Role of long non-coding RNAs in cancer: From subcellular localization to nanoparticle-mediated targeted regulation

Abstract

Long non-coding RNAs (lncRNAs) are a class of RNA transcripts more than 200 nucleotides in length that play crucial roles in cancer development and progression. With the rapid development of high-throughput sequencing technology, a considerable number of lncRNAs have been identified as novel biomarkers for predicting the prognosis of cancer patients and/or therapeutic targets for cancer therapy. In recent years, increasing evidence has shown that the biological functions and regulatory mechanisms of lncRNAs are closely associated with their subcellular localization. More importantly, based on the important roles of lncRNAs in regulating cancer progression (e.g., growth, therapeutic resistance, and metastasis) and the specific ability of nucleic acids (e.g., siRNA, mRNA, and DNA) to regulate the expression of any target genes, much effort has been exerted recently to develop nanoparticle (NP)-based nucleic acid delivery systems for in vivo regulation of lncRNA expression and cancer therapy. In this review, we introduce the subcellular localization and regulatory mechanisms of various functional lncRNAs in cancer and systemically summarize the recent development of NP-mediated nucleic acid delivery for targeted regulation of lncRNA expression and effective cancer therapy.

Keywords: MT: Non-coding RNAs; cancer therapy; long non-coding RNAs; nanoparticles; nucleic acid delivery; subcellular localization; targeted regulation.

Graphical abstract

Figure 1

Schematic illustration of the way lncRNAs exert biological functions (A) LncRNAs can recruit various proteins to change the organizational pattern of chromatin. (B) LncRNAs can regulate gene transcription via interaction with transcription factors. (C) LncRNAs can modulate mRNA slicing pattern via interaction with splicing factors. (D and E) LncRNAs can regulate the translation and scaffolding of mRNA. (F) LncRNAs can affect miRNA sequestration. (G) LncRNAs can work as precursors for small regulatory RNAs.

Figure 2

Schematic illustration of several functional lncRNAs localized in different subcellular organelles and their regulatory mechanisms In the nucleus, the metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) involves gene transcription regulation by interacting with transcription factors, such as Polycomb 2 (Pc2) protein and TEA domain family member 1 (TEAD) proteins,^, or through combining histone modification enzymes such as zeste homolog 2 (EZH2) and zeste 12 homolog (SUZ12).^,, Xist is also involved in targeting epigenetic regulatory factors, such as enhancer of EZH2, suppressing p21 expression in osteosarcoma. Overexpression of MTA2 transcriptional regulator lncRNA (MTA2TR) in pancreatic cancer patient tissues was associated with a reduction in overall survival in patients. Activating transcription factor 3 (ATF3) is recruited to metastasis-associated protein 2 (MTA2) promoter area by MTA2TR to upregulate MTA2 transcription. Lysosome cell death regulator (lncLCDR) is a cofactor for heterogeneous nuclear ribonucleoprotein K (hnRNP K) to potentiate the stabilization of lysosomal membrane protein lysosomal-associated protein transmembrane (LAPTM5), which prevents lysosomal membrane permeabilization and promotes cancer cell survival. Overexpression of growth arrest-specific transcript 5 (GAS5) could bind to cytoplasmic GRP78 protein (the 78 kDa glucose-regulated protein) to suppress HepG2 cell growth, invasion, and migration via activating the CHOP-dependent endoplasmic reticulum (ER) stress pathway. Long noncoding ribonucleic acid (lncRNA) zinc finger antisense 1 (FAS1) is associated with ribosome synthesis and assembly by interacting with the 40S subunit and modulating the phosphorylation of ribosomal protein RPS6. Survival-associated mitochondrial melanoma-specific oncogenic noncoding RNA (SAMMSON) regulates mitochondrial homeostasis and metabolism by interacting with p32, a key regulator of tumor metabolism. GAS5 increase SIRT3-mediated MDH2 deacetylation to directly block the tricarboxylic acid (TCA) cycle as a tumor suppressor. Lnc-DC interacts with signal transducer and activator of transcription 3 (STAT3) to prevent dephosphorylation of STAT3 by SHP1, a tyrosine phosphatase that can negatively regulate the Jak/STAT signaling pathway, and subsequently modulate T cell responses and differentiation.^, The HOX transcript antisense intergenic RNA (LncRNA HOTAIR) involves the degradation of Runx3 by recruiting runt-related transcription factor 3 (Mex3b), an E3 ubiquitin ligase, to modulate the ubiquitination of Runx3 and promote the invasion of tumor cells in gastric cancer. A nuclear factor κB (NF-κB)-interacting long noncoding RNA (NKILA) is upregulated by NF-κB and inhibits the phosphorylation of inhibitor of NF-κB (IκB) by binding to the motif of NF-κB/IκB. SNHG16 and MALAT1 can act as a ceRNA to regulate mRNA and protein expression in the cytoplasm.^, LINC00152 and LncRNA-H19 were shown to be packaged in exosomes as a biomarker for gastric cancer or to regulate tumor microenvironment.^,

Figure 3

Schematic illustration of different types of NPs for nucleic acid delivery These NPs include lipid-based NPs, polymeric NPs, Bio-inspired NPs, polymeric micelles, and inorganic NPs.

Figure 4

Schematic illustration of folate-modified liposomes for systemic co-delivery of ferroptosis inducer erastin and plasmid encoding lncMT1DP for combination NSCLC therapy. After treatment of E/M@FA-LPs to NSCLC, ROS are highly generated, while GSH is depelted, leading to ferroptosis induction, increasing miR-365a-3p/NRF2 axis to inhibite NRF2 to ultimately decrease tumor growth.

Figure 5

Representative NPs for targeting various intracellular compartments (A) Reduction-responsive NPs for systemic siRNA delivery to silence lncAFAP1-AS1 expression and synergistically reverse TNBC radioresistance. (B) Schematic illustration of liver-targeting NPs made with polymer PuPGEA for systemic co-delivery of plasmids encoding lncMEG3 and P53 for combination HCC therapy. (C) Schematic illustration of nucleus-targeting NPs encapsulating siRNA to specifically downregulate the nucleus-localized lncLCDR expression, and (D) mitochondrion-targeting NPs encapsulating plasmid encoding circRNA SCAR to specifically upregulate the mitochondrion-localized circRNA SCAR expression.

Figure 6

Representative schematic diagrams for lncRNAs as therapeutics (A) Schematic illustration of nucleus-targeting ASO-Au-TAT NPs for MALAT1 silencing and fluorescent images of lung cancer A549 cells treated with the ASO-Au-TAT NPs and subcellular localization of ASO₁₅-Au-TAT_7.5 nanostructures visualized by laser scanning confocal microscopy. (B) Schematic illustration of manganese-based MOFs for systemic co-delivery of siRNA against lncOUM1, siRNA against PTPRZ1, cisplatin, and near-infrared dye ICG for dual-modal imaging and synergistic UM treatment. (C) Schematic illustration of lncPTENP1-containing exosomes for bladder cancer therapy, and (D) cyclic RGD peptide-decorated lncMEG3-containing exosomes for targeted osteosarcoma therapy.