Integrin subunit ß-like 1 mediates angiotensin II-induced myocardial fibrosis by regulating the forkhead box Q1/Snail axis.

Cardiac fibrosis is a severe condition with limited therapeutic options and often occurs in chronic cardiovascular diseases such as hypertension and myocardial infarction. There is currently a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of more effective therapeutic strategies targeting cardiac fibrosis. Integrin subunit ß-like 1 (ITGBL1), an extracellular matrix protein, has previously been implicated in various fibrotic diseases. However, the precise role of ITGBL1 in regulating myocardial fibrosis remains unknown. The present study was designed to investigate whether ITGBL1 regulates angiotensin II (Ang II)-induced myocardial fibrosis in vitro and in vivo and the possible mechanism of action. It was found that the protein expressions of ITGBL1, Forkhead box Q1 (FOXQ1), and Snail were all increased significantly in fibrotic heart tissues from Ang II-infused mice and Ang II-stimulated cardiac fibroblasts, all of which were inhibited by the Ang II type I (AT1) receptor antagonist losartan. Silencing the ITGBL1/FOXQ1/Snail axis with specific siRNAs reversed Ang II-induced fibrotic effects and upregulation of FOXQ1 and Snail expressions in cardiac fibroblasts. FOXQ1 siRNA inhibited Snail expression in Ang II-induced cardiac fibroblasts. Furthermore, ITGBL1/FOXQ1 interacted with the TGF-ß1 signaling to form a positive feedback loop. Our findings suggest that the extracellular matrix protein ITGBL1 mediates Ang II-induced cardiac fibrosis via the FOXQ1/Snail axis, which identifies ITGBL1 as a novel mediator of cardiac fibrosis and represents a potential therapeutic target for cardiac fibrosis.

Forkhead Box q1 promotes invasion and metastasis in colorectal cancer by activating the epidermal growth factor receptor pathway.

BACKGROUND: Colorectal cancer (CRC) is an extremely malignant tumor with a high mortality rate. Little is known about the mechanism by which forkhead Box q1 (FOXQ1) causes CRC invasion and metastasis through the epidermal growth factor receptor (EGFR) pathway. AIM: To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor (HB-EGF)/EGFR pathway. METHODS: We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis (GEPIA) website (http://gepia.cancer-pku.cn/index.html). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues, and we constructed a stable low-expressing FOXQ1 cell line and verified it with the above method. The expression changes of membrane-bound HB-EGF (proHB-EGF) and soluble HB-EGF (sHB-EGF) in the low-expressing FOXQ1 cell line were detected by flow cytometry and ELISA. Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells. Proliferation experiments, transwell migration experiments, and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF, and then to evaluate the clinical relevance of FOXQ1 and HB-EGF. RESULTS: GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate. PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways. Knockdown of FOXQ1 suppressed the expression of HB-EGF, and led to a decrease in EGFR and its downstream genes AKT, RAF, KRAS expression levels. After knockdown of FOXQ1 in CRC cell lines, cell proliferation, migration and invasion were attenuated. Adding HB-EGF restored the migration and invasion ability of CRC, but not the cell proliferation ability. Kaplan-Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival. CONCLUSION: Based on these collective data, we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.

FOXQ1-mediated SIRT1 upregulation enhances stemness and radio-resistance of colorectal cancer cells and restores intestinal microbiota function by promoting ß-catenin nuclear translocation.

BACKGROUND: Resistance of colorectal cancer (CRC) cells to radiotherapy considerably contributes to poor clinical outcomes of CRC patients. Microarray profiling in this study revealed the differentially expressed forkhead box Q1 (FOXQ1) in CRC, and thus we aimed to illustrate the role of FOXQ1 in CRC by modulating stemness and radio-resistance of CRC cells. METHODS: CRC and adjacent normal tissues were collected from CRC patients, and the correlation between FOXQ1 expression and CRC prognosis was analyzed. Subsequently, we determined the expression of FOXQ1, sirtuin 1 (SIRT1) and ß-catenin in CRC tissues and cell lines. The binding affinity between FOXQ1 and SIRT1 and that between SIRT1 and ß-catenin were validated with luciferase reporter gene, Co-IP and ChIP assays. Following a metagenomics analysis of CRC intestinal microbiota, the effects of the FOXQ1/SIRT1/ß-catenin axis on CRC stem cell phenotypes and radio-resistance was evaluated in vitro and in vivo through manipulation of gene expression. Besides, mouse feces were collected to examine changes in intestinal microbiota. RESULTS: FOXQ1 was highly expressed in CRC tissues and cells and positively correlated with poor prognosis of CRC patients. FOXQ1 overexpression contributed to resistance of CRC cells to radiation. Knockdown of FOXQ1 inhibited the stemness of CRC cells and reversed their radio-resistance. FOXQ1 enhanced the transcriptional expression of SIRT1, and SIRT1 enhanced the expression and nuclear translocation of ß-catenin. Knockdown of FOXQ1 repressed SIRT1 expression, thus reducing the stemness and radio-resistance of CRC cells. Moreover, FOXQ1 knockdown suppressed CRC xenograft formation in xenograft-bearing nude mice through inhibiting SIRT1 and ß-catenin to reduce the content of pathological bacteria that were up-regulated in CRC. CONCLUSION: FOXQ1-mediated SIRT1 upregulation augments expression and nuclear translocation of ß-catenin and benefits CRC-related intestinal pathological bacterial, thereby enhancing the stemness and radio-resistance of CRC cells.

Tumor Forkhead Box Q1 Is Elevated, Correlates with Increased Tumor Size, International Federation of Gynecology and Obstetrics Stage but Worse Overall Survival in Epithelial Ovarian Cancer Patients.

Background: Forkhead box Q1 (FOXQ1) regulates epithelial ovarian cancer (EOC) cell proliferation, migration, and invasion; however, its prognostic effect in EOC patients is unclear. This study assessed FOXQ1 expression in EOC patients by immunohistochemical (IHC) staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and to analyze its correlation with EOC patients' clinical features and prognosis. Materials and Methods: FOXQ1 protein level in tumor and adjacent tissues from 173 EOC patients who underwent resection was detected by IHC staining and further scored by a semiquantitative scoring method; meanwhile, FOXQ1 mRNA level in tumor and adjacent tissues from 105 out of 173 EOC patients (whose fresh-frozen tissues were available) was detected by RT-qPCR. Besides, EOC patients' clinical features and survival data were collected. Results: Both FOXQ1 protein (n = 173) and mRNA (n = 105) levels were increased in tumor tissues compared with adjacent tissues (both p < 0.001) in EOC patients. Meanwhile, tumor FOXQ1 protein level was positively correlated with tumor size (p = 0.005) and International Federation of Gynecology and Obstetrics (FIGO) stage (p = 0.037), while FOXQ1 tumor mRNA level was only positively correlated with tumor size (p = 0.015) in EOC patients; however, they were not correlated with other clinical features such as histological subtypes, tumor differentiation, peritoneal cytology, and so on (all p > 0.05). Moreover, FOXQ1 protein (p = 0.030) and mRNA (p = 0.011) levels in tumors were both correlated with worse overall survival (OS) in EOC patients. Conclusion: FOXQ1 is elevated in tumor tissues, and its high tumor expression correlates with increased tumor size, elevated FIGO stage, and worse OS in EOC patients.

Identification of testicular Foxq1 as a critical modulator of lactate metabolism in mouse Sertoli cells.

Postmeiotic germ cells require the lactate produced by the adjacent Sertoli cells (SCs) as their sole energy fuels. Lactate production in SCs is elaborately regulated by monitoring the transcription of the lactate dehydrogenase A (Ldha) gene. However, the transcription factors that are responsible for the control of Ldha transcription in SCs remain ill defined. Herein, the expression of forkhead box Q1 (FOXQ1), a central modulator of glucose metabolism in liver, was demonstrated in mouse testis throughout postnatal development, with maximum levels in adult specimens. At this age, FOXQ1 was immunolocalized in the nuclei of the functionally mature SCs. Testicular levels of FOXQ1 were overtly modulated by germ cells (GCs)-derived IL-1α, in a dose- and time-dependent manner. To further clarify the biological functions of FOXQ1, we disrupted the mouse Foxq1 gene using a Cas9/RNA-mediated gene targeting strategy. Foxq1-/- males were subfertile and showed oligoasthenozoospermia due to lactate deficiency. Moreover, we provided the molecular evidence that FOXQ1 may regulate lactate production by directly targeting the transactivation of the Ldha gene in SCs. From a functional standpoint, overexpression of the exogenous Ldha ameliorated Foxq1 deficiency-impaired lactate synthesis in the SCsFoxq1-/- cells. Thus, these findings collectively underscore a reproductive facet of this recently characterized transcription factor, which may operate as a novel transcriptional integrator linking energy homeostasis and nursery function in SCs.

Progress of Research on Forkhead Box Q1 Gene in Digestive Tract Tumors / 胃肠病学

Transcription factor forkhead box Q1 (FOXQ1) is a member of forkhead box (FOX) superfamily, which exists widely in a variety of tissues and organs of human body. FOXQ1 protein affects the genesis, progression, invasion and metastasis of tumor by promoting epithelial-mesenchymal transition (EMT) and activating multiple cell signal transduction pathways. In recent years, studies have found that FOXQ1 is abnormally expressed in a variety of digestive tract tumors. In-depth study on the expression and mechanism of FOXQ1 in digestive tract tumor is of great significance for early diagnosis and specific molecular therapy of digestive tract tumors. This article reviewed the latest literatures related to FOXQ1 and digestive tract tumors, and expounding its mechanism in the progression of different digestive tract tumors, in order to provide theoretical basis and reference for the research and development of new chemotherapy drugs.

FOXQ1 promotes the osteogenic differentiation of bone mesenchymal stem cells via Wnt/ß-catenin signaling by binding with ANXA2.

BACKGROUND: This study investigated the role of Forkhead box Q1 (FOXQ1) in the osteogenic differentiation of bone mesenchymal stem cells. METHODS: Mouse bone mesenchymal stem cells (mBMSCs) were transfected with lentivirus to generate Foxq1-overexpressing mBMSCs, Foxq1-suppressed mBMSCs, and mBMSC controls. The activity of osteogenic differentiation was evaluated with alizarin red staining, alkaline phosphatase activity assay, and RT-qPCR. Wnt/ß-catenin signaling activities were compared among groups by TOPFlash/FOPFlash assay, immunofluorescence staining, and western blot assay of beta-catenin (CTNNB1). Coimmunoprecipitation mass spectrometry was also carried out to identify proteins binding with FOXQ1. RESULTS: Our data showed that FOXQ1 expression was positively correlated with the osteogenic differentiation of the mBMSCs. FOXQ1 also promoted the nuclear translocation of CTNNB1 in the mBMSCs, enhancing Wnt/ß-catenin signaling, which was also shown to be essential for the osteogenic differentiation-promoting effect of FOXQ1 in the mBMSCs. Annexin A2 (ANXA2) was bound with FOXQ1, and its depletion reversed the promoting effect of FOXQ1 on Wnt/ß-catenin signaling. CONCLUSION: These results showed that FOXQ1 binds with ANXA2, promoting Wnt/ß-catenin signaling in bone mesenchymal stem cells, which subsequently promotes osteogenic differentiation.

Overexpression of miR-106a enhances oxaliplatin sensitivity of colorectal cancer through regulation of FOXQ1.

Chemotherapy resistance poses a major challenge for the clinical treatment of colorectal cancer, therefore, the aim of the present study was to examine its underlying mechanisms. Reverse transcription-quantitative polymerase chain reaction and western blot analysis were used to determine the microRNA (miRNA)/mRNA and protein expression levels, respectively. A dual luciferase assay was conducted for verification of the interaction between miR-106a and 3'untranslated region (UTR) of Forkhead box Q1 (FOXQ1). Cell viability was assessed using an MTT assay. In the present study, it was demonstrated that miR-106a is involved in regulating oxaliplatin sensitivity of colorectal cancer. Transfection of miR-106a mimics slightly inhibited colorectal cancer cell growth and sensitized colorectal cancer cells to oxaliplatin exposure. In addition, miR-106a overexpression induced a decrease of FOXQ1 at mRNA and protein levels in colorectal cancer cells. The enhanced expression of miR-106a also increased the expression of Wnt target genes, including vascular endothelial growth factor-A and matrix metallopeptidase 2, which were reported to be regulated by FOXQ1. It was predicted and validated that miR-106a could repress FOXQ1 expression via direct binding to 3'UTR. Elevation of miR-106a and a decrease of FOXQ1 expression levels were detected in tumor tissues from patients with oxaliplatin-sensitive colorectal cancer, compared with patients with oxaliplatin-resistant colorectal cancer. Furthermore, there was a significant association between miR-106a and FOXQ1 mRNA levels. In conclusion, the present study demonstrated that miR-106a increased oxaliplatin sensitivity of colorectal cancer cells through direct repression of FOXQ1 expression.

Potentiality of forkhead box Q1 as a biomarker for monitoring tumor features and predicting prognosis in non-small cell lung cancer.

BACKGROUND: This study aimed to explore the correlation of forkhead box Q1 (FOXQ1) with clinicopathological features and survival profiles in patients with non-small cell lung cancer (NSCLC). METHODS: A total of 238 NSCLC patients with TNM stage I-III who underwent surgical resection were reviewed, and the expression of FOXQ1 in tumor and paired adjacent tissue was detected using immunohistochemistry assays. The clinical data and survival data of patients with NSCLC were retrieved and calculated. RESULTS: FOXQ1 expression was increased in tumor tissue (61.3% high expression and 38.7% low expression) compared with paired adjacent tissue (37.8% high expression and 62.2% low expression) (P < .001). In addition, high FOXQ1 expression was associated with larger tumor size (P = .042), lymph node metastasis (P = .040), and advanced TNM stage (P = .002). Disease-free survival (DFS) (P = .016) and overall survival (OS) (P = .008) were both reduced in patients with high FOXQ1 expression compared with patients with low FOXQ1 expression. Additionally, high FOXQ1 expression (P = .043), poor pathological differentiation (P = .003), and lymph node metastasis (P < .001) were independent risk factors for DFS, and high FOXQ1 expression (P = .021), tumor size (>5 cm) (P = .014), and lymph node metastasis (P < .001) were independent risk factors for OS. CONCLUSION: High FOXQ1 expression is associated with advanced tumor features as well as undesirable survival profiles in patients with NSCLC, implying the potential prognostic value of FOXQ1 for NSCLC.

Effect of Polyphyllin Ⅰ on Transcriptional Factor FOXQ1 and Epithelial-mesenchymal Transition in Colorectal Cancer Cell HCT116 / 中国实验方剂学杂志

Objective:To observe the effect of polyphyllin Ⅰ on the expressions of forkhead box Q1（FOXQ1）and epithelial-mesenchymal transition (EMT)-related factors, in order to explore the possible mechanism of polyphyllin Ⅰ in inhibiting the metastasis of colon cancer. Method:After the treatment with 1.25，2.50 μmol·L-1 polyphyllin Ⅰ on HCT116 cells, Western blot and Real-time PCR were used to detect the expressions of FOXQ1，E-cadherin，Vimentin protein and mRNA. Result:Compared with the blank group, relative expressions of FOXQ1 protein and mRNA in low-concentration polyphyllin Ⅰ group were decreased, while relative expression of E-cadherin mRNA was increased, the differences were not statistically significant, and relative expressions of Vimentin protein and mRNA in low-concentration polyphyllin Ⅰ group were decreased (P<0.05)， and relative expression of E-cadherin protein in low-concentration polyphyllin Ⅰ group was increased (P<0.01). Compared with the blank group, relative expressions of FOXQ1, Vimentin protein and mRNA in high-concentration polyphyllin Ⅰ group were decreased，while relative expressions of E-cadherin protein and mRNA were increased (P<0.05, P<0.01). Compared with low-concentration polyphyllin Ⅰ group, relative expressions of Vimentin protein and mRNA in high-concentration polyphyllin Ⅰ group were decreased, but the difference was not statistically significant, relative expressions of E-cadherin protein and mRNA in high-concentration polyphyllin Ⅰ group were increased, whereas relative expressions of FOXQ1 protein and mRNA were decreased (P<0.05, P<0.01). Conclusion:Mechanism of polyphyllin Ⅰ inhibiting the metastasis of colon cancer may be related to the decrease of FOXQ1 and Vimentin expressions, and the up-regulation of E-cadherin.

MicroRNA-937 inhibits the malignant phenotypes of breast cancer by directly targeting and downregulating forkhead box Q1.

Purpose: Numerous microRNAs (miRNAs) are aberrantly expressed in breast cancer, and the dysregulation of miRNAs may affect the aggressiveness of this cancer. Aberrant expression of miRNA-937 (miR-937) in gastric and lung cancers has been reported, which plays tumor-suppressive or oncogenic roles in carcinogenesis including cancer progression. Our purpose was to investigate the involvement of miR-937 in breast cancer progression. Patients and methods: The expression profile of miR-937 in breast cancer was assessed by reverse-transcription quantitative PCR. Biological effects of miR-937 upregulation on the malignant characteristics of breast cancer cells were determined in a series of functional experiments. The direct target of miR-937 in breast cancer cells was also identified. Results: Herein, the expression levels of miR-937 were notably lower in breast cancer, and its underexpression was significantly correlated with lymph node metastasis and TNM stage. Patients with breast cancer underexpressing miR-937 showed shorter overall survival than did patients with breast cancer overexpressing miR-937. Proliferation, migration, and invasiveness of breast cancer cells were evidently suppressed by miR-937 upregulation. In addition, ectopic miR-937 expression hindered breast cancer tumor growth in vivo. Forkhead box Q1 (FOXQ1) mRNA was found to be a direct target of miR-937 in breast cancer. FOXQ1 turned out to be overexpressed in breast cancer tissues, and its overexpression negatively correlated with miR-937 expression. Moreover, silencing of FOXQ1 recapitulated the tumor-suppressive effects of miR-937 overexpression on breast cancer cells. Notably, FOXQ1 restoration abrogated the miR-937-mediated suppression of proliferation, migration, and invasiveness of breast cancer cells. Conclusion: These results collectively revealed that miR-937 acts as a tumor suppressor in breast cancer and restrains cancer progression by directly targeting FOXQ1 mRNA. These data suggest that targeting of the novel miR-937-FOXQ1 axis is an attractive therapeutic method against breast cancer.

[miRNA-96-5p inhibits the proliferation and migration of gastric cancer cells by targeting FoxQ1].

Objective: To investigate the role of microRNA-96-5p in the proliferation and invasion of gastric cancer cells and its molecular mechanism. Methods: From June 2015 to January 2017, 53 resected specimens were collected. The transcriptional levels of microRNA-96-5p and forkhead box Q1 (FoxQ1) in gastric cancer tissues and the matched para-cancerous tissues were quantified by quantitative real-time PCR (qRT-PCR). The expression of FoxQ1 protein was also detected by immunohistochemistry (IHC). The relationship between microRNA-96-5p expression and the clinicopathological features of gastric cancer and its correlation with FoxQ1 expression were analyzed. The expressions of miRNA-96-5p in gastric cancer tissue and adjacent normal tissue were detected by qRT-PCR. miRNA-96-5p mimics was transfected to BGC-823 gastric cancer cells. The effects of miRNA-96-5p on cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and Transwell assay, respectively. The protein expressions of FoxQ1, E-cadherin and vimentin were determined by western blot. The relationship between FoxQ1 and miRNA-96-5p expressed in BGC-823 cells was detected by dual-luciferase reporter assay. Results: The median expression of miRNA-96-5p in gastric cancer tissue was 1.05, significantly lower than 3.23 of para-cancerous tissues (P<0.05). The positive rate of FoxQ1 expression in gastric cancer tissue was 71.7%, significantly higher than 28.3% of para-cancerous tissues (P<0.05). The expression of FoxQ1 was negatively corelated with the level of miRNA-96-5p (r=-0.613, P=0.006). The expression of miRNA-96-5p in gastric cancer cell BGC-823 was significantly decreased compared with normal gastric epithelial cell (0.96±0.08 vs 2.84±0.15, P<0.05). The results of CCK-8 assay and Transwell assay showed that overexpression of miRNA-96-5p significantly reduced the proliferation and invasion abilities of gastric cancer cells (P<0.05). Overexpression of miRNA-96-5p decreased the protein level of FoxQ1. Moreover, it upregulated the expression of E-cadherin and downregulated the expression of vimentin. The result of dual-luciferase-3'-UTR reporter assay confirmed that miRNA-96-5p binds to the 3'UTR of FoxQ1. Conclusion: miRNA-96-5p may suppress the proliferation, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cell by down-regulation of FoxQ1.

miRNA-96-5p inhibits the proliferation and migration of gastric cancer cells by targeting FoxQ1 / 中华肿瘤杂志

Objective@#To investigate the role of microRNA-96-5p in the proliferation and invasion of gastric cancer cells and its molecular mechanism.@*Methods@#From June 2015 to January 2017, 53 resected specimens were collected. The transcriptional levels of microRNA-96-5p and forkhead box Q1 (FoxQ1) in gastric cancer tissues and the matched para-cancerous tissues were quantified by quantitative real-time PCR (qRT-PCR). The expression of FoxQ1 protein was also detected by immunohistochemistry (IHC). The relationship between microRNA-96-5p expression and the clinicopathological features of gastric cancer and its correlation with FoxQ1 expression were analyzed. The expressions of miRNA-96-5p in gastric cancer tissue and adjacent normal tissue were detected by qRT-PCR. miRNA-96-5p mimics was transfected to BGC-823 gastric cancer cells. The effects of miRNA-96-5p on cell proliferation and invasion were detected by cell counting kit-8 (CCK-8) assay and Transwell assay, respectively. The protein expressions of FoxQ1, E-cadherin and vimentin were determined by western blot. The relationship between FoxQ1 and miRNA-96-5p expressed in BGC-823 cells was detected by dual-luciferase reporter assay.@*Results@#The median expression of miRNA-96-5p in gastric cancer tissue was 1.05, significantly lower than 3.23 of para-cancerous tissues (P<0.05). The positive rate of FoxQ1 expression in gastric cancer tissue was 71.7%, significantly higher than 28.3% of para-cancerous tissues (P<0.05). The expression of FoxQ1 was negatively corelated with the level of miRNA-96-5p (r=-0.613, P=0.006). The expression of miRNA-96-5p in gastric cancer cell BGC-823 was significantly decreased compared with normal gastric epithelial cell (0.96±0.08 vs 2.84±0.15, P<0.05). The results of CCK-8 assay and Transwell assay showed that overexpression of miRNA-96-5p significantly reduced the proliferation and invasion abilities of gastric cancer cells (P<0.05). Overexpression of miRNA-96-5p decreased the protein level of FoxQ1. Moreover, it upregulated the expression of E-cadherin and downregulated the expression of vimentin. The result of dual-luciferase-3′-UTR reporter assay confirmed that miRNA-96-5p binds to the 3′UTR of FoxQ1.@*Conclusion@#miRNA-96-5p may suppress the proliferation, migration and epithelial-mesenchymal transition (EMT) of gastric cancer cell by down-regulation of FoxQ1.

Research progress on the regulation of tumor initiation and development by the forkhead box Q1 gene.

Transcription factor forkhead box Q1 (FOXQ1), a member of the forkhead box superfamily, has been involved in various biological processes and plays important roles in tumor initiation and progression. The FOXQ1 protein activated transcription of target genes directly by binding to the promoters of target genes or indirectly by interacting with other transcription factors. FOXQ1 affected the initiation, progression, invasion, and metastasis of many kinds of tumor by promoting the epithelial-mesenchymal transition, regulating cell cycle, promoting cell proliferation, regulating senescence-associated inflammation, and activating many cellular signal pathways. In this review, we have focused on the possible molecular mechanisms for FOXQ1 gene in tumor initiation and progression. Medline literature review related to this subject was performed by the electronically retrieval with the keywords "forkhead box Q1" and "tumor" on PubMed for including previous publications, and then, it further reviewed reference articles on the biological function of FOXQ1 gene and target genes transcription directly regulated by FOXQ1.

FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells.

Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans-activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC.

MicroRNA-125b promotes neurons cell apoptosis and Tau phosphorylation in Alzheimer's disease.

Alzheimer's disease (AD) is considered as one of the most common neural degenerative diseases in human. Although the continuous investigations about AD have been made in recent decades, the pathogenesis of this disease is still not definitely confirmed. MicroRNA-125b (miR-125b) is extensive expressed in many types of human tissues and played pivotal regulatory roles in diverse biological process. In the present study, we aimed to explore the roles of miR-125b in regulating neurons cell apoptosis under AD condition. The possible molecular mechanisms were also investigated. We found that miR-125b was up-regulated in patients with AD. Transfection with miR-125b significantly enhanced the apoptosis of neurons cells and phosphorylation of Tau by activation of cyclin-dependent kinase 5 (CDK5) and p35/25. Forkhead box Q1 (FOXQ1) was the direct target gene of miR-125b, which involved in the effects of miR-125b on neurons cell apoptosis and phosphorylation of Tau. Our research interpreted the mechanism of up-regulation of miR-125b in pathological Tau phosphorylation and AD occurrence. miR-125b may be a novel regulator of AD progress and could be as a therapeutic target for AD therapy.

Relationship between forkhead box Q1 and tumors of digestive system / 中华肝胆外科杂志

Forkhead box Q1 (FoxQ1) is a transcription factor protein with the function of cell differentiation regulation.Recently,increasing evidence has demonstrated that FoxQ1 is significantly associated with pathogenesis of digestive system tumors.This article systematically reviewed the expression and the role of FoxQ1 in the pathogenesis of digestive system tumors.Potential therapeutic target of FoxQ1 was discussed as well.

FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion.

Forkhead box Q1 (FOXQ1) is a forkhead transcription factor that is involved in numerous biological processes and has been shown to participate in tumorigenesis. However, the clinical significance of the expression of this protein in laryngeal carcinoma, and the mechanisms underlying its regulation in this disease remain unclear. The aim of present study was to measure the expression of FOXQ1 in laryngeal carcinoma, and to examine its effect on tumorigenesis. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were employed to measure FOXQ1 expression in laryngeal carcinoma tissue samples, small interfering RNA specific to FOXQ1, was transfected into Hep2 cells and its effect on cell proliferation, cell cycle progression and cell migration was examined, using a CCK-8 assay, flow cytometry and a transwell migration assay, respectively. The results showed overexpression of FOXQ1 mRNA and protein in laryngeal cancer tissue samples. Inhibition of FOXQ1 suppressed cell growth and invasion, and arrested cells in the G0/G1 phase. Overexpression of FOXQ1 is associated with the development of laryngeal carcinoma and may enhance tumorigenesis through its effects on cell proliferation, cell cycle progression and cell migration.

FOXQ1 mediates the crosstalk between TGF-ß and Wnt signaling pathways in the progression of colorectal cancer.

A wide variety of signaling transduction pathways contribute to tumorigenesis. Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family and its upregulation is closely correlated with tumor progression and prognosis of multiple cancer types, including colorectal cancer. However, the molecular mechanisms by which FOXQ1 promotes tumorigenesis, especially cancer cell invasion and metastasis in colorectal cancer, have not been fully elucidated. In the present study, we demonstrate that FOXQ1 is overexpressed in colorectal tumor tissues and its expression level is closely correlated with the stage and lymph node metastasis of colorectal cancer. In in vitro cultured SW480 colorectal cancer cells, knockdown of FOXQ1 expression by small interfering RNA greatly diminished the aggressive tumor behaviors of SW480 cells, including angiogenesis, invasion, epithelial-mesenchymal transition, and resistance to chemotherapy drug-induced apoptosis. Further mechanistic investigation showed that FOXQ1 silencing prevents the nuclear translocation of ß-catenin, thus reducing the activity of Wnt signaling. Moreover, TGF-ß1 induced the expression of FOXQ1 as well as the migration and invasion of SW480 cells, which was partially prevented following knockdown of FOXQ1. Our results demonstrate that FOXQ1 plays a critical role during the tumorigenesis of colorectal cancer and is a mediator of the crosstalk between Wnt and TGF-ß signaling pathways. Our findings provide further insight into the cancer biology of colorectal cancer and suggest that FOXQ1 is a potential therapeutic target for the development of therapies for colorectal cancer.

Expression levels and clinical significance of FOXQ1 and E-cadherin in esophageal squamous cell carcinoma / 天津医药

Objective To investigate the expression levels and clinical significance of (forkhead box Q1) FOXQ1 and E-cadherin in esophageal squamous cell carcinoma (ESCC). Methods Expression levels of FOXQ1 and E-cadherin were in ESCC tissues (ESCC group, n=42) and adjacent normal esophageal tissues (control group, n=42) were detected using im?munohistochemistry. Correlations of FOXQ1 and E-cadherin expressions with clinical pathological parameters and progno?sis were analyzed between two groups. Results The expression level of FOXQ1 was significantly higher in ESCC group than that in control group(64.29% vs 28.57%,χ2=5.384,P<0.05). The expression level of E-cadherin was significantly lower in ESCC group than that incontrol group(52.38%vs 90.48%,χ2=7.691,P<0.05). There were significant differences in FOXQ1 expressions between different TNM stages and whether lymph node metastasis is involved within ESCC group. There were significant differences in expression of E-cadherin between different tumor differentiation, depth of invasion, TNM stage and whether lymph node metastasis is involved within ESCC group. The expression of FOXQ1 was negatively cor?related with E-cadherin in ESCC (r=-0.412, P<0.05). The 5-year survival rates were significantly lower with high expres?sion of FOXQ1 or with low expression of FOXQ1(18.52%vs 66.67%,χ2=9.737,P<0.05). The 5-year survival rates were significantly higher with high expression of E-cadherinor low expression of E-cadherin(59.09%vs 10.00%,χ2=10.996,P<0.05). A multivariate Cox's proportional hazard regression analysis indicated that high FOXQ1 expression, low E-cadherin expression and lymph node metastasis were independent prognostic factors for ESCC. Conclusion The expression of FOXQ1 and E-cadherin showed a good correlation with ESCC. And examining expressions of both FOXQ1 and E-cadherin in ESCC may have practical values in estimating the prognosis of ESCC and directing future treatment .