Abstract
Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC.Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation.Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis.Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.
Highlights
Kidney renal clear cell carcinoma (KIRC) is a malignant cancer originated from renal epitheliums, accounting for about 75% of kidney tumors (Hsieh et al, 2017)
The sequencing data of 537 cases KIRC were downloaded from the the Cancer Genome Atlas (TCGA) database, with the median overall survival of 1,091 days
A total of 6,081 OSASEs from 3,444 parent genes were identified and the UpSet plot revealed that AP was the most common splicing patterns associated with KIRC prognosis (Figure 2B)
Summary
Kidney renal clear cell carcinoma (KIRC) is a malignant cancer originated from renal epitheliums, accounting for about 75% of kidney tumors (Hsieh et al, 2017). Radical nephrectomy is performed for localized renal masses, distant metastasis may be observed in a large proportion of patients at diagnosis, especially metastasis in lung, bone and brain (Gupta et al, 2008) With regard to these advanced KIRCs, the treatment option was limited with only sunitinib widely approved (Porta et al, 2019). Alternative splicing (AS), plays an important role in the maturation of mRNAs from its precursors, leading to diverse mRNA isoforms spliced and protein variants translated (Montes et al, 2019) In this process, splicing factors (SFs) work as regulatory catalyst of alternative splicing events (ASEs) and both build up an intricate regulatory network (Frankiw et al, 2019; Wu et al, 2019). The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC
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