Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Lin, Yi-Chun; Shyu, Woei Cherng; Chang, Chi Wei; Wang, Chi Chung; Wu, Chung Pu; Lee, Hsu Tung; Chen, Liang-Jwu; Hsieh, Chi-Hsun

doi:10.7150/thno.17895

Cited by 32 publications

(35 citation statements)

References 47 publications

(50 reference statements)

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“…Hypoxia exerts a crucial role in the tumor microenvironment, particularly in solid tumors (4). Accumulating evidence shows that hypoxia plays a key role in tumorigenesis, including angiogenesis and migration (5)(6)(7). Hypoxia-inducible factor-1α (HIF-1α) is sensitive to cellular oxygen levels, and is stabilized under conditions of hypoxia such that it may activate its target genes (8), particularly vascular endothelial growth factor (VEGF) (9).…”

Section: Introductionmentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF-1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF-1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real-time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF-1α was significantly upregulated in GBC tissues. HIF-1α overexpression was closely associated with lymph node metastasis and tumor-lymph node-metastasis (TNM) stages. HIF-1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC-SD cells, an effect which was partly reversed by small-interfering RNA HIF-1α (siHIF-1α) and 2-methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia-induced migration via HIF-1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF-1α and VEGF in a GBC-SD cell xenograft model. Taken together, these results suggest that HIF-1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF-1α/VEGF pathway.

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Section: Introductionmentioning

confidence: 99%

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Chen

et al. 2018

Oncol Rep

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“…ChIP and real-time PCR assays confirmed the binding of FOXC1 to the beta-catenin promoter (− 997/− 987). Beta-catenin is considered to be a major contributor to high metastatic potential, a characteristic of CSCs [ 41 , 57 ], and FOXC1 has been proven to promote metastasis in NSCLC [ 18 , 19 ]. These observations are consistent with our finding that FOXC1 promotes beta-catenin expression.…”

Section: Discussionmentioning

confidence: 99%

FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

Cao

Wang

Gao

et al. 2018

J Exp Clin Cancer Res

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BackgroundAccumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC).MethodsWe analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133+ cells was analyzed by flow cytometric analysis. Self-renewal ability was detected by sphere-formation analysis. Real-time PCR, western blotting and immunohistochemical staining were employed to detect mRNA and protein levels. Tumorigenicity was determined based on a xenograft formation assay, and effects of FOXC1 on drug resistance were assessed by cell viability and apoptosis assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to investigate the binding of FOXC1 to beta-catenin promoter.ResultsFOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133+ cell percentage, suppressed self-renewal ability, decreased expression of stemness-related genes (Oct4, NANOG, SOX2 and ABCG2) and inhibited NSCLC cell tumorigenicity in vivo. Moreover, FOXC1 knockdown increased cisplatin and docetaxel sensitivity and reduced gefitinib resistance, whereas FOXC1 overexpression enhanced CSC-like properties. Luciferase reporter and ChIP assays showed beta-catenin to be a direct transcriptional target of FOXC1. Furthermore, overexpression of beta-catenin reversed the CSC-like property inhibition induced by FOXC1 knockdown, and knockdown of beta-catenin attenuated the CSC-like properties induced by FOXC1 overexpression.ConclusionsThis study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC.

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“…FOXC1, which is a novel hypoxiainduced transcription factor, is upregulated in hypoxic areas of lung cancer tissues and plays a key role in the tumor microenvironment and promotes lung cancer progression [17]. TGF-β1 is a key mediator of fibrosis and induces the differentiation of fibroblasts into myofibroblasts, which are the effector cells in asthma whose expression is increased in asthma [46].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200a Affects the Proliferation of Airway Smooth Muscle Cells and Airway Remodeling by Targeting FOXC1 via the PI3K/AKT Signaling Pathway in Ovalbumin-Induced Asthmatic Mice

Liu¹,

Miao²,

Gào³

et al. 2018

Cell Physiol Biochem

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Background/Aims: The etiology of asthma, which is a complicated disorder with various symptoms, including wheezing, coughing, and airflow obstruction, remains poorly understood. In addition, the effects of microRNAs (miRs) have not been explored. This study explored the effect of microRNA-200a (miR-200a) on airway smooth muscle cells (ASMCs) and airway remodeling in asthmatic mice. Furthermore, we speculated that miR-200a achieves its effect by targeting FOXC1 via the PI3K/AKT signaling pathway based on differentially expressed gene screening, target miR predictions and a bioinformatics analysis. Methods: Eighty mice were assigned to a saline group or an ovalbumin (OVA) group, and the OVA group was transfected with a series of inhibitors, activators, and siRNAs to test the established mouse model. Airway reactivity and the ratio of eosinophils (EOSs) to leukocytes were detected. An ELISA was adopted to measure the levels of interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor (TNF)-α, and immunoglobulin E (IgE). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to determine the expression of FOXC1, PI3K, AKT, NF-κB, cyclin D1, TGF-β1 and p-AKT in ASMCs. Finally, CCK-8 assays were performed to detect cell proliferation and flow cytometry to detect apoptosis and cell cycle entry. Results: The bioinformatics analysis indicated that miR-200a mediated the PI3K/AKT signaling pathway by targeting FOXC1. In addition, mouse models of asthma were established. An elevated expression of miR-200a, a decreased mRNA and protein expression of FOXC1, PI3K, AKT, NF-κB, cyclin D1 and TGF-β1, a decreased expression of p-AKT, suppressed cell proliferation, accelerated apoptosis, and an increased number of cells at the G0/G1 phase were observed following the upregulation of miR-200a and downregulation of FOXC1. Conclusion: The overexpression of miR-200a may downregulate FOXC1, thereby inhibiting the activation of the PI3K/AKT signaling pathway and ultimately suppressing ASMC proliferation and airway remodeling in asthmatic mice. This evidence supports the potential that miR-200a represents a new approach to treating asthma.

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Tumor Hypoxia Regulates Forkhead Box C1 to Promote Lung Cancer Progression

Cited by 32 publications

References 47 publications

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

Metformin suppresses hypoxia‑induced migration via the HIF‑1α/VEGF pathway in gallbladder cancer in�vitro and in�vivo

FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC

MicroRNA-200a Affects the Proliferation of Airway Smooth Muscle Cells and Airway Remodeling by Targeting FOXC1 via the PI3K/AKT Signaling Pathway in Ovalbumin-Induced Asthmatic Mice

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