancer, and others . lncRNAs are known to regulate cell proliferation, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, autophagy, and so forth. Considering their cancer specific expression and detectable presence in clinical samples like blood and urine, lncRNAs are potential diagnostic markers for tumors. Therefore, a better understanding of HCC specific lncRNAs will greatly contribute to the diagnosis and treatment of HCC.
lncRNAs exhibit both tumor suppressive and oncogenic roles. In the present review, we will concentrate mainly on the functions, molecular mechanisms, and potential clinical implications of HCC-related lncRNAs that are abnormally expressed and therefore have critical roles in hepatocarcinogenesis.
2. Upregulated/Oncogenic lncRNAs in HCC
“Highly upregulated in liver cancer” or HULC, a 500 bp lncRNA, was the earliest lncRNA reported to be highly expressed in HCC . In addition to the tumor tissues, significantly greater levels of HULC were also found in HCC cell lines and plasma of patients [12–16], indicating its potential role as a biomarker of HCC. HULC is involved in multiple cellular processes like proliferation, EMT, angiogenesis, autophagy, and chemoresistance (Table 1). Furthermore, HULC overexpression was linked with tumor size , clinical TNM stage , and recurrence and overall survival (OS) in HCC .
+: increase; −: decrease.
Wang et al. reported a decoy role of HULC wherein it downregulated miR-327 by its molecular sponge function . HULC-induced miR-327 inhibition lifted the miR-327-mediated translational suppression of PRKACB, which consecutively activated the cAMP response element binding protein (CREB) . CREB induced expression of HULC, thereby forming a CREB-HULC-PRKACB positive feedback loop . HULC also acted as a molecular decoy to downregulate miR-186 which upregulated HMGA2 and lead to HCC progression. In this model, HULC expression was regulated by IGF2BP1 by accelerating HULC degradation . Various studies have elucidated the pathways through which HULC promotes hepatocarcinogenesis: it activates angiogenesis via the HULC/miR-107/E2F1/SPHK1 axis , enhances EMT and metastasis via the HULC/miR-200a-3p/ZEB1 axis , induces autophagy via the HULC/USP22/Sirt1 axis , and augments cell proliferation by stabilizing COX-2  (Table 2). HULC is also involved in hepatitis B virus (HBV) induced HCC, in which HBx plays an important role . HBx markedly increased cell proliferation by upregulating HULC and inhibiting p18, while HULC inhibition abolished HBx-induced cell proliferation accompanied by p18 upregulation . Taken together, HULC is a potential biomarker for diagnosing HCC.
+: increase; −: decrease.
“HOX transcript antisense intergenic RNA” or HOTAIR is a lncRNA (2.2 kb length) which originates from the HOXC antisense strand . HOTAIR is overexpressed in HCC cells and tissues [24–27] and is associated with worse prognosis, shorter recurrence-free survival, and increased risk of recurrence after hepatic transplantation [26, 28, 29]. Functionally, HOTAIR enhances proliferation, migration, glycolysis, autophagy, and chemoresistance in HCC cells (Table 1).
HOTAIR-mediated inhibition of miRNA-218 induced Bmi-1 expression and activated downstream P14 and P16 signaling, contributing to hepatocarcinogenesis . FOXC1 upregulated HOTAIR in HCC cells via miR-1 inhibition, thereby increasing proliferation . In addition, HOTAIR also increased cell proliferation by regulating OGFr . HOTAIR silencing in Huh7 cells decreased proliferation and induced cisplatin resistance via inhibition of STAT3 and ABCB1, which was rescued by inhibiting STAT3 phosphorylation  (Table 1). Wei et al. showed that HOTAIR-induced upregulation of GLUT1 and activation of mTOR signaling pathway facilitate glycolysis in HCC cells , indicating a direct association between HOTAIR and glucose metabolism in cancer cells. RNAi-mediated HOTAIR knockdown in HCC cells upregulated the RNA binding motif protein 38 (RBM38)  (Table 1). Furthermore, knockdown of RBM38 could restore HOTAIR-knockdown-induced decrease in cell migration and invasion . Thus, HOTAIR likely enables HCC metastasis and invasion by inhibiting RBM38. The PRC2 complex, consisting of SUZ12 and EZH2, plays a key role in hepatocarcinogenesis [34–36]. HOTAIR also acts as a scaffold by recruiting PRC2 to the LSD1/Co-REST/HDAC1 complex . In addition, HOTAIR also promotes HBV-mediated HCC by accelerating the degradation of SUZ12 and ZNF198  (Table 1). Finally, HOTAIR could also induce autophagy in HCC cells by upregulating ATG3 and ATG7  (Table 1). Taken together, HOTAIR promotes hepatocarcinogenesis by multiple mechanisms.
Overexpressed “metastasis-associated lung adenocarcinoma transcript 1” or MALAT1 has been initially discovered in human non-small-cell lung cancer (NSCLC) . MALAT1 is overexpressed in HCC tissues and cell lines [41, 42] and is linked with a higher tumor recurrence rate in patients after hepatic transplantation, indicating a predictive role of MALAT1 in HCC recurrence . Functionally, MALAT1 promotes proliferation, invasion, metastasis, chemosensitivity, and autophagy in HCC cells (Table 1).
MALAT1 is upregulated by Sp1 and Sp3 and downregulated by MIT (Sp1 binding inhibitor), indicating a possibility of targeting MALAT1 in HCC patients by MIT . High expression of MALAT1 is linked with 5-FU resistance in HCC cell line . In addition, HIF-2α inhibits miR-216b through MALAT1, where the HIF-2α-MALAT1-miR-216b axis promotes autophagy with LC3-II upregulation and p62 downregulation, contributing to HCC chemosensitivity  (Table 1). MALAT1 also promotes arsenite-induced glycolysis via stabilizing HIF-1α in human hepatic L-02 cells . Moreover, MALAT1, negatively regulated by p53, enhanced proliferation during liver regeneration through stimulation of the Wnt/β-catenin pathway  (Table 1). The mTOR signaling pathway is essential for the oncogenic role of MALAT1, which further mediates SRSF1 upregulation and mTOR activation . MALATI promotes tumor growth, invasion, and metastasis of HCC as a decoy lncRNA through the MALAT1/miR-143-3p/ZEB1 axis and inhibiting miR-146b-5p [48, 49]. It can also act as a ceRNA for miR-195 and reverse miR-195-mediated EGFR inhibition and further promote cell proliferation by activating the PI3K/AKT and JAK/STAT pathways, indicating a role of MALAT1-miR-195-EGFR axis in HCC  (Table 1). Like HULC and HOTAIR, MALAT1 is also involved in HBx-mediated hepatocarcinogenesis ; it is upregulated by HBx and enhances proliferation and metastasis by activating LTBP3 , forming the HBx-MALAT1-LTBP3 axis. Taken together, MALAT1 regulates multiple cellular processes through its decoy or ceRNA functions, indicating a potential target for HCC therapy.
“HOXA transcript at the distal tip” or HOTTIP is greatly expressed in HCC tumor tissues and cells  and is linked with a greater threat of metastasis and poor OS . Studies have shown the effect of HOTTIP on HCC proliferation, metastasis, and glutamine metabolism (Table 1) [52–54].
HOTTIP downregulates miR-125b, miR-192, and miR-204 and enhances the cell growth and migration through the miR-192/-204-HOTTIP axis [53, 54], while HOTTIP inhibition decreases growth of HCC cells [52, 54]. In addition, HOXA13 and GLS1 are further revealed to be the likely target genes of miR-192/-204-HOTTIP axis, and overexpression of miR-192 and miR-204 is associated with increased survival in the patients . Taken together, these findings imply the oncogenic role of HOTTIP in hepatocarcinogenesis through miRNA interaction.
“Microvascular invasion in HCC” or MVIH is situated at chromosome 10 and was firstly identified by Yuan et al. in HCC . High levels of MVIH in HCC were correlated with enhanced invasion and poor prognosis with decreased RFS and OS . As shown in Table 1, MVIH plays important roles in proliferation, migration, apoptosis, metastasis, and angiogenesis in HCC [55–57].
MVIH exerts its proangiogenic action by inhibiting PGK1 secretion . It also acts like a sponge for miR-199, and MVIH-mediated inhibition of miR-199 leads to increased proliferation and apoptosis inhibition in HCC cells . Recently, MVIH was reported to control proliferation and migration of HCC cells via modulation of ARID1A-mediated regulation of CDKN1A . Taken together, these findings underscore the oncogenic role of MVIH in HCC.
Murine PVT1 was first identified in the liver where it accelerated proliferation and cell cycling and enhanced stem-cell-associated properties . Human PVT1 is overexpressed in HCC tumor tissues and cell lines and is linked with advanced TNM stage and poor prognosis as well as RFS [58–60], and upregulation of PVT1 can also predict HCC recurrence . As shown in Table 1, PVT1 plays an oncogenic role in multiple cellular processes like proliferation and invasion and increases the stemness of HCC cells [58, 60, 61].
Functionally, through interaction between PVT1 and NOP2, PVT1 enhances the expression of NOP2 via stabilizing NOP2, thus promoting proliferation, cell cycle, and stemness of HCC cells  (Table 1). In addition, PVT1 can also induce miR-214 inhibition via interaction with EZH2 to promote cell proliferation and invasion , forming a PVT1/EZH2/miR-214 axis (Table 1) . The clearly oncogenic role of PVT1 indicates its potential use as a biomarker in diagnosing and predicting recurrence in HCC.
In addition to the lncRNAs mentioned above, several others are upregulated during hepatocarcinogenesis, including DANCR, HEIH, and Linc-ROR (Table 1).
3. Downregulated/Tumor Suppressive lncRNAs in HCC
H19 is situated on chromosome 11p15.5  and plays a key role in various cancers including HCC, where the abnormal expression of H19 is linked with late stages of cancer and poor DSF and outcome [63–65]. Functionally, H19 regulates proliferation, migration, invasion, EMT, metastasis, and chemoresistance in HCC cells [64, 66–68] (Table 2).
H19 is upregulated in doxorubicin-resistant R-HepG2 cells  and induces drug resistance by modulating MDR1 . H19 overexpression enhanced the tumor growth in in vivo models of HCC, while H19 inhibition decreased . HCC patients with elevated expression of H19 in the tumor tissues showed poor DFS, suggesting a predictive role of H19 in HCC prognosis . However, some studies have shown H19 to be significantly downregulated in HCC [64, 65], which is correlated with poor prognosis . In addition, H19 could also activate miR-200 and suppress tumor metastasis and EMT  (Table 2). H19 inhibition by miR-675 promoted metastasis of HCC via the AKT/GSK-3beta/Cdc25A pathway  (Table 2). Taken together, H19 seems to act as a tumor suppressor as well as an oncogene in HCC.
“Maternally expressed 3” or MEG3 is a maternally inherited lncRNA presented on chromosome 14q32.3  and was first identified by Miyoshi et al. . MEG3 expression is reportedly low in human HCC cells [71–73] and is linked with reduced OS, suggesting a predictive role of MEG3 in HCC prognosis . As shown in Table 2, MEG3 could regulate proliferation and apoptosis in HCC cells [72–75].
MEG3 can be negatively regulated by UHRF1 via modulating DNA methylation, since its promoter region is highly methylated . One mechanism of MEG3 mediated tumor suppression is the activation of p53 by increasing its stability and modulating the downstream genes [72, 74] (Table 2). Using a novel delivery system, MEG3 was introduced into HCC cells and resulted in tumor growth inhibition via the p53 signaling, indicating a bona fide tumor suppressive role of MEG3 in HCC . Furthermore, it acted as a molecular sponge for miR-664 and could inhibit cell proliferation by modulating miR-664-mediated regulation of ADH4  (Table 2). Taken together, MEG3 is a tumor suppressor and might be considered a prospective diagnostic, predictive and therapeutic biomarker in HCC.
“Downregulated expression by HBx” or Dreh was first identified by lncRNA microarray on WT and HBx-transgenic mice . It is low expressed in the tumor tissues of HBV-related HCC patients and corresponding cell lines [77, 78]. Patients with decreased expression of Dreh showed poor survival . As shown in Table 2, Dreh is linked with the proliferation and metastasis of HBV-related HCC.
A previous study revealed a negative correlation of Dreh expression with HBx and HBs . Dreh is downregulated by HBx via downregulation of vimentin, which results in the suppression of HCC growth and migration [77, 78] (Table 2), thus underscoring the tumor suppressive role of Dreh in HBV-related HCC.
“Low expression in tumor” or LET is present in significantly low levels in HCC tumor tissues  and is linked with metastasis . As shown in Table 2, LET influences the invasiveness and metastasis of HCC cells.
LET is downregulated by HDAC3 , and LET inhibition increases the stability of NF90, thus promoting hypoxia-induced invasion  (Table 2). This was successfully validated in an HCC clinical sample with abnormal histone acetylation, downregulation of LET, and upregulation of NF90. These findings suggest a tumor suppressive role of LET centered around regulating metastasis under hypoxia.
As shown in Table 2, along with the lncRNAs discussed above, several others have been indicated to influence hepatocarcinogenesis, such as ZNFX1-AS1, PTENP1, and XIST.
4. lncRNAs as Diagnostic Biomarkers and Drug Targets in HCC
Increasing evidence shows critical roles of various lncRNAs in hepatocarcinogenesis, either as tumor suppressors or as oncogenes. Abnormal expression of lncRNAs is significantly linked with cancer proliferation, metastasis, OS, DFS, RFS, and the tumor TNM stage. Multivariate analyses have further revealed that lncRNAs can independently predict recurrence and outcomes of HCC. With the rapid development of molecular diagnostics such as sequencing technology, qRT-PCR, microarrays, and RNA immunoprecipitation, lncRNAs can be easily detected in various body fluids, thus paving the way for lncRNA as novel diagnostic and prognostic markers of HCC. For example, the oncogenic HULC is significantly upregulated in plasma of patients as well the HCC tumor tissues; thus, it could serve as a novel diagnostic biomarker for HCC (Table 3) [15, 17]. In addition to plasma, serum and exosomes can also be used for lncRNA detection. For example, HEIH, an oncogenic lncRNA expressed highly in HCC tissues, was also found to be overexpressed in the serum and exosomes of patients with HCV-related HCC (Table 3). In addition to HULC and HEIH, many other lncRNAs could also serve as biomarkers of HCC which are shown in Table 3.
Since various lncRNAs are abnormally expressed in HCC and affect many downstream genes and related signaling pathways through oncogenic or tumor suppressive action, restoring these lncRNAs to their normal expression level is a therapeutic option worth considering, especially as an alternative to the chemotherapeutic drugs which usually result in chemoresistance . Pharmaceutical companies have recently shown a great interest in lncRNA-targeted therapy and have already taken actions [81, 82]. lncRNAs could be upregulated by exogenous overexpression and directly targeted by their specific siRNAs or antisense oligonucleotides [83, 84]. For example, the tumor suppressor MEG3 introduced into HCC tumor through a novel delivery system effectively induced apoptosis in HCC cells , presenting a potential lncRNA-targeted therapy with fewer side effects. Therefore, clarifying the specific mechanism of lncRNA action will greatly promote the advancement of lncRNA-based diagnosis and therapy for HCC.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Xiaoge Hu and Jiahong Jiang contributed equally to this work.
The present study was supported by the Key Research Project of Science Technology Department of Zhejiang Province (no. 2015C03030), the Science Technology Department of Zhejiang Province (no. 2016C33116), the National Natural Science Foundation of China (nos. 81772575 and 81502463); the Key Project of Health Bureau of Zhejiang Province (no. 2018274734); the Natural Science Foundation of Zhejiang Province (Y15H160158, Q15H070012), and the CSCO Merck Serono Oncology Research Fund, SCORE (no. Y-MX2015-038).
- L. A. Torre, F. Bray, R. L. Siegel, J. Ferlay, and J. Lortet-Tieulent, “Global cancer statistics, 2012,” CA: A Cancer Journal for Clinicians, vol. 65, no. 2, pp. 87–108, 2015.
- H. Alotaibi, N. Atabey, K. Diril, E. Erdal, and M. Ozturk, “Molecular mechanisms of hepatocellular carcinoma,” Hepatology, vol. 48, no. 6, pp. 2047–2063, 2016.
- R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer statistics, 2018,” CA: A Cancer Journal for Clinicians, vol. 68, no. 1, pp. 7–30, 2018.
- International Human Genome Sequencing Consortium, “Finishing the euchromatic sequence of the human genome,” Nature, vol. 431, pp. 931–945, 2004.
- E. P. Consortium, E. Birney, and J. A. Stamatoyannopoulos, “Identification and analysis of functional elements in 1% of the human genome by the encode pilot project,” Nature, vol. 447, no. 7146, pp. 799–816, 2007.
- M. Guttman, I. Amit, M. Garber et al., “Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals,” Nature, vol. 458, no. 7235, pp. 223–227, 2009.
- J. L. Rinn and H. Y. Chang, “Genome regulation by long noncoding RNAs,” Annual Review of Biochemistry, vol. 81, pp. 145–166, 2012.
- C. P. Ponting, P. L. Oliver, and W. Reik, “Evolution and functions of long noncoding RNAs,” Cell, vol. 136, no. 4, pp. 629–641, 2009.
- L. Ma, V. B. Bajic, and Z. Zhang, “On the classification of long non-coding RNAs,” RNA Biology, vol. 10, no. 6, pp. 925–933, 2013.
- K. C. Wang and H. Y. Chang, “Molecular mechanisms of long noncoding RNAs,” Molecular Cell, vol. 43, no. 6, pp. 904–914, 2011.
- A. Bhan, M. Soleimani, and S. S. Mandal, “Long noncoding RNA and cancer: A new paradigm,” Cancer Research, vol. 77, no. 15, pp. 3965–3981, 2017.
- K. Panzitt, M. M. O. Tschernatsch, C. Guelly et al., “Characterization of HULC, a novel gene with striking up-regulation in hepatocellular carcinoma, as noncoding RNA,” Gastroenterology, vol. 132, no. 1, pp. 330–342, 2007.
- J. Wang, X. Liu, H. Wu et al., “CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer,” Nucleic Acids Research, vol. 38, no. 16, pp. 5366–5383, 2010.
- Y. Du, G. Kong, X. You et al., “Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18,” The Journal of Biological Chemistry, vol. 287, no. 31, pp. 26302–26311, 2012.
- H. Xie, H. Ma, and D. Zhou, “Plasma HULC as a promising novel biomarker for the detection of hepatocellular carcinoma,” BioMed Research International, vol. 2013, Article ID 136106, 5 pages, 2013.
- M. Hämmerle, T. Gutschner, H. Uckelmann et al., “Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1),” Hepatology, vol. 58, no. 5, pp. 1703–1712, 2013.
- J. Li, X. Wang, J. Tang et al., “HULC and Linc00152 Act as novel biomarkers in predicting diagnosis of hepatocellular carcinoma,” Cellular Physiology and Biochemistry, vol. 37, no. 2, pp. 687–696, 2015.
- S. Li, H. Xu, Y. Yu et al., “LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway,” Oncotarget , vol. 7, no. 27, pp. 42431–42446, 2016.
- Z. Lu, Z. Xiao, F. Liu et al., “Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1),” Oncotarget , vol. 7, no. 1, pp. 241–254, 2016.
- H. Xiong, Z. Ni, J. He et al., “LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells,” Oncogene, vol. 36, no. 25, pp. 3528–3540, 2017.
- H. Xiong, B. Li, J. He, Y. Zeng, Y. Zhang, and F. He, “lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein,” Biochemical and Biophysical Research Communications, vol. 490, no. 3, pp. 693–699, 2017.
- X. Zhang, H. Zhang, and L. Ye, “Effects of hepatitis B virus X protein on the development of liver cancer,” Journal of Laboratory and Clinical Medicine, vol. 147, no. 2, pp. 58–66, 2006.
- J. L. Rinn, M. Kertesz, J. K. Wang et al., “Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs,” Cell, vol. 129, no. 7, pp. 1311–1323, 2007.
- D.-N. Zhong, Y.-H. Luo, W.-J. Mo et al., “High expression of long non-coding HOTAIR correlated with hepatocarcinogenesis and metastasis,” Molecular Medicine Reports, vol. 17, no. 1, pp. 1148–1156, 2018.
- W.-M. Fu, X. Zhu, W.-M. Wang et al., “Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling,” Journal of Hepatology, vol. 63, no. 4, pp. 886–895, 2015.
- Z. Yang, L. Zhou, L.-M. Wu et al., “Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation,” Annals of Surgical Oncology, vol. 18, no. 5, pp. 1243–1250, 2011.
- S. Wei, Q. Fan, Y. Liang et al., “Promotion of glycolysis by HOTAIR through GLUT1 upregulation via mTOR signaling,” Oncology Reports, vol. 38, no. 3, pp. 1902–1908, 2017.
- M. Ishibashi, R. Kogo, K. Shibata et al., “Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma,” Oncology Reports, vol. 29, no. 3, pp. 946–950, 2013.
- Y. J. Geng, S. L. Xie, Q. Li, J. Ma, and G. Y. Wang, “Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression,” Journal of International Medical Research, vol. 39, no. 6, pp. 2119–2128, 2011.
- D.-N. Su, S.-P. Wu, H.-T. Chen, and J.-H. He, “HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma,” Oncology Letters, vol. 12, no. 5, pp. 4061–4067, 2016.
- Y. Wu, Q. Xiong, S. Li, X. Yang, and F. Ge, “Integrated Proteomic and Transcriptomic Analysis Reveals Long Noncoding RNA HOX Transcript Antisense Intergenic RNA (HOTAIR) Promotes Hepatocellular Carcinoma Cell Proliferation by Regulating Opioid Growth Factor Receptor (OGFr),” Molecular & Cellular Proteomics, vol. 17, no. 1, pp. 146–159, 2018.
- J.-J. Zhou, D. Cheng, X.-Y. He, Z. Meng, H.-L. Ye, and R.-F. Chen, “Knockdown of long non-coding RNA HOTAIR sensitizes hepatocellular carcinoma cell to cisplatin by suppressing the STAT3/ABCB1 signaling pathway,” Oncology Letters, vol. 14, no. 6, pp. 7986–7992, 2017.
- C. Ding, S. Cheng, Z. Yang et al., “Long non-coding RNA HOTAIR promotes cell migration and invasion via down-regulation of RNA binding motif protein 38 in hepatocellular carcinoma cells,” International Journal of Molecular Sciences, vol. 15, no. 3, pp. 4060–4076, 2014.
- S. L.-K. Au, C. C.-L. Wong, J. M.-F. Lee et al., “Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis,” Hepatology, vol. 56, no. 2, pp. 622–631, 2012.
- S.-B. Gao, B. Xu, L.-H. Ding et al., “The functional and mechanistic relatedness of EZH2 and menin in hepatocellular carcinoma,” Journal of Hepatology, vol. 61, no. 4, pp. 832–839, 2014.
- A. Kirmizis, S. M. Bartley, and P. J. Farnham, “Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy,” Molecular Cancer Therapeutics, vol. 2, no. 1, pp. 113–121, 2003.
- M.-C. Tsai, O. Manor, Y. Wan et al., “Long noncoding RNA as modular scaffold of histone modification complexes,” Science, vol. 329, no. 5992, pp. 689–693, 2010.
- H. Zhang, A. Diab, H. Fan et al., “PLK1 and HOTAIR accelerate proteasomal degradation of SUZ12 and ZNF198 during hepatitis B virus-induced liver carcinogenesis,” Cancer Research, vol. 75, no. 11, pp. 2363–2374, 2015.
- L. Yang, X. Zhang, H. Li, and J. Liu, “The long noncoding RNA HOTAIR activates autophagy by upregulating ATG3 and ATG7 in hepatocellular carcinoma,” Molecular BioSystems, vol. 12, no. 8, pp. 2605–2612, 2016.
- P. Ji, S. Diederichs, W. Wang et al., “MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer,” Oncogene, vol. 22, no. 39, pp. 8031–8041, 2003.
- R. Lin, S. Maeda, C. Liu, M. Karin, and T. S. Edgington, “A large noncoding RNA is a marker for murine hepatocellular carcinomas and a spectrum of human carcinomas,” Oncogene, vol. 26, no. 6, pp. 851–858, 2007.
- M.-C. Lai, Z. Yang, L. Zhou et al., “Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation,” Medical Oncology, vol. 29, no. 3, pp. 1810–1816, 2012.
- Z. Huang, L. Huang, S. Shen et al., “Sp1 cooperates with Sp3 to upregulate MALAT1 expression in human hepatocellular carcinoma,” Oncology Reports, vol. 34, no. 5, pp. 2403–2412, 2015.
- P. Yuan, W. Cao, Q. Zang, G. Li, X. Guo, and J. Fan, “The HIF-2α-MALAT1-miR-216b axis regulates multi-drug resistance of hepatocellular carcinoma cells via modulating autophagy,” Biochemical and Biophysical Research Communications, vol. 478, no. 3, pp. 1067–1073, 2016.
- F. Luo, X. Liu, M. Ling et al., “The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1862, no. 9, pp. 1685–1695, 2016.
- C. Li, L. Chang, Z. Chen, Z. Liu, Y. Wang, and Q. Ye, “The role of lncRNA MALAT1 in the regulation of hepatocyte proliferation during liver regeneration,” International Journal of Molecular Medicine, vol. 39, no. 2, pp. 347–356, 2017.
- P. Malakar, A. Shilo, A. Mogilevsky et al., “Long noncoding RNA MALAT1 promotes hepatocellular carcinoma development by SRSF1 upregulation and mTOR activation,” Cancer Research, vol. 77, no. 5, pp. 1155–1167, 2017.
- C. Li, R. Miao, S. Liu et al., “Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis,” Oncotarget , vol. 8, no. 17, pp. 28683–28695, 2017.
- L. Chen, H. Yao, K. Wang, and X. Liu, “Long Non-Coding RNA MALAT1 Regulates ZEB1 Expression by Sponging miR-143-3p and Promotes Hepatocellular Carcinoma Progression,” Journal of Cellular Biochemistry, vol. 118, no. 12, pp. 4836–4843, 2017.
- D. Liu, Y. Zhu, J. Pang, X. Weng, X. Feng, and Y. Guo, “Knockdown of long non-coding RNA MALAT1 inhibits growth and motility of human hepatoma cells via modulation of miR-195,” Journal of Cellular Biochemistry, vol. 119, no. 2, pp. 1368–1380, 2018.
- Z. Hou, X. Xu, X. Fu et al., “HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma,” American Journal of Cancer Research, vol. 7, no. 4, pp. 845–856, 2017.
- L. Quagliata, M. S. Matter, S. Piscuoglio et al., “Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients,” Hepatology, vol. 59, no. 3, pp. 911–923, 2014.
- F. H. C. Tsang, S. L. K. Au, L. Wei et al., “Long non-coding RNA HOTTIP is frequently up-regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR-125b,” Liver International, vol. 35, no. 5, pp. 1597–1606, 2015.
- Y. Ge, X. Yan, Y. Jin et al., “fMiRNA-192 and miRNA-204 directly suppress lncRNA HOTTIP and interrupt GLS1-mediated glutaminolysis in hepatocellular carcinoma,” PLoS Genetics, vol. 11, no. 12, Article ID e1005726, 2015.
- S.-X. Yuan, F. Yang, Y. Yang et al., “Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients' poor recurrence-free survival after hepatectomy,” Hepatology, vol. 56, no. 6, pp. 2231–2241, 2012.
- Y. Shi, Q. Song, S. Yu, D. Hu, and X. Zhuang, “Microvascular invasion in hepatocellular carcinoma overexpression promotes cell proliferation and inhibits cell apoptosis of hepatocellular carcinoma via inhibiting miR-199a expression,” OncoTargets and Therapy, vol. 8, pp. 2303–2310, 2015.
- S. Cheng, L. Wang, C.-H. Deng, S.-C. Du, and Z.-G. Han, “ARID1A represses hepatocellular carcinoma cell proliferation and migration through lncRNA MVIH,” Biochemical and Biophysical Research Communications, vol. 491, no. 1, pp. 178–182, 2017.
- F. Wang, J.-H. Yuan, S.-B. Wang et al., “Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2,” Hepatology, vol. 60, no. 4, pp. 1278–1290, 2014.
- C. Ding, Z. Yang, Z. Lv et al., “Long non-coding RNA PVT1 is associated with tumor progression and predicts recurrence in hepatocellular carcinoma patients,” Oncology Letters, vol. 9, no. 2, pp. 955–963, 2015.
- X. Gou, X. Zhao, and Z. Wang, “Long noncoding RNA PVT1 promotes hepatocellular carcinoma progression through regulating miR-214,” Cancer Biomarkers, vol. 20, no. 4, pp. 511–519, 2017.
- H. Cui, Y. Zhang, Q. Zhang, W. Chen, H. Zhao, and J. Liang, “A comprehensive genome-wide analysis of long noncoding RNA expression profile in hepatocellular carcinoma,” Cancer Medicine, vol. 6, no. 12, pp. 2932–2941, 2017.
- M. P. Leibovitch, V. C. Nguyen, M. S. Gross, B. Solhonne, S. A. Leibovitch, and A. Bernheim, “The human ASM (Adult Skeletal Muscle) gene Expression and chromosomal assignment to 11p15,” Biochemical and Biophysical Research Communications, vol. 180, no. 3, pp. 1241–1250, 1991.
- N. Iizuka, M. Oka, T. Tamesa, Y. Hamamoto, and H. Yamada-Okabe, “Imbalance in expression levels of insulin-like growth factor 2 and H19 transcripts linked to progression of hepatocellular carcinoma,” Anticancer Reseach, vol. 24, no. 6, pp. 4085–4089, 2004.
- L. Zhang, F. Yang, J.-H. Yuan et al., “Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma,” Carcinogenesis, vol. 34, no. 3, pp. 577–586, 2013.
- Z. Yang, Y. Lu, Q. Xu, B. Tang, C.-K. Park, and X. Chen, “HULC and H19 played different roles in overall and disease-free survival from hepatocellular carcinoma after curative hepatectomy: a preliminary analysis from gene expression omnibus,” Disease Markers, vol. 2015, Article ID 191029, 9 pages, 2015.
- W. P. Tsang and T. T. Kwok, “Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells,” Oncogene, vol. 26, no. 33, pp. 4877–4881, 2007.
- I. J. Matouk, N. DeGroot, S. Mezan et al., “The H19 non-coding RNA is essential for human tumor growth,” PLoS ONE, vol. 2, no. 9, article e845, 2007.
- J. Lv, L. Ma, X.-L. Chen, X.-H. Huang, and Q. Wang, “Downregulation of LncRNAH19 and MiR-675 promotes migration and invasion of human hepatocellular carcinoma cells through AKT/GSK-3β/Cdc25A signaling pathway,” Journal of Huazhong University of Science and Technology (Medical Sciences), vol. 34, no. 3, pp. 363–369, 2014.
- A. A. Wylie, S. K. Murphy, T. C. Orton, and R. L. Jirtle, “Novel imprinted DLK1/GTL2 domain on human chromosome 14 contains motifs that mimic those implicated in IGF2/H19 regulation,” Genome Research, vol. 10, no. 11, pp. 1711–1718, 2000.
- N. Miyoshi, H. Wagatsuma, S. Wakana et al., “Identification of an imprinted gene, Meg3/Gtl2 and its human homologue MEG3, first mapped on mouse distal chromosome 12 and human chromosome 14q,” Genes to Cells, vol. 5, no. 3, pp. 211–220, 2000.
- C. Braconi, T. Kogure, N. Valeri et al., “MicroRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer,” Oncogene, vol. 30, no. 47, pp. 4750–4756, 2011.
- J. Zhu, S. Liu, F. Ye et al., “Long noncoding RNA MEG3 interacts with p53 protein and regulates partial p53 target genes in hepatoma cells,” PLoS ONE, vol. 10, no. 10, Article ID e0139790, 2015.
- H. Zhuo, J. Tang, Z. Lin et al., “The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma,” Molecular Carcinogenesis, vol. 55, no. 2, pp. 209–219, 2016.
- L. Chang, G. Wang, T. Jia et al., “Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma,” Oncotarget , vol. 7, no. 17, pp. 23988–24004, 2016.
- W. Ni, Y. Zhang, Z. Zhan et al., “A novel lncRNA uc.134 represses hepatocellular carcinoma progression by inhibiting CUL4A-mediated ubiquitination of LATS1,” Journal of Hematology & Oncology, vol. 10, no. 1, pp. 1–17, 2017.
- J.-H. He, Z.-P. Han, J.-M. Liu et al., “Overexpression of Long Non-Coding RNA MEG3 Inhibits Proliferation of Hepatocellular Carcinoma Huh7 Cells via Negative Modulation of miRNA-664,” Journal of Cellular Biochemistry, vol. 118, no. 11, pp. 3713–3721, 2017.
- J. F. Huang, Y. J. Guo, C. X. Zhao et al., “Hepatitis B virus X protein (HBx)-related long noncoding RNA (lncRNA) down-regulated expression by HBx (Dreh) inhibits hepatocellular carcinoma metastasis by targeting the intermediate filament protein vimentin,” Hepatology, vol. 57, no. 5, pp. 1882–1892, 2013.
- D. Lv, Y. Wang, Y. Zhang, P. Cui, and Y. Xu, “Downregulated long non-coding RNA DREH promotes cell proliferation in hepatitis B virus-associated hepatocellular carcinoma,” Oncology Letters, vol. 14, no. 2, pp. 2025–2032, 2017.
- F. Yang, X.-S. Huo, S.-X. Yuan et al., “Repression of the long noncoding RNA-LET by histone deacetylase 3 contributes to hypoxia-mediated metastasis,” Molecular Cell, vol. 49, no. 6, pp. 1083–1096, 2013.
- J. C. Henry, A. C. P. Azevedo-Pouly, and T. D. Schmittgen, “MicroRNA replacement therapy for cancer,” Pharmaceutical Research, vol. 28, no. 12, pp. 3030–3042, 2011.
- H. Ling, M. Fabbri, and G. A. Calin, “MicroRNAs and other non-coding RNAs as targets for anticancer drug development,” Nature Reviews Drug Discovery, vol. 12, no. 11, pp. 847–865, 2013.
- C. H. Li and Y. Chen, “Targeting long non-coding RNAs in cancers: progress and prospects,” The International Journal of Biochemistry & Cell Biology, vol. 45, no. 8, pp. 1895–1910, 2013.
- J. Y. Park, J. E. Lee, J. B. Park, H. Yoo, S. H. Lee, and J. H. Kim, “Roles of long non-coding RNAs on tumorigenesis and glioma development,” Brain Tumor Research and Treatment, vol. 2, no. 1, pp. 1–6, 2014.
- V. Tripathi, Z. Shen, A. Chakraborty et al., “Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB,” PLoS Genetics, vol. 9, no. 3, Article ID e1003368, 2013.
- Y. Zhang, Z. Li, Y. Zhang, Q. Zhong, Q. Chen, and L. Zhang, “Molecular mechanism of HEIH and HULC in the proliferation and invasion of hepatoma cells,” International Journal of Clinical and Experimental Medicine, vol. 8, no. 8, pp. 12956–12962, 2015.
- Y. Wang, F. Chen, M. Zhao et al., “The long noncoding RNA HULC promotes liver cancer by increasing the expression of the HMGA2 oncogene via sequestration of the microRNA-186,” The Journal of Biological Chemistry, vol. 292, no. 37, pp. 15395–15407, 2017.
- H. Li, J. An, M. Wu et al., “LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2,” Oncotarget , vol. 6, no. 29, pp. 27847–27864, 2015.
- Z. Zheng, C. Pang, Y. Yang, Q. Duan, J. Zhang, and W. Liu, “Serum long noncoding RNA urothelial carcinoma-associated 1: A novel biomarker for diagnosis and prognosis of hepatocellular carcinoma,” Journal of International Medical Research, vol. 46, no. 1, pp. 348–356, 2017.
- J.-N. Xiao, T.-H. Yan, R.-M. Yu et al., “Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression,” Journal of Cancer Research and Clinical Oncology, vol. 143, no. 6, pp. 981–990, 2017.
- J.-J. Hu, W. Song, S.-D. Zhang et al., “HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling,” Scientific Reports, vol. 6, Article ID 23521, 2016.
- F. Wang, H.-Q. Ying, B.-S. He et al., “Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway,” Oncotarget , vol. 6, no. 10, pp. 7899–7917, 2015.
- Y. Li, Y. Ye, and H. Chen, “Astragaloside IV inhibits cell migration and viability of hepatocellular carcinoma cells via suppressing long noncoding RNA ATB,” Biomedicine & Pharmacotherapy, vol. 99, pp. 134–141, 2018.
- S. Y. Jang, G. Kim, S. Y. Park et al., “Clinical significance of lncRNA-ATB expression in human hepatocellular carcinoma,” Oncotarget , vol. 8, no. 45, pp. 78588–78597, 2017.
- J. H. Yuan, F. Yang, F. Wang et al., “A long noncoding RNA activated by TGF-beta promotes the invasion-metastasis cascade in hepatocellular carcinoma,” Cancer Cell, vol. 25, no. 5, pp. 666–681, 2014.
- K. Takahashi, I. K. Yan, T. Kogure, H. Haga, and T. Patel, “Extracellular vesicle-mediated transfer of long non-coding RNA ROR modulates chemosensitivity in human hepatocellular cancer,” FEBS Open Bio, vol. 4, pp. 458–467, 2014.
- K. Takahashi, I. K. Yan, H. Haga, and T. Patel, “Modulation of hypoxia-signaling pathways by extracellular linc-RoR,” Journal of Cell Science, vol. 127, no. 7, pp. 1585–1594, 2014.
- C. Li, L. Lu, B. Feng et al., “The lincRNA-ROR/miR-145 axis promotes invasion and metastasis in hepatocellular carcinoma via induction of epithelial-mesenchymal transition by targeting ZEB2,” Scientific Reports, vol. 7, no. 1, article no. 4637, 2017.
- K. Takahashi, I. K. Yan, J. Wood, H. Haga, and T. Patel, “Involvement of extracellular vesicle long noncoding RNA (linc-VLDLR) in tumor cell responses to chemotherapy,” Molecular Cancer Research, vol. 12, no. 10, pp. 1377–1387, 2014.
- H. Zhu, X. Zhou, H. Chang et al., “CCAT1 promotes hepatocellular carcinoma cell proliferation and invasion,” International Journal of Clinical and Experimental Pathology, vol. 8, no. 5, pp. 5427–5434, 2015.
- J. Tang, H. Zhuo, X. Zhang et al., “A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma,” Cell Death & Disease, vol. 5, no. 12, Article ID e1549, 2014.
- Z. Liu, X. Wei, A. Zhang, C. Li, J. Bai, and J. Dong, “Long non-coding RNA HNF1A-AS1 functioned as an oncogene and autophagy promoter in hepatocellular carcinoma through sponging hsa-miR-30b-5p,” Biochemical and Biophysical Research Communications, vol. 473, no. 4, pp. 1268–1275, 2016.
- C. Wang, L. Mou, H.-X. Chai, F. Wang, Y.-Z. Yin, and X.-Y. Zhang, “Long non-coding RNA HNF1A-AS1 promotes hepatocellular carcinoma cell proliferation by repressing NKD1 and P21 expression,” Biomedicine & Pharmacotherapy, vol. 89, pp. 926–932, 2017.
- C. Zhang, X. Yang, Q. Qi, Y. Gao, Q. Wei, and S. Han, “lncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma,” Cancer Biomarkers, vol. 21, no. 3, pp. 651–659, 2017.
- H.-W. Liang, N. Wang, Y. Wang et al., “Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122,” Journal of Hepatology, vol. 64, no. 2, pp. 278–291, 2016.
- C. C. Lau, T. Sun, A. K. Ching et al., “Viral-human chimeric transcript predisposes risk to liver cancer development and progression,” Cancer Cell, vol. 25, no. 3, pp. 335–349, 2014.
- Y. Wang, H. Lei, D. Ying et al., “The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling,” Cell Stem Cell, vol. 16, no. 4, pp. 413–425, 2015.
- S. X. Yuan, J. Wang, F. Yang et al., “Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1,” Hepatology, vol. 63, no. 2, pp. 499–511, 2016.
- X. Ma, X. Wang, C. Yang et al., “DANCR acts as a diagnostic biomarker and promotes tumor growth and metastasis in hepatocellular carcinoma,” Anticancer Reseach, vol. 36, no. 12, pp. 6389–6398, 2016.
- T. Zhou and Y. Gao, “Increased expression of LncRNA BANCR and its prognostic significance in human hepatocellular carcinoma,” World Journal of Surgical Oncology, vol. 14, no. 1, pp. 1–8, 2016.
- T. Li, J. Xie, C. Shen et al., “Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma,” Oncogene, 2015.
- J.-L. Huang, T.-Y. Ren, S.-W. Cao et al., “HBx-related long non-coding RNA DBH-AS1 promotes cell proliferation and survival by activating MAPK signaling in hepatocellular carcinoma,” Oncotarget , vol. 6, no. 32, pp. 33791–33804, 2015.
- W. Jin, L. Chen, X. Cai et al., “Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1,” Oncology Reports, vol. 37, no. 1, pp. 273–280, 2017.
- Y.-H. Lin, M.-H. Wu, Y.-H. Huang et al., “Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma,” Hepatology, vol. 67, no. 1, pp. 188–203, 2018.
- J. Li, Q. Zhang, X. Fan et al., “The long noncoding RNA TUG1 acts as a competing endogenous RNA to regulate the Hedgehog pathway by targeting miR-132 in hepatocellular carcinoma,” Oncotarget , vol. 8, no. 39, pp. 65932–65945, 2017.
- J. Ma, T. Li, X. Han, and H. Yuan, “Knockdown of LncRNA ANRIL suppresses cell proliferation, metastasis, and invasion via regulating miR-122-5p expression in hepatocellular carcinoma,” Journal of Cancer Research and Clinical Oncology, pp. 1–10, 2018.
- L. Hua, C. Y. Wang, K. H. Yao, J. T. Chen, J. J. Zhang, and W. L. Ma, “High expression of long non-coding RNA ANRIL is associated with poor prognosis in hepatocellular carcinoma,” International Journal of Clinical and Experimental Pathology, vol. 8, no. 3, pp. 3076–3082, 2015.
- W. H. Xu, J. B. Zhang, Z. Dang et al., “Long non-coding RNA URHC regulates cell proliferation and apoptosis via ZAK through the ERK/MAPK signaling pathway in hepatocellular carcinoma,” International Journal of Biological Sciences, vol. 10, no. 7, pp. 664–676, 2014.
- J.-Y. Zhang, M.-Z. Weng, F.-B. Song et al., “Long noncoding RNA AFAP1-AS1 indicates a poor prognosis of hepatocellular carcinoma and promotes cell proliferation and invasion via upregulation of the RhoA/Rac2 signaling,” International Journal of Oncology, vol. 48, no. 4, pp. 1590–1598, 2016.
- S.-X. Yuan, Q.-F. Tao, J. Wang et al., “Antisense long non-coding RNA PCNA-AS1 promotes tumor growth by regulating proliferating cell nuclear antigen in hepatocellular carcinoma,” Cancer Letters, vol. 349, no. 1, pp. 87–94, 2014.
- F. Chen, G. Bai, Y. Li, Y. Feng, and L. Wang, “A positive feedback loop of long noncoding RNA CCAT2 and FOXM1 promotes hepatocellular carcinoma growth,” American Journal of Cancer Research, vol. 7, no. 7, pp. 1423–1434, 2017.
- Y. Xu, B. Wang, F. Zhang et al., “Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating Snail2-mediated epithelial–mesenchymal transition,” OncoTargets and Therapy, vol. 10, pp. 1191–1198, 2017.
- N. Zhou, Z. Si, T. Li, G. Chen, Z. Zhang, and H. Qi, “Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation, migration and apoptosis,” Oncology Letters, vol. 12, no. 1, pp. 132–138, 2016.
- H. Zhang, D. Zhou, M. Ying et al., “Expression of long non-coding RNA (LncRNA) small nucleolar rna host gene 1 (SNHG1) exacerbates hepatocellular carcinoma through suppressing miR-195,” Medical Science Monitor, vol. 22, Article ID 898574, pp. 4820–4829, 2016.
- M. Zhang, W. Wang, T. Li et al., “Long noncoding RNA SNHG1 predicts a poor prognosis and promotes hepatocellular carcinoma tumorigenesis,” Biomedicine & Pharmacotherapy, vol. 80, pp. 73–79, 2016.
- C. Xie, F. Wang, S. Zhang et al., “Long Noncoding RNA HCAL Facilitates the Growth and Metastasis of Hepatocellular Carcinoma by Acting as a ceRNA of LAPTM4B,” Molecular Therapy - Nucleic Acids, vol. 9, pp. 440–451, 2017.
- X. Yan, D. Zhang, W. Wu et al., “Mesenchymal stem cells promote hepatocarcinogenesis via lncRNA–MUF interaction with ANXA2 and miR-34a,” Cancer Research, vol. 77, no. 23, pp. 6704–6716, 2017.
- H. Wang, X. Huo, X.-R. Yang et al., “STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4,” Molecular Cancer, vol. 16, no. 1, article no. 136, 2017.
- S. Lu, J. Zhou, Y. Sun et al., “The noncoding RNA HOXD-AS1 is a critical regulator of the metastasis and apoptosis phenotype in human hepatocellular carcinoma,” Molecular Cancer, vol. 16, no. 1, article no. 125, 2017.
- X. Zhao, Y. Liu, and S. Yu, “Long noncoding RNA AWPPH promotes hepatocellular carcinoma progression through YBX1 and serves as a prognostic biomarker,” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, vol. 1863, no. 7, pp. 1805–1816, 2017.
- T. Lan, W. Ma, Z. Hong, L. Wu, X. Chen, and Y. Yuan, “Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma,” Journal of Experimental & Clinical Cancer Research, vol. 36, no. 1, article no. 11, 2017.
- P. Zhu, Y. Wang, J. Wu et al., “LncBRM initiates YAP1 signalling activation to drive self-renewal of liver cancer stem cells,” Nature Communications, vol. 7, Article ID 13608, 2016.
- J. Lv, H.-X. Fan, X.-P. Zhao et al., “Long non-coding RNA Unigene56159 promotes epithelial–mesenchymal transition by acting as a ceRNA of miR-140-5p in hepatocellular carcinoma cells,” Cancer Letters, vol. 382, no. 2, pp. 166–175, 2016.
- C. Cao, T. Zhang, D. Zhang et al., “The long non-coding RNA, SNHG6-003, functions as a competing endogenous RNA to promote the progression of hepatocellular carcinoma,” Oncogene, vol. 36, no. 8, pp. 1112–1122, 2017.
- P. Zhu, Y. Wang, G. Huang et al., “Lnc-β-Catm elicits EZH2-dependent β-catenin stabilization and sustains liver CSC self-renewal,” Nature Structural & Molecular Biology, vol. 23, no. 7, pp. 631–639, 2016.
- T. Wang, S. Ma, X. Qi et al., “Long noncoding RNA ZNFX1-AS1 suppresses growth of hepatocellular carcinoma cells by regulating the methylation of miR-9,” OncoTargets and Therapy, vol. 9, pp. 5005–5014, 2016.
- C.-L. Chen, Y.-W. Tseng, J.-C. Wu et al., “Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and MicroRNA regulation,” Biomaterials, vol. 44, pp. 71–81, 2015.
- T.-H. Wang, Y.-S. Lin, Y. Chen et al., “Long non-coding RNA AOC4P suppresses hepatocellular carcinoma metastasis by enhancing vimentin degradation and inhibiting epithelial-mesenchymal transition,” Oncotarget , vol. 6, no. 27, pp. 23342–23357, 2015.
- F. Liu, J.-H. Yuan, J.-F. Huang et al., “Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a,” Oncogene, vol. 35, no. 41, pp. 5422–5434, 2016.
- L. K. Zhuang, Y. T. Yang, X. Ma et al., “MicroRNA-92b promotes hepatocellular carcinoma progression by targeting Smad7 and is mediated by long non-coding RNA XIST,” Cell Death & Disease, vol. 7, no. 4, Article ID e2203, 2016.
- S. Chang, B. Chen, X. Wang, K. Wu, and Y. Sun, “Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression,” BMC Cancer, vol. 17, no. 1, article no. 248, 2017.
- W.-G. Tang, B. Hu, H.-X. Sun et al., “Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis,” Oncotarget , vol. 8, no. 60, pp. 102006–102019, 2017.
- J. Sui, X. Yang, W. Qi et al., “Long Non-Coding RNA Linc-USP16 Functions As a Tumour Suppressor in Hepatocellular Carcinoma by Regulating PTEN Expression,” Cellular Physiology and Biochemistry, pp. 1188–1198, 2017.
- F. Zeng, Y. Le, J. Fan, and L. Xin, “LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR-24-3p,” Journal of Cellular Biochemistry.
- Y. Wang, Z. Liu, B. Yao et al., “Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis,” Molecular Cancer, vol. 16, no. 1, article no. 123, 2017.
- B. Hu, H. Cai, R. Zheng, S. Yang, Z. Zhou, and J. Tu, “Long non-coding RNA 657 suppresses hepatocellular carcinoma cell growth by acting as a molecular sponge of miR-106a-5p to regulate PTEN expression,” The International Journal of Biochemistry & Cell Biology, vol. 92, pp. 34–42, 2017.
- J. Wu, J. Huang, W. Wang et al., “Long non-coding RNA Fer-1-like protein 4 acts as a tumor suppressor via miR-106a-5p and predicts good prognosis in hepatocellular carcinoma,” Cancer Biomarkers, vol. 20, no. 1, pp. 55–65, 2017.
- X. Wang, W. Sun, W. Shen et al., “Long non-coding RNA DILC regulates liver cancer stem cells via IL-6/STAT3 axis,” Journal of Hepatology, vol. 64, no. 6, pp. 1283–1294, 2016.
- W. Yuan, Y. Sun, L. Liu, B. Zhou, S. Wang, and D. Gu, “Circulating LncRNAs Serve as Diagnostic Markers for Hepatocellular Carcinoma,” Cellular Physiology and Biochemistry, pp. 125–132, 2017.
- K. Wang, W. X. Guo, N. Li et al., “Serum LncRNAs profiles serve as novel potential biomarkers for the diagnosis of HBV-positive hepatocellular carcinoma,” PLoS ONE, vol. 10, no. 12, Article ID e0144934, 2015.
- J. Yu, J. Han, J. Zhang et al., “The long noncoding RNAs PVT1 and uc002mbe.2 in sera provide a new supplementary method for hepatocellular carcinoma diagnosis,” Medicine, vol. 95, no. 31, Article ID e4436, 2016.
- J. Tang, R. Jiang, L. Deng, X. Zhang, K. Wang, and B. Sun, “Circulation long non-coding RNAs act as biomarkers for predicting tumorigenesis and metastasis in hepatocellular carcinoma,” Oncotarget , vol. 6, no. 6, pp. 4505–4515, 2015.
- A. H. F. El-Tawdi, M. Matboli, H. H. Shehata et al., “Evaluation of Circulatory RNA-Based Biomarker Panel in Hepatocellular Carcinoma,” Molecular Diagnosis & Therapy, vol. 20, no. 3, pp. 265–277, 2016.
Copyright © 2018 Xiaoge Hu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.