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Timeline for FOXP family research history. DLBCL, diffuse large B-cell lymphoma; FOXP1-4, forkhead box P1-4; NFAT, Nuclear factor of activated T-cells; Th17, T helper 17; Treg, T regulatory; nTreg cells, naïve T regulatory cells; NF-kappa B, Nuclear factor kappa B. The numbers in references indicate PMID of PubMed
Source publication
Though Forkhead box P (FOXP) transcription factors comprising of FOXP1, FOXP2, FOXP3 and FOXP4 are involved in the embryonic development, immune disorders and cancer progression, the underlying function of FOXP3 targeting CD4 + CD25+ regulatory T (Treg) cells and the dual roles of FOXP proteins as an oncogene or a tumor suppressor are unclear and c...
Context in source publication
Context 1
... back on research history of FOXP family, as first discovery of FOXP family, Godfrey et al. [41] suggested that T lymphocytes mediate scurfy lesions in abnormal thymic environment in 1991, since regulatory T cell-deficient scurfy mice induce severe autoimmune disorders, leading to death (Fig. 2) [45] identified and characterized FOXP1 and FOXP2 in the lungs of mice. Also, Banham et ...
Similar publications
T regulatory cells (Tregs) suppressive function can have a detrimental effect on immune responses against tumor cells. Within the Treg cells subset, a new non-classical population has been reported, which express high levels of CD49b molecule and, depending on their activation status, can also express the canonical Tregs transcription factor Foxp3....
Citations
... FOXP2 (7q31), and FOXP3 (Xp11.23). All of subfamily P of the forkhead box are comprised of immune disorders, embryonic maturity, and cancer progression [3]. Those proteins also show multifarious and influential roles in the development and organogenesis for the regulation of metabolism and the immune system [4]. ...
In humans, FOXP gene family is involved in embryonic development and cancer progression. The FOXP4 (Forkhead box protein P4) gene belongs to this FOXP gene family. FOXP4 gene plays a crucial role in oncogenesis. Single nucleotide polymorphisms are biological markers and common determinants of human diseases. Mutations can largely affect the function of the corresponding protein. Therefore, the molecular mechanism of nsSNPs in the FOXP4 gene needs to be elucidated. Initially, the SNPs of the FOXP4 gene were extracted from the dbSNP database and a total of 23124 SNPs was found, where 555 nonsynonymous, 20525 intronic, 1114 noncoding transcript, 334 synonymous were obtained and the rest were unspecified. Then, a series of bioinformatics tools (SIFT, PolyPhen2, SNAP2, PhD SNP, PANTHER, I-Mutant2.0, MUpro, GOR IV, ConSurf, NetSurfP 2.0, HOPE, DynaMut2, GeneMANIA, STRING and Schrodinger) were used to explore the effect of nsSNPs on FOXP4 protein function and structural stability. First, 555 nsSNPs were analyzed using SIFT, of which 57 were found as deleterious. Following, PolyPhen2, SNAP2, PhD SNP and PANTHER analyses, 10 nsSNPs (rs372762294, rs141899153, rs142575732, rs376938850, rs367607523, rs112517943, rs140387832, rs373949416, rs373949416 and rs376160648) were common and observed as deleterious, damaging and diseases associated. Following that, using I-Mutant2.0 and MUpro servers, 7 nsSNPs were found to be the most unstable. GOR IV predicted that these seven nsSNPs affect protein structure by altering the protein contents of alpha helixes, extended strands, and random coils. Following DynaMut2, 5 nsSNPs showed a decrease in the ΔΔG value compared with the wild-type and were found to be responsible for destabilizing the corresponding protein. GeneMANIA and STRING network revealed interaction of FOXP4 with other genes. Finally, molecular dynamics simulation analysis revealed consistent fluctuation in RMSD and RMSF values, Rg and hydrogen bonds in the mutant proteins compared with WT, which might alter the functional and structural stability of the corresponding protein. As a result, the aforementioned integrated comprehensive bioinformatic analyses provide insight into how various nsSNPs of the FOXP4 gene change the structural and functional properties of the corresponding protein, potentially proceeding with the pathophysiology of human diseases.
... Ovarian cancer, a malignancy that poses a substantial threat to women globally, remains a formidable challenge in oncology. Despite constituting only 2.5% of all female malignancies, ovarian cancer contributes to 5% of cancer-related fatalities among women, highlighting its grave impact [1,2]. The majority of ovarian cancer cases are diagnosed at advanced stages, typically afflicting older individuals, resulting in dismal survival rates. ...
Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4’s function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.
... FOXP1, a member of the forkhead box protein family, is widely expressed in human tissues and plays a role in embryonic development, immune regulation, and cancer progression [28,29]. Functionally, FOXP1 acts as a tumor suppressor in some solid tumors but also plays oncogenic roles, particularly in hematological malignancies [30]. ...
Background
Forkhead-box protein P1 (FOXP1) has been proposed to have both oncogenic and tumor-suppressive properties, depending on tumor heterogeneity. However, the role of FOXP1 in intrahepatic cholangiocarcinoma (ICC) has not been previously reported.
Methods
Immunohistochemistry was performed to detect FOXP1 expression in ICC and normal liver tissues. The relationship between FOXP1 levels and the clinicopathological characteristics of patients with ICC was evaluated. Finally, in vitro and in vivo experiments were conducted to examine the regulatory role of FOXP1 in ICC cells.
Results
FOXP1 was significantly downregulated in the ICC compared to their peritumoral tissues (p < 0.01). The positive rates of FOXP1 were significantly lower in patients with poor differentiation, lymph node metastasis, invasion into surrounding organs, and advanced stages (p < 0.05). Notably, patients with FOXP1 positivity had better outcomes (overall survival) than those with FOXP1 negativity (p < 0.05), as revealed by Kaplan–Meier survival analysis. Moreover, Cox multivariate analysis showed that negative FOXP1 expression, advanced TNM stages, invasion, and lymph node metastasis were independent prognostic risk factors in patients with ICC. Lastly, overexpression of FOXP1 inhibited the proliferation, migration, and invasion of ICC cells and promoted apoptosis, whereas knockdown of FOXP1 had the opposite role.
Conclusion
Our findings suggest that FOXP1 may serve as a novel outcome predictor for ICC as well as a tumor suppressor that may contribute to cancer treatment.
... The FOXP family of proteins are multifunctional transcription factors. They act as both tumor suppressors and oncogenes depending on the neoplasm (18). Two aspects of FOXP1 make it a potential target for PE pathogenesis. ...
... First, FOXP1 expression is associated with fibrosis and stromal cell proliferation in endometriosis which is important as stromal cells are the main reason of polyp formation. Second, its organ specific function on cell proliferation is demonstrated in different neoplasms (7,18,19). In our study, OE cases showed results in line with the first the aspect of FOXP1. ...
... FOXP subfamily is involved in cancer progression and embryonic development through interacting with noncoding RNAs and signaling pathways [83,140]. They are one of the main effectors in PI3K/AKT pathway (Fig. 3). ...
Gynecological and breast tumors are one of the main causes of cancer-related mortalities among women. Despite recent advances in diagnostic and therapeutic methods, tumor relapse is observed in a high percentage of these patients due to the treatment failure. Late diagnosis in advanced tumor stages is one of the main reasons for the treatment failure and recurrence in these tumors. Therefore, it is necessary to assess the molecular mechanisms involved in progression of these tumors to introduce the efficient early diagnostic markers. Fokhead Box (FOX) is a family of transcription factors with a key role in regulation of a wide variety of cellular mechanisms. Deregulation of FOX proteins has been observed in different cancers. MicroRNAs (miRNAs) as a group of non-coding RNAs have important roles in post-transcriptional regulation of the genes involved in cellular mechanisms. They are also the non-invasive diagnostic markers due to their high stability in body fluids. Considering the importance of FOX proteins in the progression of breast and gynecological tumors, we investigated the role of miRNAs in regulation of the FOX proteins in these tumors. MicroRNAs were mainly involved in progression of these tumors through FOXM, FOXP, and FOXO. The present review paves the way to suggest a non-invasive diagnostic panel marker based on the miRNAs/FOX axis in breast and gynecological cancers.
... Interestingly, these three proteins have potential implications for cervical cancer. For example, FOXP proteins regulate the transcription of differentiation and immune system-related genes and have been implicated in angiogenesis and tumorigenesis [36]. VPS4B belongs to the AAA (ATPase associated with diverse cellular activities) protein family and functions during the endosomal sorting and lysosomal degradation of membrane proteins. ...
Early diagnosis and therapeutic targeting are continuing challenges for gynecological cancers. Here, we focus on cancer transcriptomes and describe the differential expression of 3′UTR isoforms in patients using an algorithm to detect differential poly(A) site usage. We find primarily 3′UTR shortening cases in cervical cancers compared with the normal cervix. We show differential expression of alternate 3′-end isoforms of FOXP1, VPS4B, and OGT in HPV16-positive patients who develop high-grade cervical lesions compared with the infected but non-progressing group. In contrast, in ovarian cancers, 3′UTR lengthening is more evident compared with normal ovary tissue. Nevertheless, highly malignant ovarian tumors have unique 3′UTR shortening events (e.g., CHRAC1, SLC16A1, and TOP2A), some of which correlate with upregulated protein levels in tumors. Overall, our study shows isoform level deregulation in gynecological cancers and highlights the complexity of the transcriptome. This transcript diversity could help identify novel cancer genes and provide new possibilities for diagnosis and therapy.
... In contrast to the extensive body of study directed toward FOXP1 transcription and function (recently reviewed by [35]), its protein modification and the effects thereof are largely unknown. In this report, we show that FOXP1 is deacetylated and stabilized by HDAC7 to promote self-renewal of BM MSCs. ...
... As shown by our mass spectral (MS) analysis (Additional file 1: Fig. S1b), an array of amino acids composed of lysine and threonine was detected in acetylated clusters within the conserved leucine zipper (LZ), zinc finger (ZF) and forkhead (Fkh) domains. Recurrent variants within these domains are frequently observed in cohorts of neurodevelopmental disorders [45] as well as in cardiovascular, immunologic and several cases of malignancy [35,46,47], highlighting the susceptibility to mutation within these regions. Of note, there are two residues (T172 and T273) within the N-terminal QRF region, which lie distant, both linearly and three dimensionally [48], from the above "core conserved, " singly acetylated residues. ...
Background
Mesenchymal stem cells (MSCs) are widely used in a variety of tissue regeneration and clinical trials due to their multiple differentiation potency. However, it remains challenging to maintain their replicative capability during in vitro passaging while preventing their premature cellular senescence. Forkhead Box P1 (FOXP1), a FOX family transcription factor, has been revealed to regulate MSC cell fate commitment and self-renewal capacity in our previous study.
Methods
Mass spectra analysis was performed to identify acetylation sites in FOXP1 protein. Single and double knockout mice of FOXP1 and HDAC7 were generated and analyzed with bone marrow MSCs properties. Gene engineering in human embryonic stem cell (hESC)-derived MSCs was obtained to evaluate the impact of FOXP1 key modification on MSC self-renewal potency.
Results
FOXP1 is deacetylated and potentiated by histone deacetylase 7 (HDAC7) in MSCs. FOXP1 and HDAC7 cooperatively sustain bone marrow MSC self-renewal potency while attenuating their cellular senescence. A mutation within human FOXP1 at acetylation site (T176G) homologous to murine FOXP1 T172G profoundly augmented MSC expansion capacity during early passages.
Conclusion
These findings reveal a heretofore unanticipated mechanism by which deacetylation of FOXP1 potentiates self-renewal of MSC and protects them from cellular senescence. Acetylation of FOXP1 residue T172 as a critical modification underlying MSC proliferative capacity. We suggest that in vivo gene editing of FOXP1 may provide a novel avenue for manipulating MSC capability during large-scale expansion in clinical trials.
... As a forkhead transcription factor, FOXP2 is one of the forkhead box family (4). It was implicated in language and speech development in humans and verified to be a tumor suppressor (5,6). FOXP2 inhibits the transcriptional activity through its zinc finger domain, and involved in the occurrence and progression of numerous tumors (7). ...
... We confirmed that FOXP2, as a transcription factor, could negatively regulate the expression of c-MET by binding to its promoter region. It is consistent with the previous study (6). A potential interaction between FOXP2 and c-MET might contribute to DDP-resistance in CC cancer. ...
Background:
The drug resistance of chemotherapeutic agents leads to unsatisfactory survival rates for cervical cancer (CC) patients. We aimed to explore the effect of FOXP2 on the sensitivity of CC cells to cisplatin (DDP) and its mechanism in Changde, China in 2018.
Methods:
A Total of 6 cervical cancer tissue samples including 3 patients with cisplatin sensitivity and 3 patients with cisplatin resistance, who received DDP-based treatment, were obtained from Changde First People's Hospital, Changde City during 2021, and FOXP2 level was detected by Western blot. The expression levels of FOXP2 and c-MET (hepatocyte growth factor receptor, c-MET) in cells were determined by q-PCR and Western blot analysis. The cell survival, apoptosis, and clone formation were analyzed by flow cytometry, MTT assay, or clone formation assay. Dual-luciferase reporter assays and Chromatin immunoprecipitation were applied to verify the regulation between FOXP2 and c-MET.
Results:
FOXP2 was downregulated in cisplatin-resistant cervical cancer tissues and cells compared with control. FOXP2 overexpression in SiHa/DDP cells inhibited cell proliferation and promoted cell apoptosis, whereas down-regulation of FOXP2 in SiHa cells had the opposite result. FOXP2 enhanced chemosensitive to DDP in CC cells. FOXP2 is negatively correlated with c-MET expression level in SiHa and SiHa/DDP cells. Mechanistically, FOXP2 binds to the promoter region of c-MET to regulate its expression in CC cells negatively. Overexpression of c-MET can attenuate the enhancement of DDP-induced apoptosis caused by FOXP2 overexpression.
Conclusion:
This is a novel study on the role of FOXP2 in promoting the DDP sensitivity of CC cells by inhibiting c-MET. The FOXP2/c-MET signaling axis uncovered in the present study may be a novel therapeutic target for the DDP therapy resistance of CC.
... The current study also indicates an association between FOXP4 and depth of invasion, which suggests high FOXP4 expression is a catalyst for the partial invasion and direct spread of CRAC cells to some extent. FOXP4 also regulates intercellular adhesion molecules, decreases homogeneous adhesion, and increases heterogeneous adhesion, which eases tumor cell spread [20,21] along with the degradation of the basement membrane [22,23]. Scholars have identified miR-101-3p and miR-423-5p as upstream regulators of FOXP4 [24] modulating tumor growth. ...
Objectives
Forkhead Box P4 (FOXP4) is a transcription factor that promotes tumor formation and progression. However, studies on its roles in colorectal adenocarcinoma (CRAC) and cell proliferation regulation are few to date. This work investigates the expression of FOXP4 in CRAC, explores the characteristic of FOXP4 in different clinicopathological features, and analyzes its regulation of cell proliferation.
Methods
The GEPIA database was used to predict the trend of FOXP4 expression in colon cancer and normal mucosa. Tumor tissue and normal paracancerous mucosal tissue were sampled from 64 cases diagnosed with CRAC and who were receiving radical surgery at Tianjin Hospital from January 2017 and December 2022. FOXP4 and proliferating cell nuclear antigen (PCNA) were detected by the immunohistochemistry EnVision method. The colon cancer cell lines SW480, HCT15, and SW620 and the normal colon cell line NCM460 were selected, and expression of FOXP4 was detected by the Western blot method. The siRNA-FOXP4 plasmid was synthesized and transfected with SW480 and HCT15 cell lines, respectively, to establish si-FOXP4 groups, and empty vector transfection group (NC-FOXP4) and blank control group (NC) was set up. The expression levels of FOXP4 and PCNA were detected by the Western blot method, while the cell proliferation activity was assessed using CCK-8. Normally distributed quantitative data were compared between two and more groups with ANOVA (SNK-based pairwise comparison), while intergroup enumeration data comparisons were performed through χ ² test and assessed through linear correlation analysis.
Results
GEPIA-based prediction shows a potential rise in FOXP4 expression in colon cancer. The rate of positive FOXP4 expression is significantly higher in CRAC tissue than in normal mucosa (p<0.05). The difference in FOXP4 is statistically significant in the comparison of maximum tumor diameter and depth of invasion in CRAC (p<0.05) but not in the comparison of gender, age, degree of differentiation, tumor focus, tumor embolism, and lymph node metastasis (p>0.05). The expression levels of FOXP4 and PCNA in CRAC are positively correlated (p<0.05). FOXP4 expression is significantly higher in cell lines SW480, HCT15, and SW620 than in cell line NCM460. The cell proliferation activity and PCNA expression are significantly lower in si-FOXP4 group than in NC-FOXP4 and NC groups for cell lines SW480 and HCT15.
Conclusions
FOXP4 is highly expressed and has a proliferative effect on tumor cells in CRAC.
... Wang et al. revealed the differential methylation of PRDM1 to be associated with decreased pulmonary function [37]. Both FOXO3 and FOXP1 belong to the forkhead family of transcription factors and are well-known for their regulatory roles in tumorigenesis [38,39]. Nevertheless, the importance of this family has been recently recognized in pulmonary hypertension [40]. ...
A number of processes and pathways have been reported in the development of Group I pulmonary hypertension (Group I PAH); however, novel biomarkers need to be identified for a better diagnosis and management. We employed a robust rank aggregation (RRA) algorithm to shortlist the key differentially expressed genes (DEGs) between Group I PAH patients and controls. An optimal diagnostic model was obtained by comparing seven machine learning algorithms and was verified in an independent dataset. The functional roles of key DEGs and biomarkers were analyzed using various in silico methods. Finally, the biomarkers and a set of key candidates were experimentally validated using patient samples and a cell line model. A total of 48 key DEGs with preferable diagnostic value were identified. A gradient boosting decision tree algorithm was utilized to build a diagnostic model with three biomarkers, PBRM1, CA1, and TXLNG. An immune-cell infiltration analysis revealed significant differences in the relative abundances of seven immune cells between controls and PAH patients and a correlation with the biomarkers. Experimental validation confirmed the upregulation of the three biomarkers in Group I PAH patients. In conclusion, machine learning and a bioinformatics analysis along with experimental techniques identified PBRM1, CA1, and TXLNG as potential biomarkers for Group I PAH.
