Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment

Murphy, Anthony; Li, Alex H; Li, Peichao; Sun, Hong

doi:10.3389/fonc.2022.868664

Cited by 32 publications

(23 citation statements)

References 104 publications

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“…As a result of abnormal spliceosomes or splicing factors, aberrant splicing can drive the development and progression of cancer, as shown in a review by Murphy [ 116 ].…”

Section: Resultsmentioning

confidence: 99%

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

et al. 2022

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Male breast cancers are uncommon, as men account for less than 1 percent of all breast carcinomas. Among the predisposing risk factors for male breast cancer, the following appear to be significant: (a) breast/chest radiation exposure, (b) estrogen use, diseases associated with hyper-estrogenism, such as cirrhosis or Klinefelter syndrome, and (c) family health history. Furthermore, there are clear familial tendencies, with a higher incidence among men who have a large number of female relatives with breast cancer and (d) major inheritance susceptibility. Moreover, in families with BRCA mutations, there is an increased risk of male breast cancer, although the risk appears to be greater with inherited BRCA2 mutations than with inherited BRCA1 mutations. Due to diagnostic delays, male breast cancer is more likely to present at an advanced stage. A core biopsy or a fine needle aspiration must be performed to confirm suspicious findings. Infiltrating ductal cancer is the most prevalent form of male breast cancer, while invasive lobular carcinoma is extremely uncommon. Male breast cancer is almost always positive for hormone receptors. A worse prognosis is associated with a more advanced stage at diagnosis for men with breast cancer. Randomized controlled trials which recruit both female and male patients should be developed in order to gain more consistent data on the optimal clinical approach.

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“…As a result of abnormal spliceosomes or splicing factors, aberrant splicing can drive the development and progression of cancer, as shown in a review by Murphy [ 116 ].…”

Section: Resultsmentioning

confidence: 99%

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

et al. 2022

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“…Spliceosome disorders are closely related to the development and progression of cancer. Small molecule inhibitors and other novel therapies that target spliceosomes or their cofactors could become new options for cancer treatment [ 16 , 17 ]. The molecules B/D1/D2/D3/E/F/G are the core Sm proteins that make up splice snRNPs and have a significant role in the development of cancer, according to previous research [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Significance of Spliceosome-Related Genes in the Prediction of Prognosis and Treatment Strategies for Lung Adenocarcinoma

Yang

Huang

Fan

et al. 2022

BioMed Research International

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Background. The leading cause of cancer-related fatalities globally is lung cancer; lung adenocarcinoma (LUAD) is the most common histological type in it. The spliceosome plays an important role in a majority of malignancies. However, it is yet unclear how spliceosome-related genes affect patients with LUAD in terms of treatment course and prognosis. Methods. Spliceosome-related genes were assessed from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database to obtain clinical information and gene expression in patients with LUAD. A spliceosome-related gene signature and prognostic model were constructed by using the least absolute shrinkage and selection operator (LASSO), time-dependent receiver operating characteristic (ROC), and nomogram. Immune infiltrate levels, mutation analysis, and pathway enrichment were predicted potential mechanisms of the signature by using single-sample gene set enrichment analysis (ssGSEA), Gene Set Cancer Analysis (GSCA) database, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) database. Then, a protein–protein interaction (PPI) network and transcription factor- (TF-) hub gene and drug mining network were also established by Cytoscape software. Results. Firstly, we constructed a prognostic model for 11 spliceosome signature genes. Based on the prognostic risk score, we stratified patients with LUAD into high- and low-risk groups. The high- and low-risk groups were closely related to the OS, tumor immune infiltration level, immune checkpoint molecules, and tumor mutation burden (TMB) of LUAD patients. Based on PPI networks, we also predict relevant TF genes that may regulate signature prognostic genes. Finally, drugs including oxaliplatin, arsenic trioxide, cisplatin, and sunitinib were excavated for the treatment of the 11 spliceosome signature genes in LUAD patients. Conclusion. In conclusion, this study is the first to explore the importance of spliceosome-related genes in the prognosis and treatment of LUAD. Through our study, we have innovatively provided potential prognosis genes and new therapeutic drug targets for the treatment of LUAD patients.

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“…AS plays essential roles in cell differentiation and organ development t [ 2 ]. Generally, five basic modes of AS are classified: alternative 5′ splice site (A5SS), skipped exon (SE), mutually exclusive exons (MXE), retained intron (RI), and alternative 3′ splice site (A3SS) [ 3 ]. AS dynamically changes during aging, and aberrant AS events have been observed in numerous diseases including cancer through providing malignant protein isoforms [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Distinct microglia alternative splicing in Alzheimer's disease

Tan

Xie

et al. 2022

Aging

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Numerous alternative splicing (AS) events have been documented in Alzheimer's disease (AD). However, cell type-specific AS analysis is still lacking. We described AS events in the hippocampal microglia sorted by CD45 and CD11b from Aβ precursor protein (APP) and non-transgenic (Ntg) mice. GSE171195 dataset was downloaded from GEO database, aligned to GRCm39 genome. Skipped exon (SE), alternative 3'SS (A3SS), retained intron (RI), alternative 5'SS (A5SS), and mutually exclusive exons (MXE) were evaluated using rMATS and maser. Differential expressed genes or transcripts were analyzed via limma. Gene ontology and correlation analyses were performed with clusterProfiler and ggcorrplot R packages. 36,340 raw counts of AS were identified, and 95 significant AS events were eventually selected with strict criteria: (1) average coverage >5; (2) delta percent spliced in >0.1. SE was the most common AS events (68.42%), followed by A3SS and RI. Autophagy genes were mainly spliced in SE events, actin depolymerization genes spliced in A3SS events, while synaptic plasticity related genes were mainly spliced in RI pattern. These significant AS events may be regulated by dysregulated splicing factors in AD. In conclusion, we revealed microglia specific AS events in AD, and our study provides novel pathological mechanisms in the pathogenesis of AD.

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Therapeutic Targeting of Alternative Splicing: A New Frontier in Cancer Treatment

Cited by 32 publications

References 104 publications

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

Significance of Spliceosome-Related Genes in the Prediction of Prognosis and Treatment Strategies for Lung Adenocarcinoma

Distinct microglia alternative splicing in Alzheimer's disease

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