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Prognostic Value of Survival-Associated Splicing Factor SNRPA1 Overexpression and its Potential Mechanism in Liver Cancer

Author(s): Mengying Liu, Yueda Lu, Lei Wei, Xiaowo Wang, Yinying Lu, Xiaodong Jia, Shihui Wang, Wenlin An

Background: Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA1) is a Splicing Factor (SF) responsible for the processing of pre-mRNA into mRNA. The expression level of SNRPA1 associated with several cancer types. However, the expression level of SNRPA1 and its role as a splicing factor in hepatocellular carcinoma remain unclear. The purpose of this study was to explore the clinicopathological characteristics and prognostic significance of SNRPA1 mRNA expression level and Percent-Spliced-In (PSI) values in liver cancer.

Methods: A total of 418 RNA−Seq and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. Alternative Splicing (AS) profiles were downloaded from TCGA SpliceSeq. Wilcoxon rank-sum tests were used to compare the expression levels of normal tissues with tumor tissues. The Kruskal Wallis tests were used to analyze the expression difference in grade, stage, and T classification among normal tissues with tumor tissues. The Kaplan-Meier analysis method was used to draw the survival curves. Univariate and multivariate Cox analyses were employed to estimate the prognostic value of SNRPA1. Gene Set Enrichment Analysis (GSEA) was performed to identify the signaling pathways. Then we used univariate and Pearson's correlation tests to analyze the correlation between SFs and Exon Skip (ES) events. Wilcoxon rank-sum tests were applied to analyze the relationships between different spliceosome and cancers. Furthermore, we evaluated the expression levels of SNRPA1 with clinical samples and The Clinical Proteomic Tumor Analysis Consortium (CPTAC) database.

Results: The level of SNRPA1 mRNA expression in liver cancer was significantly up-regulated in tumor tissues compared with normal tissues (p=1.411e−27) in liver cancer and was positively correlated with survival status (p=0.035). In addition, we found that SNRPA1 mRNA expression levels can reflect the prognosis of liver cancer (Hazard Ratio [HR]=1.08, 95% Confidence Interval [CI]: 1.02–1.14, p=0.005). The enriched KEGG pathway by GESA revealed the splice some as the main pathway of SNRPA1. SNRPA1 as a splicing factor could has the correlation with the AS events of SCP2. SNRPA1 exon 6 skip and SCP2 exon 12 skip correlated with many cancer types. Furthermore, PSI values of SNRPA1 and SCP2 positively correlated with survival status (p=3.022e−04 and p=2.932e−03). Finally, SNRPA1 protein expression level was significantly up-regulated in tumor tissues compared with normal tissues (p=3.197e−47) in CPTAC database. Our clinical samples also support the results of TCGA, with a significantly up-regulated in tumor tissues compared with normal tissues (p=0.029).

Conclusions: The expression level of SNRPA1 and the PSI value of SNRPA1 could be the biomarkers of liver cancer. Furthermore, the PSI value of splicing factor SNRPA1 is superior to its mRNA expression level in predicting the prognosis of liver cancer. SNRPA1 plays an important role in tumorigenesis as a splicing factor in hepatocellular carcinoma.

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