HNF1A: an important transcription factor in gastric cancer
HNF1A: an important transcription factor in gastric cancer
Sadra Salehi-Mazandarani ,1Mohammad Hossein Donyavi,2Parvaneh Nikpour,3,*
1. Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 2. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran 3. Department of Genetics and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
Introduction: Gastric cancer (GC) is one of the most common cause of cancer-related death in the world. Although many studies have dealt with the molecular and cellular mechanisms of GC, it has not been completely understood. Investigation of regulatory molecules such as transcription factors can give us a deeper view of molecular alterations happening in GC. It also can help us to identify new biomarkers and therapeutic targets for this type of cancer. In this study, we performed bioinformatic analyses to reveal important transcription factors as well as signaling pathways and gene ontologies in GC.
Methods: RNAseq data of GC were retrieved from The Cancer Genome Atlas (TCGA) database using TCGAbiolinks package in the RStudio software. Spearman correlation (correlation > 0.6) among the samples was evaluated by TCGAanalyze_Preprocessing function of TCGAbiolinks package. Then data were normalized and not-correlated RNAs were filtered by TCGAanalyze_Normalization and TCGAanalyze_Filtering functions of TCGAbiolinks package, respectively. TCGAanalyze_DEA was utilized to identify differentially expressed RNAs (DERs) according to adjusted p-value < 0.01 and logFC > 2. DERs were annotated by biomaRt package and differentially expressed mRNAs (DEMs) were identified. Transcription factors regulating the DEMs were then predicted by the FunRich software (version 3.1.3). Furthermore, enrichment analyses on the DEMs were performed using Enrichr online database.
Results: RNAseq data from 407 GC samples including 32 paracancerous and 375 cancerous samples were retrieved from the TCGA database. All samples showed high correlation with each other. According to adjusted p-value < 0.01 and logFC > 2, 1836 differentially expressed RNAs between cancerous and paracancerous GC samples were identified. DERs were annotated and 1546 differentially expressed mRNAs including 734 up- and 812 down-regulated mRNAs were extracted. Five predictive transcription factors regulating the DEMs were identified which among them only Hepatocyte Nuclear Factor 1-Alpha (HNF1A) was significantly (p-value < 0.05) correlated with DEMs by regulating 8.2 % of them. Significant KEGG pathways and GO terms relating to the DEMs were then identified. Neuroactive ligand-receptor interaction, fat digestion and absorption, protein digestion and absorption, metabolism of xenobiotics by cytochrome P450 and bile secretion were the most significant KEGG pathways. Besides, epidermis development (GO:0008544), receptor ligand activity (GO:0048018) and cornified envelope (GO:0001533) were the most significant GO terms relating to biological process, molecular function and cellular component, respectively.
Conclusion: In the current study, we identified HNF1A as an important transcription factor in GC which regulates a lot of critical genes. Although various studies have revealed important roles of HNF1A in different cancers, few studies have dealt with its functions in GC. It has been reported that HNF1A induces the expression of HLA Complex Group 18 (HCG18) gene. Then, overexpression of HCG18 by preventing the binding of miR-152-3p to DNAJB12 leads to upregulation of DNAJB12 by which promotes GC. Furthermore, we revealed significant signaling pathways and gene ontologies correlating with GC. Future studies are needed to increase our insight into the cellular and molecular aspects of GC which are modulated by transcription factors.