AUTHOR=Yang Changhong , Chen Jialei , Yu Zhe , Luo Jing , Li Xuemei , Zhou Baoyong , Jiang Ning 

TITLE=Mining of RNA Methylation-Related Genes and Elucidation of Their Molecular Biology in Gallbladder Carcinoma

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.621806

DOI=10.3389/fonc.2021.621806

ISSN=2234-943X

ABSTRACT=<p>Gallbladder carcinoma (GBC), which has high invasion and metastasis risks, remains the most common biliary tract malignancy. Surgical resection for GBC is the only effective treatment, but most patients miss the opportunity for curative surgery because of a lack of timely diagnosis. The aim of this study was to identify and verify early candidate diagnostic and prognostic RNA methylation related genes for GBC <italic>via</italic> integrated transcriptome bioinformatics analysis. Lists of GBC-related genes and methylation-related genes were collected from public databases to screen differentially expressed genes (DEGs) by using the limma package and the RobustRankAggreg (RRA) package. The core genes were collected with batch effects corrected by the RRA algorithm through protein interaction network analysis, signaling pathway enrichment analysis and gene ranking. Four modules obtained from four public microarray datasets were found to be related to GBC, and <italic>FGA</italic>, <italic>F2</italic>, <italic>HAO1</italic>, <italic>CFH</italic>, <italic>PIPOX</italic>, <italic>ITIH4</italic>, <italic>GNMT</italic>, <italic>MAT1A</italic>, <italic>MTHFD1</italic>, <italic>HPX</italic>, <italic>CTH</italic>, <italic>EPHX2</italic>, <italic>HSD17B6</italic>, <italic>AKR1C4</italic>, <italic>CFHR3</italic>, <italic>ENNP1</italic>, and <italic>NAT2</italic> were revealed to be potential hub genes involved in methylation-related pathways and bile metabolism-related pathways. Among these, <italic>FGA</italic>, <italic>CFH</italic>, <italic>F2</italic>, <italic>HPX</italic>, and <italic>PIPOX</italic> were predicted to be methylated genes in GBC, but <italic>POPIX</italic> had no modification sites for RNA methylation. Furthermore, survival analysis of TCGA (the Cancer Genome Atlas) database showed that six genes among the hub genes, <italic>FGA</italic>, <italic>CFH</italic>, <italic>ENPP1</italic>, <italic>CFHR3</italic>, <italic>ITIH4</italic>, and <italic>NAT2</italic>, were highly expressed and significantly correlated with worse prognosis. Gene correlation analysis revealed that the <italic>FGA</italic> was positively correlated with the <italic>ENPP1</italic>, <italic>NAT2</italic>, and <italic>CFHR3</italic>, while <italic>CFH</italic> was positively correlated with the <italic>NAT2</italic>, <italic>CFHR3</italic>, and <italic>FGA</italic>. In addition, the results of immunohistochemistry (IHC) showed that the expressions of FGA, F2, CFH, PIPOX, ITIH4, GNMT, MAT1A, MTHFD1, HPX, CFHR3, NAT2, and ENPP1 were higher in GBC tissues than that in control tissues. In conclusion, two genes, <italic>FGA</italic> and <italic>CFH</italic>, were identified as RNA methylation-related genes also involved in bile metabolism in GBC, which may be novel biomarkers to early diagnose and evaluate prognosis for GBC.</p>