Multi-omics analysis reveals RNA splicing alterations and their biological and clinical implications in lung adenocarcinoma

Abstract

Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.

Non-coding RNAs regulate mitochondrial dynamics in the development of gastric cancer

“…ncRNAs can be used not only as potential biological diagnostic indicators but also as therapeutic targets or combined with other therapies to improve their anti-tumor effects. Some studies have shown that RNA-based therapies have good clinical potential because RNA can directly target specific genes and their products ( Lin et al, 2020 ; Wu et al, 2022 ). At present, some RNA-based therapies approved worldwide target specific genes in liver or muscle cells and change gene expression by injecting siRNA or oligonucleotide chains ( Shaw et al, 2022 ).…”

Multi-omics approach to identifying isoform variants as therapeutic targets in cancer patients

“…Alternative splicing is one of the major contributors to protein variation and diversity, which provide cancer cells the cellular plasticity to survive stress ( 123 ). With the availability of CPTAC data, emerging studies are investigating a multi-omics approach for integrated splice variants discovery but are limited to the purpose of disease monitoring and prognosis determination ( 124 , 125 ). Here, our scientific predicate (in this review) is that cancer-specific alternative splicing event is an untapped source of targets for therapeutic intervention, and a complete multi-omics characterization will enable the discovery, validation, and prioritization of the ASE targets.…”

Ferroptosis in lung cancer: dual role, multi-level regulation, and new therapeutic strategies

“…In addition, the sponging effect of miRNA molecules is essential for the post-transcriptional regulation of genes, and circSCN8A reduces its level by sponging miR-1290 and promotes ferroptosis, thereby inhibiting NSCLC proliferation and metastasis ( 41 ). Regarding RNA splicing, some articles screened splicing factors related to ferroptosis, such as RBM10 and SRSF2, which can regulate the splicing of ferroptosis-related genes such as TP53 ( 42 ). However, there is a lack of evidence for the role of RNA splicing in the regulation of ferroptosis in lung cancer, and this part of the study needs to be further explored.…”