Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk

Abstract

Objective Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. Methods We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. Results The results indicated that SNP rs7128029 A<G was significantly associated with an increased risk of endometrial cancer (odds ratio=1.384; 95% confidence interval=1.038–1.964). Moreover, the carcinogenic effect of SNP rs7128029 A<G was consistently revealed by propensity matching analysis, an additive model, and a dominant model. Importantly, sQTL analysis showed that SNP rs7128029 could affect the transcriptional modification of PSMD13 via regulating the exon skipping of PSMD13 . When the rs7128029 allele was mutated from A to G, the expression of exon 2 of PSMD13 was markedly lower (p<0.001). Furthermore, compared with participants who had higher PSMD13 expression, those who had lower PSMD13 expression had shorter survival times. Conclusion These findings suggest that SNP rs7128029-mediated alternative splicing events in PSMD13 are associated with endometrial cancer risk and may be a potential early screening biomarker for endometrial cancer-susceptible populations.

An Analysis Regarding the Association Between Proteasome (PSM) and Hepatocellular Carcinoma (HCC)

“…Based on the few studies on the association of PSMD13 with tumors, selective splicing events mediated by single nucleotide polymorphism (SNP) rs7128029 in PSMD13 have been identified to be associated with endometrial cancer risk. 61 Based on a holistic bioinformatics approach, PSMD family members are now hypothesized to be possible prognostic biomarkers for breast and bladder cancer progression and to be promising therapeutic targets. 62 , 63 …”

“…Based on the few studies on the association of PSMD13 with tumors, selective splicing events mediated by single nucleotide polymorphism (SNP) rs7128029 in PSMD13 have been identified to be associated with endometrial cancer risk. 61 Based on a holistic bioinformatics approach, PSMD family members are now hypothesized to be possible prognostic biomarkers for breast and bladder cancer progression and to be promising therapeutic targets. 62,63 Past attention to cancer research has focused on cancer cells, and over time, cancer has been recognized as an evolutionary and ecological process involving continuous, dynamic and interactive interactions between cancerous and mesenchymal components.…”

The Long Non-Coding RNA ANRIL in Cancers

“…SNPs may also disrupt the interaction between splicing factors (such as SR or hnRNPs) and regulatory elements (Exonic Splicing Enhancer ESE, Exonic Splicing Silencer ESS, Intronic Splicing Silencer ISS and Intronic Splicing Enhancer ISE) within ANRIL. This may lead to a similar effect observed for PSMD13, where the presence of the SNP rs7128029 affects its splicing pattern, leading to the exclusion of an exon in EC [ 222 ]. If so, the heterogeneity of ANRIL isoforms observed in pathological situations may be attributed to the presence of peculiar SNPs.…”