The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective

Abstract

LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.

Keywords: biomarkers; hallmarks of cancer; hepatocellular carcinoma; long non-coding RNAs; translational research.

Figure 1

Mechanisms of action enabled by lncRNAs in HCC. LncRNAs can work at several levels to impact HCC development and progression. See text for details. LncRNA-linked blue arrows depict activation while red arrows indicate inhibition.

Figure 2

Sankey diagram linking mechanisms of action and hallmarks of cancer of HCC-relevant lncRNAs. LncRNAs selected according to scientific significance, preclinical validation and/or association with relevant clinical parameters have been classified according to their mechanism of action (left) and the cancer hallmark they modulate (right). Note that some lncRNAs have been assigned to several mechanisms of action and/or different cancer hallmarks. LncRNAs downregulated in HCC are shown in blue while those upregulated are in red. The full list of candidates in shown in Table 1.

Figure 3

Degree of in vivo validation of HCC lncRNAs stratified according to hallmarks of cancer. LncRNAs described in Figure 1 and classified according to the hallmarks of cancer they modulate have been stratified in three steps called “levels of evidence” of their clinical relevance. Level 1 requires preclinical validation in model animals and has been done for all cases. Level 2 indicates that lncRNA expression and/or clinical associations have been studied in at least two independent cohorts of patients (n > 50). Level 3 is granted when the expression of the lncRNA has a significant association with overall survival.

Figure 4

Heatmap of clinical associations. LncRNAs (left) with at least two clinical associations have been ordered according to the number of significant associations from top (highest) to bottom (lowest). Clinical associations have been also ordered from left to right. The numbers of lncRNAs per clinical association (top) and the clinical associations per lncRNA (right) are also indicated. Significances (p-values) were extracted from the publications describing each lncRNA and are indicated with a color gradient described to the right of the heatmap.

Figure 5

Sankey diagram of suggested combination therapies. Approved drugs for HCC and their main molecular targets are shown to the left and linked to their main cancer hallmark and the hallmark druggability, including those based on potential lncRNA targeting. The box at the bottom shows ongoing Phase III clinical trials that could also benefit from lncRNA therapy.