In 2005, Inagaki et al. reported for the first time that a large number of mRNA-like long non-coding RNAs were expressed in a tissue- and cell-specific manner in model species. In 2008, Mercer et al. used in situ hybridization to identify the expression of a large number of long non-coding RNAs in mouse brain tissues, and confirmed that the expression levels of these long non-coding RNAs were related to specific neuroanatomical locations, cell types, and subcellular locations. After 2010, as the academic community continued to heat up its research on IncRNA, the level of related basic research has advanced by leaps and bounds, and has gradually begun to shift from academia to industry. However, due to the short history of lncRNA research, lncRNA drug development is still in its early stages.
Advantages And Challenges of IncRNA Therapy
Long non-coding RNA (lncRNA) is a non-coding RNA with a length greater than 200 nucleotides. It and small non-coding RNA with a nucleotide count of ≤200 together form non-coding RNA (ncRNA). lncRNA is widely involved in various physiological regulatory processes. It is a key regulatory factor in the process of gene expression regulation and a key molecule that determines species differences and disease development. Therefore, in theory, the study of IncRNA provides new targets and treatment options for clinical treatment of diseases.
Because it can easily bind to homologous DNA sequences, homologous RNA sequences and proteins, it has the following major advantages compared to other therapies:
- IncRNA combines the advantages of small molecule drugs, protein drugs and gene drugs, and can target all molecules such as DNA, RNA and protein.
- Because extracellular, cell membrane or intracellular molecules can be potential targets of lncRNA drugs, lncRNA is not limited by target location.
- The difference between normal and abnormal tissues is most significant. For example, the difference in lncRNA expression between tumor tissue and normal tissue can reach dozens of times or even higher, far exceeding that of protein.
- The size of lncRNA is between mRNA and small nucleic acid and can be modified. lncRNA has low immunogenicity and good stability, and has relatively low requirements for the conservation of target sequences.
Due to its large size, lncRNA is extremely difficult to screen and identify. Compared with technologies such as mRNA, it also has some challenges:
- Low expression: lncRNA expression levels are usually low, which makes lncRNA difficult to detect and annotate, especially when using non-specific sequencing technologies.
- Complex relationship between sequence and function: Unlike protein-coding genes, the functions of lncRNAs cannot always be directly inferred from their sequences, which makes the understanding of lncRNA functions more complicated.
- Diverse subcellular localization: lncRNAs can be expressed inside and outside the nucleus and have different molecular functions. For example, lncRNAs in the nucleus may regulate transcription, while lncRNAs in the cytoplasm may be associated with post-transcriptional functions. This diverse subcellular localization increases the difficulty of predicting their functions.
- Lack of clear functional elements: lncRNAs may contain functional elements (such as protein binding sites, miRNA binding sites, and DNA binding sites), but the availability and stability of these functional elements are affected by the low expression and rapid evolution of lncRNAs.
In any case, lncRNA has become the third emerging type of nucleic acid drugs after mRNA and small nucleic acid drugs. With more and more research progress on lncRNA and various human diseases, the research on lncRNA in the fields of tumors, immune diseases and metabolic diseases has achieved initial results and is expected to expand to broader fields in the future.
LncRNA And Tumors
In recent years, more and more mechanisms of action of IncRNA in tumors have been gradually analyzed, and the relationship with tumor treatment has become more in-depth.
- Participating in the occurrence and development of tumors: Studies have found that lncRNA can play a mediating role in the occurrence and development of tumors. For example, oncogenes RAS and MYC can participate in the occurrence and development of tumors through lncRNA Orilnc1 and DANCR, respectively.
- Participating in tumor invasion and metastasis: A variety of lncRNAs have been shown to regulate the invasion and metastasis of tumor cells. For example, in non-small cell lung cancer, lncRNA XIST can promote TGF-beta-induced EMT by regulating miR-367/141-ZEB2.
- As a biomarker: lncRNA is secreted outside the cell in the form of exosomes. lncRNA in body fluids has the potential to be a biomarker, indicating the progression and malignancy of tumors. At the same time, it can provide therapeutic targets to guide personalized treatment.
- Solving chemotherapy resistance: The differential expression of lncRNA is one of the main factors leading to differences in clinical efficacy of the same treatment for patients. In the future, it is expected that lncRNA can be used to control the consistency of efficacy.
From the current research, the main research directions of IncRNA and tumors are concentrated in relatively high-incidence areas such as prostate cancer, lung cancer, colorectal cancer, and hepatocellular carcinoma, where the mechanism is relatively clear.
LncRNA And Immune Inflammation
In recent years, the key role of IncRNA in the pathogenesis of rheumatoid arthritis (RA) has been discovered. IncRNA can also be used as a clinical diagnosis basis or new target for treatment of RA. For example, a research team led by Katherine A. Fitzgerald of the University of Massachusetts Medical School confirmed that a long non-coding RNA lincRNA-EPS acts as a transcription brake to limit inflammation. This provides an important reference for the study of immune diseases such as rheumatoid arthritis.
The main mechanisms between IncRNA and rheumatoid arthritis are as follows:
- IncRNA can regulate FLS proliferation, migration and invasion: fibroblast-like synoviocytes (FLS) are the main cell population of synovial cells in RA patients. They are activated in a chronic inflammatory environment and have certain characteristics similar to tumor cells, and CAIF can inhibit the apoptosis of FLS in RA by promoting the maturation of miR-20a.
- IncRNA affects the secretion and expression of pro-inflammatory cytokines: CASC2 is an oncogenic IncRNA found in different types of cancer in recent years. Its expression is downregulated in the plasma of RA patients, which indicates that this IncRNA may be involved in the pathogenesis of RA.
- IncRNA can regulate RA cartilage proliferation and apoptosis: Studies have found that GAS5 overexpression inhibits chondrocyte proliferation, reduces Bcl-2 protein expression, and increases Bax protein expression.
LncRNA And Metabolism
Obesity is a multifactorial disease that is part of today's epidemic and also increases the risk of other metabolic diseases. Long noncoding RNAs (lncRNAs) provide a layer of regulatory mechanisms to maintain metabolic homeostasis. Although the vast majority of studies on lncRNAs focus on tumors, immune inflammation and other fields, there is increasing evidence that lncRNAs are closely linked to obesity, making technology platforms such as Haya also show great potential in the field of obesity treatment.
In the article published by Adv Sci in May 2024 on "Long noncoding RNA Obr promotes lipid metabolism through epigenetic regulation", a developmentally regulated lncRNA called Obr was identified, whose expression in metabolism-related tissues (such as skeletal muscle, liver and pancreas) is altered in diet-induced obesity. Obr binds to cAMP response element binding protein (Creb) and activates different transcription factors involved in lipid metabolism. Its binding to the Creb histone acetyltransferase complex (including cAMP response element binding protein (CBP) and p300) positively regulates the transcription of genes involved in lipid metabolism.
In the future, innovative therapies to change patients' obesity may evolve towards the genetic level, and it may also be possible to control obesity by targeting leptin-related pathways.
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Reference
Fang Y, Fullwood M J. Roles, functions, and mechanisms of long non-coding RNAs in cancer. Genomics, Proteomics and Bioinformatics, 2016, 14(1): 42-54.
Wang J, et al. Exosome-transported lncRNA H19 regulates insulin-like growth factor-1 via the H19/let-7a/insulin-like growth factor-1 receptor axis in ischemic stroke. Neural Regeneration Research, 2023, 18(6): 1316-1320.