Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma

Kelley, Dylan Z.; Flam, Emily; Guo, Theresa; Danilova, Ludmila; Zamuner, Fernando T.; Bohrson, Craig L.; Considine, Michael; Windsor, Eric; Bishop, Justin A.; Zhang, Chi; Koch, Wayne M.; Sidransky, David; Westra, William H.; Chung, Christine H.; Califano, Joseph A.; Wheelan, Sarah J.; Favorov, Alexander V.; Florea, Liliana; Fertig, Elana J.; Gaykalova, Daria A.

doi:10.1016/j.trsl.2018.07.007

Cited by 10 publications

(8 citation statements)

References 42 publications

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“…According to our results, the CASEs were significantly enriched in GO categories and KEGG pathways that were closely related to HNSC initiation or maintenance. More importantly, two AS events recently validated as functional in HNSC were also identified in our study 61, 63, which further confirms the suitability of RNA-Seq as a method to investigate AS changes in cancer. We also evaluated the 473 CASEs in an independent cohort.…”

Section: Discussionsupporting

confidence: 85%

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Zheng

Wei

et al. 2019

Theranostics

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Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

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Section: Discussionsupporting

confidence: 85%

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Zheng

Wei

et al. 2019

Theranostics

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“…The investigation and clinical application of biomarkers is the key to prognosis assessment, molecular classification, grade determination, recurrence assessment, and early selection of appropriate therapeutics and means. According to the literature, the abnormal splicing level of the GSN gene is remarkably higher in tumor tissues than in para-carcinoma tissues and regulates the proliferation process of the HNSCC cell line (51). Meanwhile, the oncogene DOCK5 variant plays a critical role in the human papilloma virus (HPV)-negative HNSCC and is involved in tumor proliferation, migration, and invasion (52).…”

Section: Discussionmentioning

confidence: 99%

Systemic Analysis of RNA Alternative Splicing Signals Related to the Prognosis for Head and Neck Squamous Cell Carcinoma

Chen

Wei

et al. 2020

Front. Oncol.

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Alternative splicing (AS) is an important mechanism that is responsible for the production of protein diversity. An increasing body of evidence has suggested that out-of-control AS is closely related to the genesis and development of cancer. Systematic analysis of genome-wide AS in head and neck squamous cell carcinoma (HNSCC) has not yet been carried out, and consideration of this topic remains at the preliminary stage and requires further investigation. In this study, systemic bioinformatic analysis was carried out on the genome-wide AS events of 555 clinical HNSCC samples from the TCGA database. Firstly, we statistically analyzed the distributions of seven AS event types in HNSCC samples. Then, through univariate survival analysis, we observed the relationship between AS and the prognosis of the disease and found that 437 intersections of AS events were significantly related to overall survival. Among them, 335 cross-genes showed a high degree of consistency in the genes associated with overall survival and recurrence. The overall survival was significantly related to AS events. Besides, the frequency of overall survival-related ES events was evidently reduced, while the AP and the AT events were increased. In addition, AT events accounted for the largest proportion. Further, multiple regression model analysis proved that AS could become a new classification method for HNSCC, and KEGG enrichment analysis proved that most genes and proteins interacting with AS events had different biological functions and were associated with a variety of diseases. Finally, through the selection of characteristic HNSCC genes and the construction of a prognostic model, seven cross-genes related to survival and recurrence were screened out, and these characteristic genes were verified Li et al.RNA Alternative Splicing Signals in HNSCC by multivariate survival model analysis so as to classify the prognosis at different splicing times and gene expression levels. These results have laid a solid foundation for our further research and play a decisive role in showing the correlation of AS with the prognosis of HNSCC.

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“…In the occurrence and development of HNSCC, epigenetic events play an important role, including DNA methylation, post-translational covalent modification of histones, chromatin remodeling and the effects of non-coding RNA (11)(12)(13)(14). Currently, an increasing number of splicing patterns have been found, such as the splicing variants of laminin subunit α3 (LAMA3), dystonin (DST), dedicator of cytokinesis (DOCK5), lysyl oxidase-like 2 (LOXL2) and gelsolin (GSN), and some studies have shown that these splicing variants can be used as cancer markers and potential therapeutic targets (15)(16)(17)(18). Some of these variants could even become novel antigens for specific targeted therapy of HNSCC, such as the splicing variant of GSN, which was reported to be able to serve as a biomarker of HNSCC and a neoantigen for HNSCC treatment (18).…”

Section: Introductionmentioning

confidence: 99%

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

Zhong¹,

Chen

et al. 2020

Oncol Lett

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Approximately 500,000 new head and neck squamous cell carcinoma (HNSCC) cases are detected every year around the world, and its incidence ranks sixth among all cancer types globally. Among these cases, oral squamous cell carcinoma (OSCC) and laryngeal squamous cell carcinoma (LSCC) are HNSCC subtypes with high incidence rates, especially in China. The present study examines the association between the apolipoprotein L1 (APOL1) mRNA and protein expression and clinical parameters in HNSCC. The two most common types (oral and larynx) of HNSCC were selected for subgroup analyses. Immunohistochemistry (IHC) was used to detect APOL1 protein expression levels in HNSCC clinical specimens. It was demonstrated that APOL1 protein expression in 221 cases of HNSCC was higher compared with that in normal tissues. Consistent upregulation of APOL1 protein was also found in subgroups of OSCC and LSCC. Through mining the ArrayExpress, The Cancer Genome Atlas and the Gene Expression Omnibus databases, microarrays and RNA sequencing data for HNSCC were retrieved, which were used to analyze APOL1 mRNA expression levels. The results showed that APOL1 expression was higher in both OSCC and LSCC subtypes, as well as in HNSCC, compared with that in non-cancerous squamous epithelium. The summary receiver operating characteristic analysis showed that APOL1 had potential as a diagnostic biomarker for HNSCC, OSCC and LSCC. Thus, upregulation of APOL1 may contribute to the tumorigenesis of HNSCC.

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Functional characterization of alternatively spliced GSN in head and neck squamous cell carcinoma

Cited by 10 publications

References 42 publications

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Comprehensive characterization of the alternative splicing landscape in head and neck squamous cell carcinoma reveals novel events associated with tumorigenesis and the immune microenvironment

Systemic Analysis of RNA Alternative Splicing Signals Related to the Prognosis for Head and Neck Squamous Cell Carcinoma

The clinical significance of apolipoprotein L1 in head and neck squamous cell carcinoma

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