Dysregulation of EZH2/CDKN2A/CDKN2B in a ceRNA network promote thyroid carcinoma
Dysregulation of EZH2/CDKN2A/CDKN2B in a ceRNA network promote thyroid carcinoma
Ghazal Khodadoustan,1,*Mohammad Rezaei,2Mansoureh Azadeh,3
1. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran 2. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran 3. Zist Fanavari Novin Biotechnology Institute, Isfahan, Iran
Introduction: Thyroid carcinoma (THCA) represents the most common endocrine
malignancy, among all endocrine carcinomas.The genetic alterations identified in THCA
fail to distinguish tumors with different clinical behaviors, such as extra-thyroidal
extension and lymph node metastasis[1].
In recent decades, miRNAs and lncRNAs have been considered as potent biomarkers
in cancer. Therefore, in this bioinformatics approach, the goal was to discover a
biological network of genes, miRNAs and lncRNAs which have a remarkable impact on
progression of THCA
Methods: Initially, (GSE104005) raw data was achieved from the NCBI Gene
Expression Omnibus(GEO) and analyzed by GEO2R in order to find genes with
significant increase in expression regulation. Further, validation of expression analysis
performed by GEPIA2[2] and ENCORI[3] databases to select differentially expressed
genes (DEGs). In this investigation DEGs with adjusted p-value<0.05 and |logFC| >1.2
were considered significant. EZH2, CDKN2A, and CDKN2B were selected. The
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possible correlation between the selected genes and thyroid carcinoma is reinforced by
GEPIA2. Furthermore, biological pathway involvement are processed Through
Reactome[4] and NRICHR[5] databases. Moreover, STRING[6] and Genecards[7] are
utilized to find significant protein-protein interactions and the exact interaction among
these genes .In addition, selected genes were searched in Mirwalk[8] to find significant
miRNA-mRNA interactions and hsa-miR-4289 is identified a significant mutual miRNA
among these three genes . In addition, with the purpose of finding lncRNAs related to
this network, the miRNA was searched in LncBase V.3[9] and MALAT1 and XIST were
selected as suitable lncRNAs that construct a predictive ceRNA network among them
Results: GEO data analysis by GEO2R indicated, that EZH2 , CDKN2A and CDKN2B
as significantly up-regulated genes in the THCA samples, compared to control (DEGs
with adjusted p-value < 0.05 and |logFC| >1.2 were considered significant).The product
of EZH2 mRNA is Histone-lysine N-methyltransferase EZH2, the Catalytic subunit of the
PRC2/EED-EZH2 complex (PRC2), which methylates 'Lys-9' (H3K9me) and 'Lys- 27'
(H3K27me) of histone H3, leading to transcriptional repression of the affected target
gene. The expression of PRC2 is positively regulated in growing cells and also plays a
crucial role in oxidative stress, caused by oncogenic signaling, through trimethylation of
CDKN2A and CDKN2B loci. Analysis of possible miRNA-mRNA interactions indicated
hsa-miR-4289 is a significant interactor to EZH2 mRNA and also CDKN2B and
CDKN2A mRNAs.Co-expression analysis by ENCORI revealed a conciderable coexpression among hsa-miR-4289 and all those selected mRNAs. This miRNA was then
processed in LncBase v.3 as a result MALAT1 and XIST have strong interactions with
this miRNA.
Conclusion: In conclusion, overexpression of EZH2 along with CDKN2A and CDKN2B
in THCA forms a possible ceRNA network among hsa-miR-4289, MALAT1, and
XIST.This investigation could be suggested novel CeRNA interactions among lncRNA,
mRNA, and miRNA for the candidate diagnostic and prognostic biomarkers associated
with THCA by microarray analysis.