Strategies to target long non-coding RNAs in cancer treatment: progress and challenges

Abstract

Background: Long non-coding RNAs are important regulators of gene expression and diverse biological processes. Their aberrant expression contributes to a verity of diseases including cancer development and progression, providing them with great potential to be diagnostic and prognostic biomarkers and therapeutic targets. Therefore, they can have a key role in personalized cancer medicine. This review aims at introducing possible strategies to target long ncRNAs therapeutically in cancer. Also, chemical modification of nucleic acid-based therapeutics to improve their pharmacological properties is explained. Then, approaches for the systematic delivery of reagents into the tumor cells or organs are briefly discussed, followed by describing obstacles to the expansion of the therapeutics. Main text: Long ncRNAs function as oncogenes or tumor suppressors, whose activity can modulate all hallmarks of cancer. They are expressed in a very restricted spatial and temporal pattern and can be easily detected in the cells or biological fluids of patients. These properties make them excellent targets for the development of anticancer drugs. Targeting methods aim to attenuate oncogenic lncRNAs or interfere with lncRNA functions to prevent carcinogenesis. Numerous strategies including suppression of oncogenic long ncRNAs, alternation of their epigenetic effects, interfering with their function, restoration of downregulated or lost long ncRNAs, and recruitment of long ncRNAs regulatory elements and expression patterns are recommended for targeting long ncRNAs therapeutically in cancer. These approaches have shown inhibitory effects on malignancy. In this regard, proliferation, migration, and invasion of tumor cells have been inhibited and apoptosis has been induced in different cancer cells in vitro and in vivo. Downregulation of oncogenic long ncRNAs and upregulation of some growth factors (e.g., neurotrophic factor) have been achieved. Conclusions: Targeting long non-coding RNAs therapeutically in cancer and efficient and safe delivery of the reagents have been rarely addressed. Only one clinical trial involving lncRNAs has been reported. Among different technologies, RNAi is the most commonly used and effective tool to target lncRNAs. However, other technologies need to be examined and further research is essential to put lncRNAs into clinical practice.

Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia

“…RNAi has the capacity to theoretically target any oncogenic lncRNA present in AML [36]. Indeed, RNAi has the potential to surpass the major limitations of conventional leukemia therapies including severe off-target toxicity to healthy tissues and peripheral immune cells, a low specificity for cancer cells, and the inability to inhibit non-druggable targets, such as lncRNAs.…”

Long non-coding RNAs in breast cancer metastasis

“…There are few techniques are developed to reduce the expression of oncogenic lncRNAs. Among them, ASOs, double-stranded RNAi especially siRNAs and shRNAs, genome engineering tools are major approaches to target lncRNAs [ 108 ]. ASOs are single-stranded antisense oligonucleotides with a DNA stretch that can reduce the expression of oncogenic lncRNAs by degrading lncRNAs, cleaving endogenous RNaseH1, or regulating RNA–protein interactions [ 109 , 110 ].…”

“…Moreover, nanobodies, aptamers, RNA decoy, lncRNA regulatory elements are some new technologies to target lncRNAs. The role of these techniques to inhibit the expression of lncRNAs is discussed in some recent scientific reports [ 108 , 112 ]. Therefore, lncRNAs can be used as an early diagnostic tool as well as a therapeutic target for breast cancer metastasis.…”

(In)Distinctive Role of Long Non-Coding RNAs in Common and Rare Ovarian Cancers

“…LncRNA expression can also be suppressed using antisense oligonucleotides (ASOs), locked nucleic acid GapmeRs (LNA GapmeRs), or antagonists to natural antisense transcripts (antagoNATs) [267]. ASOs are ss antisense oligonucleotides made up of a DNA stretch at the central part with flanking RNA nucleotides.…”