An emerging role for long non-coding RNAs in cancer metastasis

Abstract

Metastasis is a multistep process beginning with the dissemination of tumor cells from a primary site and leading to secondary tumor development in an anatomically distant location. Although significant progress has been made in understanding the molecular characteristics of metastasis, many questions remain regarding the intracellular mechanisms governing transition through the various metastatic stages. Long non-coding RNAs (lncRNAs) are capable of modulating both transcriptional and post-transcriptional regulation, and thus, coordinating a wide array of diverse cellular processes. Current evidence indicates that lncRNAs may also play a crucial role in the metastatic process through regulation of metastatic signaling cascades as well as interaction with specific metastatic factors. Here we summarize a subset of lncRNAs with proposed roles in metastasis and, when applicable, highlight the mechanism by which they function.

Keywords: cancer; epithelial-mesenchymal-transition; lncRNA; metastasis; non-coding RNA.

FIGURE 1

Genomic organization of the maternal H19 locus. H19, H19 opposite tumor suppressor (HOTS), miR-675, and 91H are expressed from the H19/IGF2 locus. HOTS is a protein coding gene transcribed antisense to H19. H19 is also the host gene for the miR-675, which is a prognostic marker in several cancer types. 91H is a 120-kb nuclear localized H19-antisense transcript, which is overexpressed in breast cancer tissues.

FIGURE 2

Hox antisense intergenic RNA mediated regulation. The recruitment of PRC2 to specific gene sets is mediated by HOTAIR in trans, consequently increasing methylation and inactivation of the targeted genes promoters. Overexpression of HOTAIR causes PRC2 to target an alternative gene set, thus mediating a gene expression profile conducive to metastasis. The mechanism by which HOTAIR overexpression mediates de-repression of some genes is, thus far, unknown.

FIGURE 3

lncRNA-low expression in tumor regulation and function. Under normal conditions, lncRNA-LET is expressed (1), resulting in the degradation of NF90 and low HIF -1α levels (2). Hypoxic conditions and concomitant upregulation of HIF -1α increases levels of HDAC3, mediating deacetylation of the lncRNA-LET promoter (3). This results in decreased expression of lncRNA-LET which, in turn, causes decreased ubiquitination of NF90, and thus accumulation of HIF -1α via a positive-feedback mechanism (4). The recruitment of HDAC3, which results in deacetylation of the lncRNA-LET promoter, is currently unexplored.

FIGURE 4

Colon cancer associated transcript 2. WNT signaling, cumulating in nuclear translocation of β-catenin and interaction with TCFL72 (1), results in the expression of WNT target genes including CCAT2 (2). Chromosomes harboring the CCAT2 rs6983267 GG allele give rise to increased levels of CCAT2 transcript, and downstream targets such as MYC, compared to the TT allele. CCAT2 then exhibits a positive-feedback reinforcing WNT signaling (3). The increased levels of MYC, in turn, leads to elevated levels of its downstream targets (4) including known metastasis mediators, such as miR17HG and miR20a, and promotes an increased metastatic phenotype.

FIGURE 5

Zeb2-NAT. The Zeb2 transcript harbors a ribosome scanning inhibitory sequence (RSIS) in its 5′ UTR, which causes low levels of translation (1). Upon either SNAIL1- or TGF-β-mediated EMT induction, the expression of Zeb2-NAT causes the retention of the Zeb2 transcripts’ 5′ UTR intron by blocking its 5’ splice site (2). An internal ribosome entry sequence (IRES) located in 5′ UTR intron then permits increased ribosomal binding and thus, increased translation of Zeb2 (3).