Background

Following the completion of the Human Genome Project, non-coding RNAs that do not encode proteins were long considered 'junk' RNA. This was because they were perceived as mere transcriptional byproducts with no function within cells. However, with the development of next-generation sequencing (NGS) and transcriptome profiling technologies, it has become increasingly clear that long non-coding RNAs (lncRNAs), which are at least 200 nucleotides in length, are involved in a variety of cellular functions, including gene expression regulation, chromatin remodeling, and post-transcriptional regulation.

Cancer remains a leading cause of death worldwide, and its multifactorial nature means that the causes of its onset and progression are not always clearly understood. While targeted therapies and immune checkpoint inhibitors have been introduced into clinical practice, treatment resistance and recurrence remain unresolved problems. In this context, research has accumulated showing that aberrant expression of lncRNAs is deeply involved in tumor progression and drug resistance, and lncRNAs are being re-evaluated as key regulators of cancer biology.

Key Findings

This review systematically summarizes the various mechanisms by which lncRNAs contribute to cancer treatment resistance. lncRNAs act as oncogenes, regulating signaling pathways related to cell proliferation, metastasis, and angiogenesis, and play a critical role in maintaining cancer stem cells (CSCs). CSCs are a population of cells that are thought to be the source of drug resistance and recurrence, and it has been repeatedly confirmed through gene expression analysis, functional experiments, and animal model studies that overexpression of specific lncRNAs promotes the self-renewal ability and differentiation inhibition of CSCs.

In the diagnostic and prognostic fields, the value of lncRNAs is also highlighted. lncRNAs that can be detected in blood or other bodily fluids are promising non-invasive biomarkers and have the potential to be used for early cancer diagnosis, prognosis prediction, and treatment response monitoring. Compared to existing protein-based biomarkers, they have higher tissue specificity and more pronounced expression changes depending on the stage of the disease.

In terms of therapeutic strategies, several approaches have been described, including antisense oligonucleotides (ASOs), RNA interference (RNAi), exosome-based delivery systems, nanomedicine, virus-mediated therapy, and CRISPR-Cas technology. ASOs and RNAi are strategies that directly inhibit the expression of tumor-promoting lncRNAs, while exosomes and nanoparticles serve as carriers to increase the efficiency of delivery to target cells. CRISPR-Cas can precisely edit specific lncRNA gene loci to permanently block their function, and is attracting attention as the most fundamental intervention method.

Significance and Prospects

lncRNA research has opened a new dimension in understanding the molecular complexity of cancer. It moves beyond the traditional paradigm of protein-encoding genes to show that non-coding transcripts are a key layer that regulates the tumor microenvironment and treatment response.

However, there are still many hurdles to overcome before clinical application. lncRNAs have low sequence conservation between species, making it difficult to directly extrapolate animal model results to humans, and their short half-life in vivo poses challenges for drug delivery. Minimizing off-target effects and conducting large-scale clinical trials are also necessary. Nevertheless, the fact that ASO-based therapies have already been approved by the FDA for other diseases, such as spinal muscular atrophy, suggests that the clinical application of lncRNA-targeted anti-cancer therapies is a realistic possibility.