HCC is one of the leading causes of lethality worldwide. Although there has been an increase in the rate of survival of HCC patients with the advances in medical technology, the molecular pathogenesis of HCC and genetic factor responsible remain to be understood (2, 14–16). There has been limited success in improving DFS of HCC patients. Thus, novel cancer-promoting genes involved in HCC must be identified and characterized to obtain a better understanding of this lethal disease and develop therapeutic interventions (14). In this study, we identified a novel differentially expressed lncRNA, LINC02518, located on chromosome 6q21. LINC02518 was overexpressed in HCC tissues and positively correlated with the clinicopathological features of HCC. Importantly, higher LINC02518 levels predicted lower OS, DFS, RFS, and MFS in patients with HCC, suggesting that LINC02518 may be a promising prognostic biomarker for HCC.
The lncRNA expression profiles of HCC identified by microarray analysis have been previously reported(17, 18). Zhu et al. performed an lncRNA gene expression profile analysis in 3 pairs of human HCC and adjacent non-tumor tissues using microarray containing 33,045 lncRNAs and 30,215 coding transcripts and identified 214 lncRNAs and 338 mRNAs abnormally expressed in all three HCC tissues with the genome-wide lncRNAs and mRNAs expression profile analysis(17). Additionally, Xu et al. collected nine microarray expression data sets of mRNAs, miRNAs, and lncRNAs associated with HCC and found that 628 mRNAs, 15 miRNAs, and 49 lncRNAs were differentially expressed using integrative analysis(18). In our study, we analyzed lncRNA expression profiles of 125 HCCs with a custom microarray having a total of 2,412 lncRNA transcripts, which might significantly reduce the confounding factors caused by individual sample differences. Also, the number and probes of lncRNA transcripts in our study were different from those in the above studies; therefore, further integrative analysis is warranted to identify additional lncRNA candidates.
The differential expression of lncRNAs in HCC is correlated with the prognosis of the disease. lncRNAs, such as MVIH, MALAT-1, HULC, lncRNA-ATB, and LINC01128 are present in low amounts in normal liver cells and are upregulated in HCC (14, 19–22). Some lncRNAs are downregulated in HCC samples, such as PSTAR, MT1DP, and DILC (23–25). These lncRNAs may serve as tumor markers for the early diagnosis of HCC. The expression of these lncRNAs was also closely associated with the prognosis of patients with HCC and its clinicopathological features. Li et al. analyzed the correlation between LINC01138 levels and clinicopathological features in 120 HCC and adjacent non-cancerous tissues; LINC01138 is overexpressed in 53.3% of the HCC samples and its expression is positively correlated with tumor size, AFP levels, and hepatitis B surface antigen (HBsAg) levels (14). High LINC01138 levels are associated with poor OS in HCC patients (14). Previous studies have shown that some lncRNAs are downregulated in HCC tissues, such as p53-stabilizing and activating RNA (PSTAR) (23). PSTAR helps accumulate and transactivate p53; low levels of PSTAR predict poor OS and RFS in patients with HCC, especially those with wild-type p53 (23). In this study, LINC02518 expression was significantly upregulated in HCC samples as compared with that of adjacent non-cancerous tissues; LINC02518 expression was also correlated with tumor size, TNM staging, and BCLC staging. HCC patients with high LINC02518 levels resulted in lower RFS, MFS, and OS than those with low LINC02518 expression.
LncRNAs regulate gene expression at various levels, including chromatin modification, transcription, and posttranscriptional processing (26). Firstly, the interaction between lncRNAs and proteins modulate protein activity and localization. Secondly, lncRNAs could be processed into small, single- or double-stranded RNAs that could act as endo-siRNAs targeting other RNAs, leading to target degradation. LncRNAs can act as an “miRNA sponge” and sequester miRNAs to inactivate small regulatory RNAs that influence the expression of miRNA target genes. Furthermore, lncRNAs regulate transcription via recruiting transcription factors to their target gene promoters, thereby activating gene expression. However, they can also inhibit the binding of general transcription factors, potentially by forming RNA-DNA-triplexes. Finally, lncRNAs contribute to transcriptome complexity, as they can regulate alternative splicing of pre-mRNAs. The balance between transcriptionally active euchromatin and silent heterochromatin is controlled by lncRNAs. They can interact with chromatin remodeling complexes and induce local or global changes in chromatin packaging (26). However, the mechanism underlying the role of LINC02518 in HCC remains unclear. Previous studies have found that lncRNA localizes to the cytoplasm, suggesting a possible function as a competitive endogenous RNA acting as a molecular sponge for miRNAs. For example, lncRNA HOXD-AS1 is a competitive endogenous RNA that facilitates liver cancer metastasis by regulating SOX4 (27) and lncRNA MCM3AP-AS1 promotes the growth of HCC by targeting the miR-194-5p/FOXA1 axis (28). In this study, LINC02518 primarily localized to the cytoplasm, indicating a function as an “miRNA sponge” that sequesters miRNAs to inactivate small regulatory RNAs. However, the mechanisms underlying the role of LINC02518 as a competitive endogenous RNA need to be explored.
In conclusion, this study demonstrates that LINC02518 expression is negatively correlated with HCC prognosis. The discovery of LINC02518, a promising prognostic indicator, provides insight into hepatic carcinogenesis and may facilitate the development of approaches for cancer screening and treatment. Therefore, decreasing the expression of LINC02518 might be an effective approach for suppressing the development, metastasis, and prognosis of HCC. However, our study had a limited sample size. Thus, studies with a large sample size need to be performed for a more comprehensive understanding of the clinical potential of our findings.