Noncoding RNAs in cancer therapy resistance and targeted drug development

Abstract

Noncoding RNAs (ncRNAs) represent a large segment of the human transcriptome and have been shown to play important roles in cellular physiology and disease pathogenesis. Increasing evidence on the functional roles of ncRNAs in cancer progression emphasizes the potential of ncRNAs for cancer treatment. Here, we summarize the roles of ncRNAs in disease relapse and resistance to current standard chemotherapy and radiotherapy; the current research progress on ncRNAs for clinical and/or potential translational applications, including the identification of ncRNAs as therapeutic targets; therapeutic approaches for ncRNA targeting; and ncRNA delivery strategies in potential clinical translation. Several ongoing clinical trials of novel RNA-based therapeutics were also emphasized. Finally, we discussed the perspectives and obstacles to different target combinations, delivery strategies, and system designs for ncRNA application. The next approved nucleic acid drug to treat cancer patients may realistically be on the horizon.

Keywords: Chemoresistance; Delivery strategies; Radioresistance; Therapeutic approaches; Translational application; ncRNA.

Fig. 1

The biogenesis of several kinds of ncRNAs. a Most of miRNA genes are transcribed by Pol II and produce greater than 200-nt pre-miRNAs, which contain at least one hairpin structure harboring the miRNA sequence. In the nucleus, the pre-miRNAs are cleaved into approximately 70-nucleotide pre-miRNAs with a stem-loop structure by Drosha, an RNAse III enzyme. The pre-miRNAs are subsequently exported to the cytoplasm and then cleaved by another RNAse III enzyme, Dicer. Finally, the ~ 22 miRNA duplex was loaded into RISC and the mature single-stranded miRNA guides RISC to recognize mRNA targets. b The endogenous siRNA can be derived from shRNA. The transcription of shRNA gene is driven by a U6 or H1 promoter. ShRNA are then cleaved by Dicer to form mature ~ 21 siRNAs that subsequently are loaded into RISC. c LncRNAs are pervasively transcribed in the genome. According to the origins of transcription sites, lncRNAs can be summarized into different types, including enhancer-associated lncRNA, promoter-associated lncRNA, exonic and intronic lncRNA, long intergenic lncRNA, and antisense lncRNA. d Schematic representation of circRNA generation. Most of circRNAs are derived from pre-mRNAs and characteristic of spliceosome-dependent. CircRNA can be classified into various types, including exon circRNA, intron circRNA, and extron-intron circRNA. A novel type circRNA, called read-through circRNA (rt-circRNA), has been identified (marked in dotted line). The rt-circRNA is circularized from read-through transcripts

Fig. 2

NcRNAs in cancer therapy resistance. a The network of miRNA, lncRNA, and circRNA in chemoresistance and the drug resistance pathways. b ncRNAs play a part in cancer radioresistance and concomitantly promote various events in the recurrence and metastasis of malignant tumors, including apoptosis, DNA damage repair, cell cycle checkpoints, autophagy, epithelial–mesenchymal transition, and cancer stem cells

Fig. 3

Schematic illustration of ncRNAs in cancer therapy from delivery to targeting. a ASO sequence searching and hybridization to the cognate site of mRNA and RNase H1 recruitment and cleavage. The schematic illustration of LNA (b) and MO (c) molecules, and their sequence hybridization to the cognate site of mRNA and RNase H1 recruitment and cleavage. d The mature miRNAs incorporated into RISC, then binded with a 6mer to 8mer seed sequence to the 3′UTR of an mRNA molecule, complementarity targeting the mRNA transcript for degradation, and imperfect complementarity inhibiting translation. e SiRNA interacts with RISC and binds to the target mRNA, resulting in the mRNA degradation. f Selective infectivity of the oncolytic virus shows that the delivery vehicle armed shRNA into cancer cells and inserted into DNA. The system can restrict shRNA expression to the cancer microenvironment and is expected to augment antitumor outcomes by siRNA-mediated knockdown of oncogene expression. g Engineering of 20 nucleotides in the sgRNA can be specifically delivered and expressed in cancer cells. The expressed sgRNA combines with Cas9 can recognize the complementary DNA sequence and generate the site-specific genomic double-strand breaks (DSBs)

Fig. 4

Schematic illustration of the delivery strategies of ncRNAs in cancer therapy. a SiRNA, ASOs, saRNA, and miRNA can be encapsulated inside the LNP to be protected from biological conditions and delivered into cancer cells. b SiRNA is chemically conjugated with carriers forming carrier-siRNA conjugates. c SAMiRNA, the siRNAs are modified with lipid and PEG molecules, and then self-assembled lipid nanoparticles. d ShRNA and sgRNA can be delivered by oncolytic adenovirus-mediated strategy and achieve a long-lasting expression of ncRNA in cancer cells.