Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

Porazinski, Sean; Ladomery, Michael

doi:10.3390/genes9030161

Cited by 17 publications

(12 citation statements)

References 140 publications

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“…Through the in-depth genomic and functional studies, AS abnormalities and generated specific subtypes have been identified as driving factors of tumors (Oltean and Bates, 2014;Todaro et al, 2014). Furthermore, AS events involving oncogenic processes have been reported, including angiogenesis, metastasis, proliferation, apoptosis, and invasion (David and Manley, 2010;Porazinski and Ladomery, 2018). Notably, AS events are mainly regulated by splicing factors (SFs), whose mutations (Salton et al, 2015) or changes in expression may cause AS abnormalities (Shilo et al, 2014;Sveen et al, 2016) and activation of oncogenes and tumorigenic pathways (Shilo et al, 2014;Koh et al, 2015;Salton et al, 2015;Dvinge et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value and Potential Role of Alternative mRNA Splicing Events in Cervical Cancer

et al. 2020

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Background: Increasing evidence suggests that aberrant alternative splicing (AS) events are associated with progression of cancer. This study evaluated the prognostic value and clarify the role of AS events in cervical cancer (CC). Methods: Based on RNA-seq AS event data and clinical information of CC patients in The Cancer Genome Atlas (TCGA) database, we sought to identify prognosisrelated AS events in this setting. We selected several survival-associated AS events to construct a prognostic predictor for CC through the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. Moreover, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses were performed on genes with prognosis-related AS events and constructed an AS-splicing factors (SFs) regulatory network. Results: 2770 AS events were significantly correlated with overall survival (OS). The area under the curve (AUC) values of receiver-operator characteristic curve (ROC) for the final prognostic predictor were 0.926, 0.946 and 0.902 at 3, 5, and 10 years, respectively. These values indicated efficiency in prognostic risk stratification for patients with CC. The final prognostic predictor was an independent predictor of OS (HR: 1.24; 95% CI: 1.020-1.504; P < 0.05). The AS-SFs correlation network may reveal an underlying regulatory mechanism of AS events. Conclusion: AS events are essential participants in the prognosis of CC and hold great potentials for the prognostic stratification and development of treatment strategy.

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Section: Introductionmentioning

confidence: 99%

Prognostic Value and Potential Role of Alternative mRNA Splicing Events in Cervical Cancer

et al. 2020

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“…Besides being decisive in the regulation of cell differentiation and cell-type-specific functions, abnormal variations in AS are also indispensable in multiple pathological processes, including cancers [ [7] , [8] , [9] ]. Accumulated evidence highlights the multifaceted AS events in several carcinogenesis hallmarks, including sustaining proliferative signaling, evading growth suppressors, angiogenesis, invasion, and metastasis [ 10 ]. More importantly, new trends in cancer research show that AS has emerging clinical potential in cancer therapy [ 5 , [11] , [12] , [13] ].…”

Section: Introductionmentioning

confidence: 99%

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Gastrointestinal Pan-Adenocarcinomas

Lin

et al. 2018

EBioMedicine

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BackgroundGastrointestinal pan-adenocarcinomas, which mainly include adenocarcinomas of the esophagus, stomach, colon, and rectum, place a heavy burden on society owing to their poor prognoses. Since aberrant alternative splicing (AS) are starting to be considered as efficacious signatures for tumor prognosis predicting and therapeutic targets, systematic analysis of AS events is urgent.MethodsPrognosis-related AS events were selected by using univariate COX regression analysis. Gene functional enrichment analysis revealed the pathways enriched by prognosis-related AS. Then, prognostic signatures based on AS events were developed for prognosis prediction. Potential mechanism to regulate splicing events by splicing factors was analyzed via Pearson correlation and regulatory networks were constructed.FindingsA total of 967, 918, 674, and 406 AS events were identified as prognosis-related AS events in esophagus, stomach, colon, and rectum adenocarcinomas, respectively. Survival-associated AS events were distinguishing in the four subtypes of adenocarcinoma. Furthermore, computational algorithm results indicated that perturbation of ribosome and ubiquitin-mediated proteolysis pathways were the potential molecular mechanisms corresponding to inferior prognoses. Most notably, several prognostic signatures based on AS events displayed moderate performance in prognosis predicting. The area under curve values of the time-dependent receiver operating characteristic were 0.961, 0.871, 0.870, and 0.890 in esophagus, stomach, colon, and rectum adenocarcinomas. Survival-associated splicing factors were submitted to construct the AS regulatory network, which could be an underlying mechanism of AS events.InterpretationAS may could be ideal indiactors in the prognosis of gastrointestinal pan-adenocarcinomas. Exploring interesting splicing regulatory networks is conducive to solve the puzzles of AS.

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“…Aberrant AS is involved in the development process of cancer [23][24][25]. TCGA RNA sequencing data and TCGA SpliceSeq data have enabled investigation of AS patterns in many different kinds of cancers, such as breast cancer (28), ovarian cancer [29].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, AS is not crucial for normal physiological processes such as hematopoiesis [19], brain development [20] and skeletal muscle function [21], but also for multiple pathological states, including tumorigenesis [22]. Aberrant AS is involved in many oncogenic processes, including uncontrolled cell proliferation, evading growth suppressors, invasion and metastasis, angiogenesis and immune escape [23][24][25]. More importantly, dysregulation of AS is a fundamental process in cancer and research shows that AS has emerging potential therapeutic targets and biomarkers in cancer therapy [16,22,26].…”

Section: Introductionmentioning

confidence: 99%

Systematic Profiling of Survival-Associated Alternative Splicing Events in Adrenocortical Carcinoma

Xia¹,

Wan²,

Yang³

et al. 2020

Preprint

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Background: Aberrant alternative splicing (AS) is involved in many oncogenic processes and systematic analysis of survival-associated aberrant AS events has been reported in many cancers. This study aims to systematic profiling the AS signature in Adrenocortical carcinoma (ACC).Methods: Data of ACC were downloaded from TCGA and TCGA SpliceSeq. Clinical information and AS events data were integrated with the same TCGA ID. Then, we performed univariate Cox analysis to identify survival-related AS events. Lasso regression and multivariate Cox analysis were used to establish prognostic model. In addition, several bioinformatics analyses were conducted to identify pathways enriched by genes of survival-associated AS events and construct splicing-factor-regulated network.Results: A total of 77 patients with complete clinical information and PSI values of AS events were included in the present study. We detected 3781 AS events in 2366 genes were associated with overall survival of ACC patients. All the predictive models showed efficiency in distinguishing good and poor outcomes of ACC patients. All the AUCs of predictive models were greater than 0.7. Functional analysis genes with survival-associated AS events suggested that the POLR2H, TCEB2, PSMA1, PSMD11 and SKP2 ranked at the core. The splicing-factor-regulated network revealed the potential regulatory mechanisms of AS events in ACC.Conclusions: Our systematic profiling of survival-associated AS events in ACC patients provides novel molecular alternations and contributes to decipher the underlying mechanisms of AS in oncogenesis of ACC.

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Alternative Splicing in the Hippo Pathway—Implications for Disease and Potential Therapeutic Targets

Cited by 17 publications

References 140 publications

Prognostic Value and Potential Role of Alternative mRNA Splicing Events in Cervical Cancer

Prognostic Value and Potential Role of Alternative mRNA Splicing Events in Cervical Cancer

Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Gastrointestinal Pan-Adenocarcinomas

Systematic Profiling of Survival-Associated Alternative Splicing Events in Adrenocortical Carcinoma

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