Role of the bHLH transcription factor TCF21 in development and tumorigenesis

Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.

New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells

OBJECTIVES: Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors. METHODS: We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting. RESULTS: Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively. CONCLUSIONS: Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors.

The effects of TCF21 genes on radiation and chemotherapy sensitivity of A549 lung adenocarcinoma cells / 重庆医学

Objective To investigate the transcription factor 21 (transcription factor 21 ,TCF21) gene on human lung cancer A549 cells sensitivity to chemotherapy .Methods Using lentivirus technology in A549 lung cancer cells highly expressed genes TCF21 ,fluorescence quantitative PCR ,Western Blot analysis were used to analyse the expression of the target gene ,MTT assay was used to detect the effect of TCF21 lung adenocarcinoma A549 cells on cisplatin (cis‐Dichlorodiamineplatinum ,DDP) chemosen‐sitivity ,and colony assay was used to detect the effect of overexpression of TCF21 lung adenocarcinoma A549 cells on radiosensitiv‐ity .Results After 72 h ,with the increasing concentration of DDP (0 ,0 .625 ,1 .250 ,2 .500 ,5 .000 ,10 .000 mg/L) ,corresponding in‐hibition rates in each group increased ,and the inhibition rate of the high expression group was significantly higher in empty vector group and untransfected group (P<0 .05) ,no significant difference between the two then;overexpression TCF21 group with drug concentration and time and increase the rate of high expression inhibition corresponding increase (P<0 .05) ;after receiving X radi‐ation ,non‐transfected group ,untransfected plus radiotherapy group ,vector group ,vector plus radiotherapy group ,high expression and high expression + radiotherapy colony formation rates were:95 .17% ± 2 .85% ,88 .20% ± 2 .03% ,93 .80% ± 4 .17% , 85 .60% ± 2 .42% ,71 .67% ± 3 .21% ,56 .00% ± 2 .65% .Conclusion TCF21 gene expression can significantly enhance the sensitiv‐ity to radiotherapy and chemotherapy DDP A549 lung cancer cells .

Effect of TCF21 on A549 human lung cancer cells in nude mice / 实用医学杂志

Objective To investigate the effect of TCF21 on human non-small cell lung cancer A549 cells , and to reveal the role of TCF21 in the development of NSCLC. Methods Overexpression of TCF21 in NSCLC A549 cells was mediated by lentivirus vector. TCF21 protein expression was identified by Western blotting assay. The experimental group, negative control group and the blank control group were set up. A549 cells were subcuta-neously seeded in BALB/c nude mice on the left armpit. Results TCF21 was successful overexpressed in the ex-perimental group. Compared with the negative control group and the blank control group , the tumor growth was slow, and the final tumor volume was significantly reduced in the experimental group. Conclusion Overexpression of TCF21 can inhibit the tumor growth of NSCLC in nude mice , indicating that TCF21 may play an important role in NSCLC development.

POD-1/Tcf21 overexpression reduces endogenous SF-1 and StAR expression in rat adrenal cells

During gonad and adrenal development, the POD-1/capsulin/TCF21transcription factor negatively regulates SF-1/NR5A1expression, with higher SF-1 levels being associated with increased adrenal cell proliferation and tumorigenesis. In adrenocortical tumor cells, POD-1 binds to the SF-1 E-box promoter region, decreasing SF-1 expression. However, the modulation of SF-1 expression by POD-1 has not previously been described in normal adrenal cells. Here, we analyzed the basal expression of Pod-1 and Sf-1 in primary cultures of glomerulosa (G) and fasciculata/reticularis (F/R) cells isolated from male Sprague-Dawley rats, and investigated whether POD-1 overexpression modulates the expression of endogenous Sf-1 and its target genes in these cells. POD-1 overexpression, following the transfection of pCMVMycPod-1, significantly decreased the endogenous levels of Sf-1 mRNA and protein in F/R cells, but not in G cells, and also decreased the expression of the SF-1 target StAR in F/R cells. In G cells overexpressing POD-1, no modulation of the expression of SF-1 targets, StAR and CYP11B2, was observed. Our data showing that G and F/R cells respond differently to ectopic POD-1 expression emphasize the functional differences between the outer and inner zones of the adrenal cortex, and support the hypothesis that SF-1 is regulated by POD-1/Tcf21 in normal adrenocortical cells lacking the alterations in cellular physiology found in tumor cells.