TCF21/POD-1, a Transcritional Regulator of SF-1/NR5A1, as a Potential Prognosis Marker in Adult and Pediatric Adrenocortical Tumors

Abstract

With recent progress in understanding the pathogenesis of adrenocortical tumors (ACTs), identification of molecular markers to predict their prognosis has become possible. Transcription factor 21 (TCF21)/podocyte-expressed 1 (POD1) is a transcriptional regulatory protein expressed in mesenchymal cells at sites of epithelial–mesenchymal transition during the development of different systems. Adult carcinomas express less TCF21 than adenomas, in addition, the KEGG pathway analysis has shown that BUB1B, among others genes, is negatively correlated with TCF21 expression. The difference between BUB1B and PTEN-induced putative kinase 1 (PINK1) expression has been described previously to be associated with survival in adult but not in pediatric carcinomas. Here, we analyzed the gene expression of TCF21, BUB1B, PINK1, and NR5A1 in adult and pediatric ACTs. We found a negative correlation between the relative expression levels of TCF21 and BUB1B in adult ACTs, but the relative expression levels of TCF21, BUB1B, PINK1, and NR5A1 were similar in childhood ACTs. In addition, we propose using the subtracted expression levels of the TCF21/POD-1 genes as a predictor of overall survival (OS) in adult carcinomas and TCF21-NR5A1 as a predictor of malignancy for pediatric tumors in patients aged <5 years. These results require further validation in different cohorts of both adult and pediatric samples. Finally, we observed that the OS for patients aged <5 years was markedly favorable compared with that for patients >5 years as well as adult patients with carcinoma. In summary, we propose TCF21/POD-1 as a new prognostic marker in adult and pediatric ACTs.

Screening Hub Genes as Prognostic Biomarkers of Hepatocellular Carcinoma by Bioinformatics Analysis

“…BUB1B, as a key mitotic spindle checkpoint, plays an important role in the development of many tumors. For example, the Upregulated DTL, CDK1, CCNB1, RACGAP1, ECT2, NEK2, BUB1B, PBK, TOP2A, ASPM, HMMR, RRM2, CDKN3, PRC1, ANLN expression of BUB1B is increased in adrenocortical carcinomas 33 , and BUB1B promotes tumor proliferation and induces radioresistance in glioblastoma 34 . We also identified other hub genes, namely, ANLN, ASPM, CDKN3, DTL, ECT2, HMMR, NEK2, PBK, PRC1, RACGAP1, and TOP2A, all of which encode proteins with high degrees in the PPI network.…”

“…BUB1B, as a key mitotic spindle checkpoint, plays an important role in the development of many tumors. For example, the expression of BUB1B is increased in adrenocortical carcinomas 33 , and BUB1B promotes tumor proliferation and induces radioresistance in glioblastoma 34 .…”

Role of the bHLH transcription factor TCF21 in development and tumorigenesis

“…In 2006, Smith et al (63) described for the first time that the promoter region on human chromosome 6q23-q24 of TCF21 was hypermethylated in non-smallcell lung cancers (NSCLC) and head and neck squamous cell carcinomas. Since then, TCF21 has been studied in other types of human cancers and is considered a tumor suppressor gene in melanomas, renal cancer, adrenocortical carcinomas, colorectal tumors, gastric cancer, and hepatocellular carcinomas (18,(64)(65)(66)(67)(68)(69). In general, the proposition is that TCF21 is downregulated primarily by DNA hypermethylation, rather than genetic mutations, in malignant tumors.…”

“…Adrenocortical carcinoma (ACC) is a rare disease with an incidence of 1 to 2 cases per million ( 83 ). Despite few defined markers for adrenocortical tumors (ACTs), TCF21 is less expressed in ACC than in adenomas (ACA) and normal tissue ( 65 , 66 ). TCF21 binds directly in the E-box promoter sequence of steroidogenic factor 1 (SF1/NR5A1), decreasing SF-1 transcription in both the human ACC cell line (H295R) and in ACC cell culture obtained from patient tumor fragment (ACC-T36).…”

“…However, TCF21 overexpression showed no difference in proliferative capacity in ACC cells ( 65 ). KEGG pathway analysis has shown that BUB1B , among other genes, is negatively correlated with TCF21 expression in ACC ( 66 ). More recently, analysis of the combined expression of TCF21 and BUB1B in adult and pediatric adrenocortical tumors showed a negative correlation between the expression levels of TCF21 and BUB1B in adult ACCs.…”