Rs۷۸۲۹۳۹۹۸ promotes the hepatocellular carcinoma by disturbing the folding and interaction of CDKN۳ protein: integrated gene expression and proteomics analyses

Hepatocellular carcinoma (HCC) is now one of the most common cancers and the top cause of cancer-relateddeath worldwide. This investigation aimed to find a novel differentially expressed gene (DEG) in the HCCpatients compared to control samples. Expression analysis of GSE۱۲۱۲۴۸ achieved from GEO۲R onlinesoftware and validation of expression analyses performed by GEPIA۲ database. Single nucleotidepolymorphisms (SNPs) of CDKN۳ extracted from dbSNP and identification of deleterious SNPs Broughtout from SIFT and PROVEAN databases. Biophysical validation of deleterious SNPs realized from HOPEsoftware. Based on microarray analysis, CDKN۳ have a significant up-regulation in the HCC samples,compared to control (logFC: ۲.۲۳۷, p-value < ۰.۰۰۰۱). From all of the extracted SNPs on the coding region,SIFT and PROVEAN online software revealed that rs۷۸۲۹۳۹۹۸ is the most significant deleterious SNP inthe protein-coding region CDKN۳. This SNP is the arginine mutation into Isoleucine at the ۷۲nd position ofCDKN۳ protein based on HOPE software. This mutation is located in the Tyrosine-protein phosphatasedomain and can disturb this function of CDKN۳ protein. Based on the biophysical validation of HOPE, themutant residue has less charge and smaller size, which can lead the protein to the loss of main interactions.Furthermore, the mutant residue is more hydrophobic than the wild one, which can result in loss of hydrogenbonds and correct protein folding of CDKN۳. In conclusion, rs۷۸۲۹۳۹۹۸ can promote the HCC developmentby changing the expression level of CDKN۳ while changing the correct folding and protein interactions ofCDKN۳ and miss-regulation of Tyrosine-protein phosphatase activity.

کلیدواژه ها:

Microarray ، Data analysis ، Protein structure ، Single nucleotide variations