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Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.

ABSTRACT: Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN.We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population.Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend=0.046), particularly for non-oropharyngeal tumors (Ptrend=0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR=1.29, 95% CI=1.01-1.64; AG/GG vs. AA: adjusted OR=1.30, 95% CI=1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR=0.54, 95% CI=0.34-0.86; TG/GG vs. TT: adjusted OR=0.76, 95% CI=0.61-0.95).Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers.

SUBMITTER: Ma H

PROVIDER: S-EPMC3142535 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.

Ma Hongxia H Wang Li-E LE Liu Zhensheng Z Sturgis Erich M EM Wei Qingyi Q

BMC cancer 20110620

<h4>Background</h4>Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share s ...[more]

PMID: 21689432

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Project description:The authors previously reported that Phospholipase C epsilon 1 (PLCE1) exacerbated esophageal squamous cell carcinoma (ESCC), however, the underlying mechanism remains to be fully elucidated. The present study aimed to identify key differentially expressed genes (DEGs) and signaling pathways regulated by PLCE1 in ESCC. EC9706 and Eca109 cell lines were transfected with the specific small interfering (si) RNA of PLCE1, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting were performed to detect the expression levels of PLCE1, and subsequently, mRNA array and multiple bioinformatics analysis were conducted. RT‑qPCR was used to verify gene expression array results. The findings of the present study indicated that PLCE1 mRNA and protein expression were significantly suppressed (P<0.05) in the PLCE1 siRNA‑transfected cells. In addition, a total of 223 DEGs with >2‑fold alterations were screened between the PLCE1 siRNA‑treated cells, including 168 upregulated and 53 downregulated DEGs. In particular, inflammation or immune‑associated molecules, including Toll‑like receptor (TLR)‑4 interleukin‑6, ‑8 and chemokine C‑X‑C motif ligand 2 were significantly increased following PLCE1 knockdown. Furthermore, Gene Ontology enrichment revealed terms associated with cell proliferation, differentiation, apoptosis, signal transduction, invasion and metastasis, which may potentially be associated with PLCE1 function. Kyoto Encyclopedia of Genes and Genomes pathway analysis demonstrated 46 pathways were disturbed by DEGs, including focal adhesion, mitogen activated protein kinase, TLR, p53 and janus kinase/signal transducer and activator of transcription signaling pathways. The RT‑qPCR results for validation of the selected DEGs were consistent with that of the microarray data. Overall, the results of the multiple bioinformatic analysis contributes to a systematic understanding of the roles of PLCE1 in ESCC.

Project description:Phospholipase C epsilon 1 (PLCE1) and the competing endogenous RNA (ceRNA) network are crucial for tumorigenesis and the progression of esophageal squamous cell carcinoma (ESCC). However, whether PLCE1 can regulate the ceRNA network in ESCC has not been clarified. In the present study, we aimed to identify the PLCE1‑regulated ceRNA network and further elucidate the regulatory mechanisms by which ESCC is promoted. Microarray analysis was used to identify differentially expressed lncRNAs (DELs) and differentially expressed genes (DEGs) from three pairs of samples of PLCE‑silenced Eca109 and control Eca109 cells. Next, the ceRNA regulatory network was established and visualized in Cytoscape, and functional enrichment analysis was performed to analyze DEGs from ceRNAs. Protein‑protein interaction (PPI) networks among the DEGs were established by the STRING database to screen hub genes. Kaplan‑Meier survival analysis was used to validate hub genes. Finally, PLCE1‑related hub gene/lncRNA/miRNA axes were also constructed based on the ceRNA network. A total of 105 DELs and 346 DEGs were found to be dysregulated in the microarray data (|log2FC| >1.5, adjusted P<0.05). We constructed a PLCE1‑regulated ceRNA network that incorporated 12 lncRNAs, 43 miRNAs, and 169 mRNAs. Functional enrichment analysis indicated that the DEGs might be associated with ESCC onset and development. A PPI network was established, and 9 hub genes [WD and tetratricopeptide repeats 1 (WDTC1), heat shock protein family A (Hsp70) member 5 (HSPA5), N‑ethylmaleimide sensitive factor, vesicle fusing ATPase (NSF), fibroblast growth factor 2 (FGF2), cyclin dependent kinase inhibitor 1A (CDKN1A or P21), bone morphogenetic protein 2 (BMP2), complement C3 (C3), GM2 ganglioside activator (GM2A) and discs large MAGUK scaffold protein 4 (DLG4)] were determined from the network. Kaplan‑Meier survival analysis validated four hub genes (BMP2, CDKN1A, GM2A, and DLG4) that were treated as prognostic factors. Ultimately, hub gene/lncRNA/miRNA subnetworks were obtained based on the 4 hub genes, 13 DEmiRNAs, and 10 DELs. In conclusion, the PLCE1‑regulated ceRNA contributes to the onset and progression of ESCC and the underlying molecular mechanisms may provide insights into personalized prognosis and new therapies for ESCC patients.

Dataset Information

Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.

Publications

Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck.

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