Non-Coding RNAs as Key Regulators in Lung Cancer

Abstract

For several decades, most lung cancer investigations have focused on the search for mutations in candidate genes; however, in the last decade, due to the fact that most of the human genome is occupied by sequences that do not code for proteins, much attention has been paid to non-coding RNAs (ncRNAs) that perform regulatory functions. In this review, we principally focused on recent studies of the function, regulatory mechanisms, and therapeutic potential of ncRNAs including microRNA (miRNA), long ncRNA (lncRNA), and circular RNA (circRNA) in different types of lung cancer.

Keywords: circRNA; lncRNA; lung cancer; miRNA; non-coding RNA.

Figure 1

Functions of the main ncRNA classes. mRNA—messenger RNA; AGO proteins—Argonaute proteins.

Figure 2

miRNA biogenesis. hnRNPs—heterogeneous nuclear ribonucleoproteins; miRISC—miRNA-induced silencing complex; TRBP—transactivation response element RNA-binding protein. I–II—synthesis of the primary miRNA (pri-miRNA) by polymerase II/III; III—processing of pri-miRNA into miRNA precursor (pre-miRNA); IV—the formation of RISC complex.

Figure 3

Mechanisms of circRNA functioning. (I) One prominent function of circRNAs is their ability to act as molecular sponges for miRNA/RBP, effectively sequestering these molecules away from their mRNA targets. This leads to gene expression alterations. (II) circRNAs can interact with U1 snRNP, facilitating their interaction with transcription complexes at host genes and subsequently inducing transcription of these genes.

Figure 4

Functions of lncRNAs. The essential roles of lncRNAs encompass various biological processes. In the nuclear compartment, lncRNAs are implicated in the regulation of epigenetic mechanisms, transcriptional processes, and splicing operations. Conversely, in the cytoplasmic domain, lncRNAs are involved in maintaining mRNA stability, acting as modulators for small regulatory RNAs, regulating mRNA translation, and exhibiting the potential to generate small peptides.

Figure 5

Schematic map of key NSCLC signaling pathways influenced by ncRNA regulators. Abbreviations: K-ras—protein encoded by the KRAS (Kirsten rat sarcoma viral) gene; PI3K—phosphatidylinositol 3-kinase; PIP3—phosphatidylinositol-3,4,5-triphosphate; PTEN—phosphatase and tensin homolog; PKB/Akt—protein kinase B, also known as Akt; BAD—Bcl-2-antagonist of cell death; EGFR—epidermal growth factor receptor; Grb2—growth factor receptor-bound protein 2; Sos—Son of Sevenless; TSC1/2—tuberous sclerosis complex 1/2; mTOR—mammalian target of rapamycin; AMPK—AMP-activated protein kinase; LKB1—liver kinase B1; EML4—echinoderm microtubule-associated protein-like 4; JAK—Janus kinase; STAT—signal transducer and activator of transcription.