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Alternative splicing and cell survival: from tissue homeostasis to disease.

ABSTRACT: Most human genes encode multiple mRNA variants and protein products through alternative splicing of exons and introns during pre-mRNA processing. In this way, alternative splicing amplifies enormously the coding potential of the human genome and represents a powerful evolutionary resource. Nonetheless, the plasticity of its regulation is prone to errors and defective splicing underlies a large number of inherited and sporadic diseases, including cancer. One key cellular process affected by alternative splicing is the programmed cell death or apoptosis. Many apoptotic genes encode for splice variants having opposite roles in cell survival. This regulation modulates cell and tissue homeostasis and is implicated in both developmental and pathological processes. Furthermore, recent evidence has also unveiled splicing-mediated regulation of genes involved in autophagy, another essential process for tissue homeostasis. In this review, we highlight some of the best-known examples of alternative splicing events involved in cell survival. Emphasis is given to the role of this regulation in human cancer and in the response to chemotherapy, providing examples of how alternative splicing of apoptotic genes can be exploited therapeutically.

SUBMITTER: Paronetto MP

PROVIDER: S-EPMC5136496 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Alternative splicing and cell survival: from tissue homeostasis to disease.

Paronetto Maria Paola MP Passacantilli Ilaria I Sette Claudio C

Cell death and differentiation 20160930 12

Most human genes encode multiple mRNA variants and protein products through alternative splicing of exons and introns during pre-mRNA processing. In this way, alternative splicing amplifies enormously the coding potential of the human genome and represents a powerful evolutionary resource. Nonetheless, the plasticity of its regulation is prone to errors and defective splicing underlies a large number of inherited and sporadic diseases, including cancer. One key cellular process affected by alter ...[more]

PMID: 27689872

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Project description:Purpose: Alternative splicing (AS) is a post-transcriptional process that plays a significant role in enhancing the diversity of transcription and protein. Accumulating evidences have demonstrated that dysregulation of AS is associated with oncogenic processes. However, AS signature specifically in lung squamous cell carcinoma (LUSC) remains unknown. This study aimed to evaluate the prognostic values of AS events in LUSC patients. Methods: The RNA-seq data, AS events data and corresponding clinical information were obtained from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was performed to identify survival-related AS events and survival-related parent genes were subjected to Gene Ontology enrichment analysis and gene network analysis. The least absolute shrinkage and selection operator (LASSO) method and multivariate Cox regression analysis were used to construct prognostic prediction models, and their predictive values were assessed by Kaplan-Meier analysis and receiver operating characteristic (ROC) curves. Then a nomogram was established to predict the survival of LUSC patients. And the interaction network of splicing factors (SFs) and survival-related AS events was constructed by Spearman correlation analysis and visualized by Cytoscape. Results: Totally, 467 LUSC patients were included in this study and 1,991 survival-related AS events within 1,433 genes were identified. SMAD4, FOS, POLR2L, and RNPS1 were the hub genes in the gene interaction network. Eight prognostic prediction models (seven types of AS and all AS) were constructed and all exhibited high efficiency in distinguishing good or poor survival of LUSC patients. The final integrated prediction model including all types of AS events exhibited the best prognostic power with the maximum AUC values of 0.778, 0.816, 0.814 in 1, 3, 5 years ROC curves, respectively. Meanwhile, the nomogram performed well in predicting the 1-, 3-, and 5-year survival of LUSC patients. In addition, the SF-AS regulatory network uncovered a significant correlation between SFs and survival-related AS events. Conclusion: This is the first comprehensive study to analyze the role of AS events in LUSC specifically, which improves our understanding of the prognostic value of survival-related AS events for LUSC. And these survival-related AS events might serve as novel prognostic biomarkers and drug therapeutic targets for LUSC.

Project description:BackgroundBRCA1 is a key protein in cell network, involved in DNA repair pathways and cell cycle. Recently, the ENIGMA consortium has reported a high number of alternative splicing (AS) events at this locus in blood-derived samples. However, BRCA1 splicing pattern in breast tissue samples is unknown. Here, we provide an accurate description of BRCA1 splicing events distribution in breast tissue samples.MethodsBRCA1 splicing events were scanned in 70 breast tumor samples, 4 breast samples from healthy individuals and in 72 blood-derived samples by capillary electrophoresis (capillary EP). Molecular subtype was identified in all tumor samples. Splicing events were considered predominant if their relative expression level was at least the 10% of the full-length reference signal.Results54 BRCA1 AS events were identified, 27 of them were annotated as predominant in at least one sample. Δ5q, Δ13, Δ9, Δ5 and ▼1aA were significantly more frequently annotated as predominant in breast tumor samples than in blood-derived samples. Predominant splicing events were, on average, more frequent in tumor samples than in normal breast tissue samples (P = 0.010). Similarly, likely inactivating splicing events (PTC-NMDs, Non-Coding, Δ5 and Δ18) were more frequently annotated as predominant in tumor than in normal breast samples (P = 0.020), whereas there were no significant differences for other splicing events (No-Fs) frequency distribution between tumor and normal breast samples (P = 0.689).ConclusionsOur results complement recent findings by the ENIGMA consortium, demonstrating that BRCA1 AS, despite its tremendous complexity, is similar in breast and blood samples, with no evidences for tissue specific AS events. Further on, we conclude that somatic inactivation of BRCA1 through spliciogenic mutations is, at best, a rare mechanism in breast carcinogenesis, albeit our data detects an excess of likely inactivating AS events in breast tumor samples.

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Alternative splicing and cell survival: from tissue homeostasis to disease.

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Alternative splicing and cell survival: from tissue homeostasis to disease.

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