|Year : 2018 | Volume
| Issue : 1 | Page : 6-11
Research progress on the regulation of tumor initiation and development by the forkhead box Q1 gene
Hui Tang1, Jinjin Zhang2, Qiang Guo3
1 Faculty of Medicine, Kunming University of Science and Technology; Institute of Basic Medical Sciences, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650504, Yunnan, China
2 Faculty of Medicine, Kunming University of Science and Technology, Kunming 650504, Yunnan, China
3 Faculty of Medicine, Kunming University of Science and Technology; Department of Gastroenterology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming 650504, Yunnan, China
|Date of Web Publication||8-Mar-2018|
Prof. Qiang Guo
College of Medicine, Kunming University of Science and Technology, No. 727 South Jingming Road, Chenggong District, Kunming 650504, Yunnan
Source of Support: None, Conflict of Interest: None
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.
Keywords: Epithelial–mesenchymal transition, forkhead box Q1 gene, signal pathways, tumor, tumorgenesis
|How to cite this article:|
Tang H, Zhang J, Guo Q. Research progress on the regulation of tumor initiation and development by the forkhead box Q1 gene. J Can Res Ther 2018;14:6-11
| > Introduction|| |
The forkhead box (FOX) family was widely present in organisms from yeast to humans, which included FOXQ1. FOX comprised a large family of transcription factors with extensive functions, which was also a subgroup of “helix-turn-helix” proteins.,, Members of the FOX family shared the common structural feature of a highly conserved forkhead DNA-binding structural domain.,,, Based on homology of DNA-binding domains, more than 100 FOX family members have been identified to date in different species. These family members can be further divided into 19 subfamilies (FOXA-S),, and more than fifty types of FOX proteins were encoded by the human genome.
FOXQ1 has been an important member of the FOX family with a highly conserved forkhead domain. FOXQ1 exerted its effects by binding to target genes through this DNA domain then initiated transcription and regulated expression of specific proteins, thus playing roles in hair follicle differentiation,, in embryonic stem cells and in vertebrate development. In recent years, studies on the association between the FOXQ 1 gene and tumor have received extensive attentions. This review has discussed the possible mechanisms by which FOXQ1 gene made effects in tumor initiation and progression. Medline literature review related to this subject was performed through the electronic 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.
| > Forkhead Box Q1 Structure|| |
The human FOXQ1 gene was 2319 bp, contained one exon, which was located at 6p23-25. The FOXQ1 protein consisted of 403 amino acids (aas), with an alanine/glycine-rich domain, a forkhead box domain (FHD) or a winged-helix domain, and a proline-rich domain arranged from the N- to the C-termini. At residues 119-214, the FHD was a DNA-binding domain of FOX proteins with 96 aa. The N-terminal alanine/glycine-rich domain (at aa 13–103) and the C-terminal proline-rich domain (at aa 221–397) were associated with the transcriptional regulatory activity of the protein. A large number of studies have confirmed that human FOXQ1 protein, as a nuclear transcription factor, manipulated the expression levels of a downstream target gene by identifying and combining with cis-regulatory elements of downstream target genes. Human FOXQ1 protein played important roles in development, metabolism, aging, and tumorigenesis.,,
| > Expression Levels of Forkhead Box Q1 in Normal Tissues and Tumor Cells|| |
With regard to normal tissues, high levels of FOXQ1 expression have been observed in the stomach, salivary gland, prostate, trachea, and fetal liver, whereas relatively weak expression levels have been detected in brain-derived tissues as well as the kidney, lung, placenta, and thyroid gland. The lowest expression levels of FOXQ1 were found in tissues such as the heart, skeletal muscle, testis, thymus, uterus, spinal cord, colon, and small intestine. Regarding cancer cell lines, expression levels of FOXQ1 in gastric cancer (GC) cells, colorectal cancer (CRC) cells, and lung cancer cells were higher than those of in breast cancer cells, ovary adenocarcinoma cells, glioma cells, and myeloid leukemia cells.
| > Biological Functions of Forkhead Box Q1 in the Tumorigenesis|| |
Various biological functions in the tumorigenesis were regulated with FOXQ1 including the following aspects.
Induction of epithelial–mesenchymal transition
FOXQ1 led to tumor invasion and migration in gastric, lung, ovarian, breast, and bladder cancers by inducting epithelial–mesenchymal transition (EMT).,,,,,, EMT was a basic process in embryonic development. In addition, EMT was critical for wound healing and the development of malignant epithelial tumor, participating in the entire malignant evolution process and promoting tumor infiltration and metastasis. EMT in tumor cells was accompanied by reduction in and loss of E-cadherin expression,,,, loss and relocation of zonula occludens-1, upregulation of vimentin, smooth muscle actin α,, and fibronectin, and matrix metalloproteinases,, and degradation of the extracellular matrix.,
Cell cycle regulation
In SKOV cells of ovarian cancer, suppression of FOXQ1 gene expression resulted in cell cycle arrest at the G1/S phase. It might be associated with downregulated cyclin D1, cyclin E, and cyclin-dependent kinase 4 (CDK4) expressions. In CRC, expression of FOXQ1 was significantly higher than that of in corresponding paracancerous tissues, and the proliferation of CRC H1299 cells was significantly inhibited by the overexpression of FOXQ1. FOXQ1 bind to the promoter region of the p21 gene to upregulate its expression, and this event might be associated with the inhibition of CDK4, CDK2, and cyclin D1 expression.
Promotion of cell proliferation
The FOXQ1 gene was highly expressed in cervical cancer CaSki and SiHa cells, and silencing of this gene was able to inhibit proliferation of these cervical cancer cells, high FOXQ1 expression was also found to make a certain promoting effect on tumor cell proliferation in liver cancer, neuroblastoma, prostate cancer, ovarian cancer, and CRC.,
Change of tumor microenvironment and involvement in maintenance of tumor stem cell characteristics
FOXQ1 promoted hepatocellular carcinoma (HCC) metastasis by transactivating VersicanV1 expression, leading to the recruitment of macrophage infiltration., It was also involved in maintenance of tumor stem cell characteristics in pancreatic cancer.
Regulation of senescence-associated inflammation
Wang et al. demonstrated that the protein level of FOXQ1 was significantly downregulated during both replicative and oncogene-induced senescence. Moreover, overexpression of FOXQ1 delayed senescence, whereas FOXQ1 silence led to premature senescence in human fibroblasts. Furthermore, FOXQ1 upregulated SIRT1 expression through transcriptional regulation through directly binding to the SIRT1 promoter. The replicative senescence would be remarkably inhibited by FOXQ1 through depressing the expression of the inflammatory cytokines interleukin-6 (IL-6) and IL-8, through the modulation of SIRT1-NF-κB pathway. In addition, FOXQ1 overexpressed in human esophageal cancer cells, and the tumorigenic ability of the esophageal cancer cells (EC109 and EC9706) was restrained after the ablation of FOXQ1 in a mouse xenograft model in vivo. In conclusion, this study uncovered a role of FOXQ1 on regulating senescence-associated secretory phenotype and tumor development at the same time.
Involvement of forkhead box Q1 in signaling pathways
Classic Wnt signaling pathway played an important role in the process of embryonic development, tumor initiation, and development., The activation of Wnt signaling pathway was particularly important for the epithelial tumor.,,, In colorectal, breast, lung, gastric, and pancreatic cancers, upregulation of FOXQ1 gene expression was associated with activation of the Wnt pathway, with the target of FOXQ1 gene. Peng et al. demonstrated that FOXQ1 was overexpressed in colorectal tumor tissues and its expression level was closely correlated with the stage and lymph node metastasis of CRC. In in vitro cultured SW480 CRC cells, knockdown of FOXQ1 expression with small interfering RNA greatly diminished the aggressive tumor behaviors of SW480 cells including angiogenesis, invasion, EMT transition, and resistance to chemotherapy drug-induced apoptosis. Further investigations on mechanism showed that FOXQ1 silencing prevented the nuclear translocation of β-catenin, thus reducing the activity of Wnt signaling. Moreover, transforming growth factor-β1 (TGF-β1) induced the expression of FOXQ1, as well as the migration and invasion of SW480 cells, which was partially prevented following the knockdown of FOXQ1. This study demonstrated that FOXQ1 played a critical role during the tumorigenesis of CRC and it was a mediator of the crosstalk between Wnt and TGF-β signaling pathways.
Regulation of tumor initiation and progression by forkhead box Q1
The mRNA and protein levels of FOXQ1 in GC tissues were found to be higher than those of in corresponding paracancerous tissues. In addition, FOXQ1 overexpression has been closely associated with tumor size, pathological grade, and lymphatic metastasis. COX regression analysis indicated that FOXQ1 overexpression was closely associated with GC progression and could serve as an independent predictor of poor prognosis for GC patients. The miR-1271 expression was downregulated in both GC tissues and cells, and expression of miR-1271 was negatively correlated with tumor size, lymph node metastasis, and tumor-nodule metastasis (TNM) staging. Moreover, abnormal expression of miR-1271 significantly inhibited proliferation and invasion of GC cells and the EMT process. FOXQ1 was a direct target of miR-1271, miR-1271-inhibited proliferation and invasion of GC cells, as well as the development of EMT through direct inhibition of FOXQ1 gene expression. Zhang et al. demonstrated that FOXQ1 was overexpressed in GC tissues and its expression level was closely correlated with histologic differentiation, pTNM stage, and lymphatic metastasis of GC. Kaplan–Meier survival analysis showed that a high expression level of FOXQ1 resulted in a significantly poor prognosis of GC patients. FOXQ1 modulated GC cell invasion in vitro and induced E-cadherin repression. The Snail signaling pathway might be involved in the induction of EMT by FOXQ1 in GC. These results demonstrated that FOXQ1 was a prognostic marker for patients with GC, FOXQ1 overexpression was involved in acquisition of the mesenchymal phenotype of GC cells, and that subsequent Snail expression was essential for induction of EMT.
Feng et al. found that mRNA and protein levels of FOXQ1 were higher in nonsmall cell lung cancer (NSCLC) than that of in normal lung tissues. FOXQ1 expression in lung adenocarcinoma was higher than that of in lung squamous cell carcinoma. In addition, FOXQ1 expression was negatively correlated with E-cadherin expression, suggesting that high FOXQ1 expression was associated with the development of EMT in NSCLC cells. As the survival rate of lung cancer patients would be significantly reduced with high FOXQ1 expression and low E-cadherin expression, these factors could be applied as independent prognostic indicators to assess survival in NSCLC. Furthermore, FOXQ1 played critical roles in the development of EMT and attenuation of sensitivity to chemical-induced apoptosis in NSCLC. Studies by Xiao et al. have shown that FOXQ1 was a downstream target of miRNA-133 and miRNA-133 was involved in inhibiting lung cancer cell migration and invasion. In addition, low FOXQ1 expression in lung cancer cells was positively correlated with TGF-β expression; therefore, FOXQ1 and TGF-β might be associated with the initiation of lung cancer.
The levels of the FOXQ1 gene were detected in cervical cancer, corresponding paracancerous tissues, and normal cervical tissues. High FOXQ1 expression was observed in adjacent tissues and normal cervical tissues and low expression was observed in cervical cancer tissues. Although low FOXQ1 expression did not correlate with tissue grade and stage, it was correlated with the development of cervical cancer. Cervical cancer CaSki and SiHa cells exhibited high FOXQ1 gene expression, and cervical cancer cell proliferation and EMT could be inhibited by silencing this gene. Moreover, dual luciferase reporter gene experiments confirmed that FOXQ1 was a target gene of miRNA-506, a miRNA that inhibited cervical cancer cell proliferation and EMT by negatively regulating the expression of FOXQ1 gene.
Wang et al. detected FOXQ1 mRNA and protein expression in 114 pairs of liver cancer tissues and corresponding paracancerous tissues. The results showed that levels in the former were far greater than those of in the latter. Furthermore, the expression level of FOXQ1 was positively correlated with liver tumor diameter, the α-fetoprotein level, and tumor lymph node metastasis. Kaplan–Meier and Cox regression analyses indicated that high FOXQ1 expression and regional lymph node metastasis were independent prognostic factors in liver cancer patients. Xia et al. studied risk factors for recurrence and survival in two independent cohorts comprising 1002 HCC patients. The results revealed high FOXQ1 expression was an independent risk factor affecting HCC recurrence and survival. FOXQ1 promoted HCC metastasis by transactivating ZEB2 and VersicanV1 expression, resulting in the induction of EMT and the recruitment of tumor-associated macrophage infiltration.
Other studies have shown that FOXQ1 was a target of miR-422a. The expression level of miR-422a in liver cancer tissues was significantly lower than that of in normal liver tissues, and the expression level negatively was correlated with HCC pathological grade, recurrence, and metastasis. In addition, cell proliferation and migration would be significantly inhibited with miR-422a expression in liver cancer cells. In a subcutaneous xenograft tumor model, HCC cell growth, and intrahepatic metastasis would be significantly inhibited with high miR-422a expression. The miR-422a functioned in the initiation and progression of HCC through its target genes FOXG 1, FOXQ 1, and FOXE 1.
Huang et al. have shown that the transcription factor sex-determining region Y-box12 (Sox12) was a direct target of FOXQ1. Silencing Sox12 expression significantly reduced FOXQ1-mediated liver cancer metastasis, whereas Sox12 overexpression was significantly correlated with the loss of tumor encapsulation, microvascular invasion, and a higher TNM stage, indicating poor prognosis in human HCC patients. Sox12 expression was an independent and significant risk factor for recurrence and reduced survival after curative resection. In addition, overexpression of Sox12 induced EMT by transactivating Twist1 expression. Knockdown of Twist1 expression reduced the liver cancer migration, invasion, and metastasis abilities, whereas Twist1 overexpression led to Sox12 silencing. Thus, the migration, invasion, and metastatic capacities of HCC cells could be restored. Fibroblast growth factor-binding protein 1 (FGFBP1) was a direct transcriptional target of Sox12, and FGFBP1 silencing reduced Sox12-mediated HCC cell invasion and metastasis. These results showed that HCC invasion and metastasis were promoted with upregulated Sox12 induced by FOXQ1, by transactivating Twist1 and FGFBP1 expression.
Zhang et al. performed comparative analysis on gene expression profiles using 22 upregulated genes and 12 downregulated genes in human and murine breast cancer cells. The FOXQ1 gene was found to be an important regulatory factor associated with breast cancer cell metastasis in both species. Abnormal FOXQ1 expression increased the migration and invasion abilities of cells and induced the development of EMT and tumor. Conversely, inhibition of FOXQ1 expression reduced the migration and invasion capacities of cells.In vivo and in vitro studies on breast cancer cells have shown that administration of benzyl isothiocyanate was able to inhibit the migration of breast cancer MDA-MB-231 cells and EMT, as well as downregulating the expression levels of FOXQ1 mRNA and protein. Therefore, it has been speculated that FOXQ1 would be involved in these processes. Through selection of multiple estrogen receptor-negative human breast cancer cells, Ross et al. evaluated the determinant factors for breast cancer reinitiation and metastasis. The results revealed the importance of laminin α4 (LAMA4). LAMA4 was able to promote cell proliferation and micrometastasis formation at an early stage and to promote tumor reinitiation in multiple organs. As FOXQ1 stimulated LAMA4 expression, the former might play a decisive role in the processes of breast cancer re-initiation and metastasis.
It has also been shown that FOXQ1 induces stem cell genetic characteristics and drug resistance in mammary epithelial cells and breast cancer cells. Twist1, ZEB2, platelet-derived growth factor receptor α (PDGFRα), and PDGFRβ are all downstream genes of FOXQ1, and silencing PDGFRα and PDGFRβ together significantly reversed the effect of FOXQ 1 in promoting tumor formation. However, FOXQ1-mediated EMT development is not entirely dependent on PDGFRα and PDGFRβ though PDGFRs driven by FOXQ1 are important mediators for the initiation and drug resistance of breast cancer.
Kim et al. examined the effects of diallyl trisulfide (DATS) and FOXQ1 on breast cancer stem cells, and the results showed that DATS could inhibit breast cancer growth. The expression level of FOXQ1 in triple-negative breast cancer was significantly higher than that of in normal mammary tissues. FOXQ1 overexpression in breast cancer MCF-7 and SUM159 cells increased the activity of aldehyde dehydrogenase 1 (ALDH1), as well as the expression of breast cancer stem cell phenotypic marker molecule CD49f +/CD24−. DATS treatment of breast cancer cells overexpressing FOXQ1 significantly suppressed proliferation activity and microsphere formation ability of cancerous cells. DATS also inhibited ALDH1 activity in mouse xenografts constructed with the breast cancer cell line Sum159. This study speculated that DATS-mediated FOXQ1 gene downregulation could be used as a new method for inhibiting the proliferation of breast cancer stem cells.
Kaneda et al. found that FOXQ1 expression in CRC was higher than that of in corresponding paracancerous tissues. FOXQ1 overexpression inhibited cell proliferation while enhanced tumorigenicity and promoted tumor growth, anti-apoptotic effects, and angiogenesis, thus promoting the initiation and progression of CRC. In addition, FOXQ1 bound to the promoter region of the p21 gene to upregulate its expression and inhibit cell proliferation. It was speculated that FOXQ1 mainly participated in antiapoptosis and tumor angiogenesis to promote initiation and progression of CRC. As also revealed in our studies, it reported that the FOXQ1 gene could be used as an indicator of a poor prognosis in CRC patients. Vishnubalaji et al. showed that miR-320 was downregulated in HCT116 cells and HCT116 cell growth and invasion would be inhibited by the overexpression of miR-320c. The genes encoding transcription factors Sox4, FOXM1, and FOXQ1 were downstream targets of miR-320c, and upregulation of miR-320c in HCT116 cells increased the sensitivity of CRC cells to 5-fluorouracil, making an inhibitory effect on growth. These results suggested that the miR-320/SOX4/FOXM1/FOXQ1 axis may be a new target of CRC treatment. Weng et al. also confirmed that the high FOXQ 1 expression in CRC can be applied as an independent indicator for prognosis of these patients. Overall, after silencing FOXQ1 expression, the proliferation, migration, and invasion of CRC cells could be inhibited.
Gao et al. compared and analyzed 18 data series in a gene expression microarray dataset (GEMD). It reported that the expression level of FOXQ1 mRNA in ovarian cancer was significantly higher than that of in normal ovarian tissues. Knockout of FOXQ1 in ovarian cancer SKOV3 cells with shRNA arrested the cell cycle at the G1/S phase, and cell proliferation, invasion, and EMT were inhibited. Furthermore, Bao et al. analyzed the gene expression profile of the CD44+/CDl33+/EpCAM + cell population with tumor stem cell-like features among human pancreatic cancer cells. It showed that FOXQ1 has important regulatory significance for the maintenance of tumor stem cell characteristics. In glioma, Sun et al. detected expression FOXQ1 mRNA and protein and showed that the level was abnormally increased and negatively correlated with that of neurexin 3 (NRXN3). The study observed the cell proliferation and migration abilities of human glioma U-87MG cells with stable FOXQ1 knockdown and human astrocytoma SW1088 cells stably overexpressing FOXQ1. The results confirmed that it bound directly to the promoter region of the NRXN3 gene to inhibit expression, thus promoting the proliferation and migration of glioma cells.
| > Conclusion|| |
Due to its important functions in tumor initiation and progression, the FOXQ1 gene has gradually become a new target in cancer research. The mechanisms of FOXQ1 can be further understood through investigation of FOXQ1 gene expression and protein functions, as well as its association with tumor initiation and progression. FOXQ1 is an important oncogene; however, there were few studies on its involvement in the regulation of signaling pathways. Studies to date have mainly focused on the regulatory mechanisms of the FOXQ1 gene and the Wnt and TGF-β pathways in CRC, whereas the mechanisms underlying the regulation of signaling pathways by FOXQ1 for promoting tumor infiltration and metastasis have not been completely elucidated. Thus, in-depth studies on signaling pathways that involved FOXQ1 would be the focus of future studies.
This study was supported by National Natural Science Foundation of China (Grant No. 81502556 and 81260323), Young Academic Talents Cultivation Foundation of Yunnan Province (Grant No. 2013HB083), and Medical Discipline Leaders Cultivate Fund of Health and Family Planning Commission of Yunnan Province (Grant No. D-201642).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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