FOXP2 was initially characterized as a transcription factor linked to speech and language disorders. Single-cell RNA sequencing reveals that Foxp2 is enriched in the gonadotrope cluster of the pituitary gland and colocalized with the hormones LHB and FSHB in chickens and mice, implying that FOXP2 might be associated with reproduction in vertebrates. Herein, we investigated the roles of foxp2 in reproduction in a Foxp2-deficient zebrafish model. The results indicated that the loss of Foxp2 inhibits courtship behavior in adult male zebrafish. Notably, Foxp2 deficiency disrupts gonad development, leading to retardation of follicle development and a decrease in oocytes in females at the full-growth stage, among other phenotypes. The transcriptome analysis (RNA-seq) also revealed that differentially expressed genes clustered into the estrogen signaling and ovarian steroidogenesis-related signaling pathways. In addition, we found that Foxp2 deficiency could modulate the hypothalamic-pituitary-gonadal axis, especially the regulation of lhb and fshb expression, in zebrafish. In contrast, the injection of human chorionic gonadotropin, a specific LH agonist, partially rescues Foxp2-impaired reproduction in zebrafish, suggesting that Foxp2 plays an important role in the regulation of reproduction via the hypothalamic-pituitary-gonadal axis in zebrafish. Thus, our findings reveal a new role for Foxp2 in the regulation of reproduction in vertebrates.

Following the publication of the above paper, it was drawn to the Editor\'s attention by a concerned reader that the images showing metastatic nodules in the mouse lung in Fig. 4 on p. 735 had apparently previously been published a few years earlier in the following paper: Jia D, Yan M, Wang X, Hao X, Liang L, Liu L, Kong H, He X, Li J and Yao M: Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion. BMC Cancer 10: 364, 2010. Moreover, among the cell migration and invasion assay data shown in Figs. 3B and D, and 6B and 7B, there were a number of overlaps noted among the data panels such that data which were intended to show results obtained under different experimental conditions were likely to have been derived from a smaller number of original sources. Owing to the fact that the contentious data in the above article had already been publihed prior to its submission to Oncology Reports, in addition the other features of concern regarding the data, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 39: 731‑738, 2018; DOI: 10.3892/or.2017.6130].

The Warburg effect is the preference of cancer cells to use glycolysis rather than oxidative phosphorylation to generate energy. Accumulating evidence suggests that aerobic glycolysis is widespread in hepatocellular carcinoma (HCC) and closely related to tumorigenesis. The purpose of this study was to investigate the role and mechanism of forkhead box P2 (FOXP2) in aerobic glycolysis and tumorigenesis in HCC. Here, we found that FOXP2 was lower expressed in HCC tissues and cells than in nontumor tissues and normal hepatocytes. Overexpression of FOXP2 suppressed cell proliferation and invasion of HCC cells and promoted cell apoptosis in vitro, and hindered the growth of mouse xenograft tumors in vivo. Further researches showed that FOXP2 inhibited the Warburg effect in HCC cells. Moreover, we demonstrated that FOXP2 up-regulated the expression of fructose-1, 6-diphosphatase (FBP1), and the inhibitory effect of FOXP2 on glycolysis was dependent on FBP1. Mechanistically, as a transcription factor, FOXP2 negatively regulated the transcription of lysine-specific demethylase 5A (KDM5A), and then blocked KDM5A-induced H3K4me3 demethylation in FBP1 promoter region, thereby promoting the expression of FBP1. Consistently, overexpressing KDM5A or silencing FBP1 effectively reversed the inhibitory effect of FOXP2 on HCC progression. Together, our findings revealed the mechanistic role of the FOXP2/KDM5A/FBP1 axis in glycolysis and malignant progression of HCC cells, providing a potential molecular target for the therapy of HCC.

Identification oncogenes is fundamental to revealing the molecular basis of cancer. Here, we found that FOXP2 is overexpressed in human prostate cancer cells and prostate tumors, but its expression is absent in normal prostate epithelial cells and low in benign prostatic hyperplasia. FOXP2 is a FOX transcription factor family member and tightly associated with vocal development. To date, little is known regarding the link of FOXP2 to prostate cancer. We observed that high FOXP2 expression and frequent amplification are significantly associated with high Gleason score. Ectopic expression of FOXP2 induces malignant transformation of mouse NIH3T3 fibroblasts and human prostate epithelial cell RWPE-1. Conversely, FOXP2 knockdown suppresses the proliferation of prostate cancer cells. Transgenic overexpression of FOXP2 in the mouse prostate causes prostatic intraepithelial neoplasia. Overexpression of FOXP2 aberrantly activates oncogenic MET signaling and inhibition of MET signaling effectively reverts the FOXP2-induced oncogenic phenotype. CUT&Tag assay identified FOXP2-binding sites located in MET and its associated gene HGF. Additionally, the novel recurrent FOXP2-CPED1 fusion identified in prostate tumors results in high expression of truncated FOXP2, which exhibit a similar capacity for malignant transformation. Together, our data indicate that FOXP2 is involved in tumorigenicity of prostate.

Crocin has been reported to have antitumor activity in several tumors including breast cancer. Nevertheless, the mechanism of action of crocin on breast cancer remains unclear. The cytotoxicity of crocin was evaluated by CCK-8 assay. Cell proliferation was assessed using EdU incorporation assay and western blot analysis. Breast cancer-related genes were extracted from GEPIA. miR-122-5p targets were predicted using Targetscan, starbase, and miRDB softwares. Luciferase reporter assay was employed to confirm whether miR-122-5p targeted sprouty2 (SPRY2) and forkhead box P2 (FOXP2). Results showed that crocin exhibited cytotoxicity and suppressed the proliferation in breast cancer cells. miR-122-5p was upregulated in breast cancer tissues and cells. Crocin suppressed miR-122-5p to block the proliferation of breast cancer cells. Seven targets of miR-122-5p were identified in breast cancer. SPRY2 and FOXP2 were selected for further experiments due to their involvement in breast cancer. miR-122-5p targeted SPRY2 and FOXP2 to inhibit their expression. miR-122-5p knockdown restrained breast cancer cell proliferation by targeting SPRY2 and FOXP2. Additionally, crocin increased SPRY2 and FOXP2 expression by inhibiting miR-122-5p expression. Together, our results suggested that crocin inhibited proliferation of breast cancer cells through decreasing miR-122-5p expression and the subsequent increase of SPRY2 and FOXP2 expression.

Vemurafenib (VEM) is a commonly used inhibitor of papillary thyroid cancer (PTC) and melanoma with the BRAFV600E mutation; however, acquired resistance is unavoidable. The present study aimed to identify a potential target to reverse resistance.
A VEM-resistant PTC cell line (B-CPAP/VR) was established by gradually increasing the drug concentration, and a VEM-resistant BRAFV600E melanoma cell line (A375/VR) was also established. RNA sequencing and bioinformatics analyses were conducted to identify dysregulated genes and construct a transcription factor (TF) network. The role of a potential TF, forkhead box P2 (FOXP2), verified by qRT-PCR, was selected for further confirmation.
The two resistant cell lines were tolerant of VEM and displayed higher migration and colony formation abilities (p < 0.05). RNA sequencing identified 9177 dysregulated genes in the resistant cell lines, and a TF network consisting of 13 TFs and 44 target genes was constructed. Alterations in FOXP2 expression were determined to be consistent between the two VEM-resistant cell lines. Finally, silencing FOXP2 resulted in an increase in drug sensitivity and significant suppression of the migration and colony formation abilities of the two resistant cell lines (p < 0.05).
The present study successfully established two VEM-resistant cell lines and identified a potential target for VEM-resistant PTC or melanoma.

UNASSIGNED: The clinical outcomes are not always favorable in certain thyroid cancer patients. The effect of Forkhead-box family on immune cells infiltration and tumor microenvironment in thyroid cancer was explored. The role of FOXP2 in tumor invasion and recurrence was investigated consequently.
UNASSIGNED: TIMER and GEPIA were firstly employed to compare FOXPs expression in normal and cancer tissues from multiple human cancers. The results from database were confirmed by quantitative Real Time-PCR and Western blot in matched thyroid cancer and adjacent normal tissues, in addition to a panel of thyroid cancer cell lines and normal thyroid cell. GEPIA platform was employed to discover the possibility of FOXPs as prognostic indicator. TISIBD and UACLCAN were then employed to estimate the influence of FOXPs on lymph node metastasis and tumor staging. GEPIA analysis was initially employed to analyze correlation of FOXPs and tumor immune infiltrating cells, and TIMER dataset was then included for standardization according to tumor purity.
UNASSIGNED: Different member of FOXPs showed divergence in expression in various cancer tissues. Lower FOXP1, FOXP2 and higher FOXP3, FOXP4 levels could be identified in thyroid cancer tissues when compared with matched normal tissue. There was an inverse correlation between FOXP2, FOXP4 and immune invasion, whereas FOXP1 and FOXP3 were positively correlated. FOXPs showed remarkable correlations with multiply immune cells. More importantly, only FOXP2 showed the significant effect on recurrence and tumor staging.
UNASSIGNED: As immune regulatory factor, the reduction of FOXP2 may affect tumor microenvironments and immune cells infiltration, enhance tumor immune escape, and promote recurrence of thyroid cancer. FOXP2 could be a new potential diagnostic and prognostic marker.

FOXP2, cognitive deficits, and schizophrenia are associated with neurodegenerative pathophyisiology. Mounting evidence suggests that body mass index (BMI) and FOXP2 may contribute to cognitive deficits in schizophrenia. However, the sex difference in the contribution of FOXP2 and BMI, as well as their potential interaction with cognitive deficits in schizophrenia, have not been investigated. A total of 867 schizophrenia patients and 402 controls were recruited. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The polymorphism rs10447760 of the FOXP2 gene was genotyped. Male schizophrenia patients had superior language performance compared to female patients (F = 17.83; p Bonferroni < 0.0001). BMI was positively associated with language scores in male patients with schizophrenia (ß = 0.60, t = 3.30, p = 0.001), as well as in patients with schizophrenia who carried the FOXP2 rs10447760 CC genotype (ß = 0.53, t = 3.16, p = 0.002). Interestingly, this association was only found in male patients with schizophrenia who also carried the FOXP2 rs10447760 CC genotype (ß = 0.63, t = 3.44, p = 0.001). Our study reveals a sex difference in the language deficits of schizophrenia patients and shows sexual dimorphism in the contribution of FOXP2, BMI, and their interaction to cognitive deficits in patients with schizophrenia.

This study aimed to explore the effects of forkhead box P2 gene (Foxp2) on T-helper 9 (Th9) differentiation in asthmatic mice. An in vivo asthmatic mouse model was induced with ovalbumin (OVA). An in vitro model was established by culturing CD4+ T cells with TGF-β, IL-4, and anti-IFN-γ. ELISA, flow cytometry, qRT-PCR and Western blot were performed to examine IL-9 secretion, Th9 cell number, and Th9 cell transcription factor expression, respectively. Pathological changes in lung tissues and airway mucus secretion were assessed with HE and PAS glycogen staining. Anti-IL-9 mAb reversed the elevation in Th9 cells and IL-9 expression in lung tissues and bronchoalveolar lavage fluid (BALF) of asthmatic mice. Foxp2 was downregulated in BALF and lung tissue of asthmatic mice and Th9 cells. Overexpression of Foxp2 inhibited Th9 cell differentiation in vitro and improved airway inflammation in vivo. Our study suggests that overexpression of Foxp2 attenuates allergic asthma by inhibiting Th9 cell differentiation.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Several studies have suggested that FOXP2 functions as a tumour suppressor. However, to date, it remains unclear how FOXP2 influences CRC occurrence. Methods: We took advantage of CRC tissue samples and compared the expression of FOXP2 via immunohistochemistry assays. We elucidated the underlying function of FOXP2 in CRC cells by constructing a cell model with FOXP2 depletion. Co-IP experiments and immunofluorescence (IF) assays were conducted, and the results demonstrated that FOXP2 can promote the activation of caspase-1 to enhance cell pyroptosis. Results: We used tissue RNA sequencing analysis in a colitis-associated cancer mouse model, and found that FOXP2 was downregulated in colitis and tumour tissues. We also found that CRC patients with low FOXP2 expression had poorer survival. Cell viability assays and electron microscopic examination showed that depletion of FOXP2 could enhance cell growth and inhibit cell pyroptosis. At the same time, knocking down FOXP2 expression was able to promote the protein expression of PCNA and cyclin D1 and downregulate the expression of the caspase family of proteins and GSDMD, which are markers of pyroptosis. A series of co-IP and IF assays revealed that FOXP2 interacts with caspase-1 and promotes its expression. Conclusion: Our findings reveal a key role for FOXP2 in CRC cell pyroptosis and provide a mechanism explaining how FOXP2 promotes cell pyroptosis.