Identification of key genes and pathways associated with cholangiocarcinoma development based on weighted gene correlation network analysis

Abstract

BackgroundAs the most frequently occurred tumor in biliary tract, cholangiocarcinoma (CCA) is mainly characterized by its late diagnosis and poor outcome. It is therefore urgent to identify specific genes and pathways associated with its progression and prognosis.Materials and MethodsThe differentially expressed genes in The Cancer Genome Atlas were analyzed to build the co-expression network by Weighted gene co-expression network analysis (WGCNA). Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted for the selected genes. Module–clinical trait relationships were analyzed to explore the association with clinicopathological parameters. Log-rank tests and cox regression were used to identify the prognosis-related genes.ResultsThe most related modules with CCA development were tan module containing 181 genes and salmon module with 148 genes. GO analysis suggested enrichment terms of digestion, hormone transport and secretion, epithelial cell proliferation, signal release, fibroblast activation, response to acid chemical, wnt, Nicotinamide adenine dinucleotide phosphate metabolism. KEGG analysis demonstrated 15 significantly altered pathways including glutathione metabolism, wnt, central carbon metabolism, mTOR, pancreatic secretion, protein digestion, axon guidance, retinol metabolism, insulin secretion, salivary secretion, fat digestion. Key genes of SOX2, KIT, PRSS56, WNT9A, SLC4A4, PRRG4, PANX2, PIR, RASSF8, MFSD4A, INS, RNF39, IL1R2, CST1, and PPP3CA might be potential prognostic markers for CCA, of which RNF39 and PRSS56 also showed significant correlation with clinical stage.DiscussionDifferentially expressed genes and key modules contributing to CCA development were identified by WGCNA. Our results offer novel insights into the characteristics in the etiology, prognosis, and treatment of CCA.

Role of Pirin, an Oxidative Stress Sensor Protein, in Epithelial Carcinogenesis

“…Similar to the aforementioned findings in lung cells [39], Pirin is strictly regulated by NRF2 in pancreas cancer cells [82]. Moreover, high Pirin levels are associated with a reduced survival probability in cholangiocarcinoma patients, suggesting that Pirin is a plausible prognostic biomarker [83].…”

Identification of prognostic factors for intrahepatic cholangiocarcinoma using long non-coding RNAs-associated ceRNA network

“…Additionally, it was also documented that the inhibition of the hedgehog signaling pathway, a potential therapeutic target for human cholangiocarcinoma, attenuated the progression of carcinogenesis in vitro and subsequently increased the necrosis rate of cholangiocarcinoma [ 17 , 18 ]. Retinol metabolism has been less studied in cholangiocarcinoma, but there is literature suggesting that retinol metabolism is a key pathway in the development of cholangiocarcinoma [ 19 ]. Moreover, diabetes is associated with an increased risk of ICC, showing similar etiologies [ 20 – 22 ].…”

“…IGF2 has been elucidated to be associated with retinol metabolism [30]. Furthermore, Liu et al observed that retinol metabolism was implicated in cholangiocarcinoma development [19].…”

Circular RNA hsa_circ_0000700 promotes cell proliferation and migration in Esophageal Squamous Cell Carcinoma by sponging miR-1229

“…The PRRG4 gene can help in the autistic symptoms of WAGR (Wilm's tumor, Aniridia, genitourinary malformations, and mental retardation) syndrome 33 . In addition, Liu et al identified proline rich and Gla domain 4 (PRRG4) as a potential prognostic marker in cholangiocarcinoma (CCA) 34 . Further study revealed that depletion of receptor expressing enhancing protein 5 (REEP5) significantly reduced growth and invasion in lung cancer 35 .…”