The emerging roles of long noncoding RNAs in lymphatic vascular development and disease

Abstract

Recent advances in RNA sequencing technologies helped uncover what was once uncharted territory in the human genome-the complex and versatile world of long noncoding RNAs (lncRNAs). Previously thought of as merely transcriptional "noise", lncRNAs have now emerged as essential regulators of gene expression networks controlling development, homeostasis and disease progression. The regulatory functions of lncRNAs are broad and diverse, and the underlying molecular mechanisms are highly variable, acting at the transcriptional, post-transcriptional, translational, and post-translational levels. In recent years, evidence has accumulated to support the important role of lncRNAs in the development and functioning of the lymphatic vasculature and associated pathological processes such as tumor-induced lymphangiogenesis and cancer metastasis. In this review, we summarize the current knowledge on the role of lncRNAs in regulating the key genes and pathways involved in lymphatic vascular development and disease. Furthermore, we discuss the potential of lncRNAs as novel therapeutic targets and outline possible strategies for the development of lncRNA-based therapeutics to treat diseases of the lymphatic system.

Keywords: Gene regulation; Long non-coding RNA; Lymph node metastasis (LNM); Lymphatic endothelial cells (LECs); Lymphatic vessels; Lymphatics; Regulation of gene expression; lncRNA.

Fig. 1

Representative lncRNA-mediated transcriptional and epigenetic mechanisms regulating the expression of the lymphangiogenic growth factor VEGF-C. a In the nucleus of bladder cancer cells, lncRNA BLACAT2 interacts with the core subunit WDR5 of the histone H3 lysine 4 (H3K4) methyltransferase complex and guides it to the VEGF-C promoter by forming a RNA–DNA triplex with the promoter sequence. The promoter H3K4 trimethylation (H3K4me3) by the catalytic subunit MLL (mixed lineage leukemia) of the methyltransferase complex drives epigenetic activation of VEGF-C transcription, which leads to the activation of the VEGF-C signaling pathway, thereby inducing tumor lymphangiogenesis and lymphatic metastasis. Based on He et al. [102]. b In triple-negative breast cancer cells, the nuclear pool of lncRNA HUMT activates FOXK1 transcription by recruiting the Y-box transcription factor YBX1 to the FOXK1 promoter. YBX1 is a known inhibitor of the histone methyltransferase activity of the polycomb repressive complex 2 (PRC2). Therefore, the YBX1-mediated inhibition of H3K27 trimethylation (H3K27me3) at the FOXK1 promoter may further contribute to the activation of FOXK1 transcription. FOXK1 subsequently activates the expression of the hypoxia-inducible transcription factor HIF-1a, which in turn activates the expression of VEGF-C. Based on Zheng et al. [134]

Fig. 2

Examples of cytoplasmic mechanisms by which lncRNAs regulate key molecular players involved in lymphangiogenesis. a MicroRNA sponging. (i) miR-181a binds to the 3′-UTR of the PROX1 mRNA inducing translational repression and mRNA decay. (ii) The lncRNA ANRIL functions as a decoy to sponge miR-181a away from PROX1 mRNA, derepressing its translation. The increased translation of PROX1 leads to the activation of genes that promote lymphangiogenesis, thereby accelerating diabetic wound healing. Based on He et al. [167]. b Regulation of mRNA stability. The natural antisense lncRNA FOXC2-AS1 forms an RNA-RNA duplex with the FOXC2 mRNA, stabilizing it and protecting it from RNase-mediated cleavage. The resulting aberrant increase in FOXC2 translation promotes EMT and tumor metastasis. In a non-cancer context, the same mechanism might regulate lymphatic valve formation and collecting lymphatic vessel specialization. Based on Zhang et al. [208] and Missaglia et al. [216]. eIF4F eukaryotic initiation factor 4F, m7G methyl-7-guanosine (cap), miRISC microRNA-induced silencing complex, ORF open reading frame, PABP poly(A)-binding protein

Fig. 3

Representative mechanism of intercellular communication between cancer cells and lymphatic endothelial cells (LECs) mediated by exosomal lncRNA. The lncRNA LNMAT2, which is overexpressed in bladder cancer cells, contains the exo-motif GGAG recognized by the RNA binding protein HNRNPA2B1. The interaction with HNRNPA2B1 facilitates LNMAT2 sorting into exosomes, which are formed during endosome maturation through inward membrane budding of multivesicular bodies (MVBs). The exosomes are secreted out of cancer cells and subsequently internalized by LECs. Upon entering LECs, the exosomes dissociate and their cargo translocates into the nucleus, where LNMAT2 forms a DNA-RNA triplex with the PROX1 promoter. The LNMAT2-tethered HNRNPA2B1 activates PROX1 transcription by increasing the levels of H3K4 trimethylation (H3K4me3) in the promoter region. The epigenetically induced overexpression of PROX1 results in aberrant transcriptional reprogramming, which promotes tumor lymphangiogenesis and LN metastasis. Based on Chen et al. [180]