Exploring the enigma: history, present, and future of long non-coding RNAs in cancer

Abstract

Long noncoding RNAs (lncRNAs), which are more than 200 nucleotides in length and do not encode proteins, play crucial roles in governing gene expression at both the transcriptional and posttranscriptional levels. These molecules demonstrate specific expression patterns in various tissues and developmental stages, suggesting their involvement in numerous developmental processes and diseases, notably cancer. Despite their widespread acknowledgment and the growing enthusiasm surrounding their potential as diagnostic and prognostic biomarkers, the precise mechanisms through which lncRNAs function remain inadequately understood. A few lncRNAs have been studied in depth, providing valuable insights into their biological activities and suggesting emerging functional themes and mechanistic models. However, the extent to which the mammalian genome is transcribed into functional noncoding transcripts is still a matter of debate. This review synthesizes our current understanding of lncRNA biogenesis, their genomic contexts, and their multifaceted roles in tumorigenesis, highlighting their potential in cancer-targeted therapy. By exploring historical perspectives alongside recent breakthroughs, we aim to illuminate the diverse roles of lncRNA and reflect on the broader implications of their study for understanding genome evolution and function, as well as for advancing clinical applications.

Keywords: Biogenesis; Gene expression; Genomic location; LncRNA; Regulatory mechanisms.

Fig. 1

Timeline of key discoveries in lncRNA research from 1980 to 2022

Fig. 2

Functional mechanisms of lncRNA A In response to diverse stimuli, lncRNA regulates signaling pathways by binding to transcription factors. B Acting as miRNA sponges, lncRNA inhibits mRNA degradation. C Serving as scaffolds, lncRNA aids in forming protein complexes, thereby regulating target gene transcription. D LncRNA also guides ribonucleoprotein complexes to specific DNA sequences, influencing gene expression

Fig. 3

Processes governing the formation of lncRNAs and their positional categorizations based on genomic location concerning nearby protein-coding genes include bidirectional, intergenic, antisense, antisense intronic, sense intronic, enhancer, and sense-overlapping classifications

Fig. 4

Regulation and classification of lncRNA. A The figure’s lower left section illustrates the transcriptional regulation mechanisms of lncRNA. It shows basal transcriptional activation ‘Part 1’, and its enhancement during inflammatory responses ‘Part 2’ triggered by the activation of pattern recognition receptors (PRR). It presents three lncRNA gene examples, labeled A, B, and C. ‘Part 3’ demonstrates the co-transcriptional regulation of lncRNA through differential isoform expression, which can involve alternative splicing or the employment of novel transcription start sites in response to inflammatory stimuli like lipopolysaccharides (LPS). The representation of post-transcriptional regulation of lncRNAs is categorized into three segments: 4, 5, and 6. Following transcription, lncRNAs undergo diverse processes. In ‘Part 4,’ RNA modifications are depicted, influencing the structural configuration of the lncRNA molecule. These modifications can be reversible, contingent upon the cellular inflammatory condition. ‘Part 5’ delineates the transformation of lncRNA into mature miRNA during miRNA biogenesis. ‘Part 6’ signifies the potential translation of lncRNAs containing small open reading frames (smORFs). B The lower right section of the figure illustrates the regulatory roles of lncRNAs within the nucleus and cytoplasm. It indicates that during transcription, both basal ‘Part 1’ and inflammatory ‘Part 2’ lncRNAs can either suppress (mRNA genes A and C) or enhance (mRNA genes A and B) gene expression

Fig. 5

LncRNA as biomarkers and therapeutic agents in human oncology. A contemporary overview of lncRNA with potential as clinical biomarkers (outermost layer) and/or as targets for therapy (represented by syringe symbols directed at the diagram), linked to various cancer forms