FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-β and miR-182-5p

Lu, Juntao; Tan, Cong-Cong; Wu, Xiaogang; He, Rui; Zhang, Xiao; Wang, Qingshan; Li, Xiaoqing; Zhang, Rui; Feng, Yuanming

doi:10.1038/s41418-020-0555-7

Cited by 28 publications

(29 citation statements)

References 47 publications

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“…FOXF2, as a transcriptional regulator, was also found to have a transcriptional repression effect on the miR-200b ∼ 200a ∼ 429 locus in lung cancer (Kundu et al, 2016). Lu et al (2020) also reported that FOXF2 can negatively regulate the transcription of TGF-β isoforms (TGFB1, TGFB2, and TGFB3) in basal-like breast cancer. Thus, FOXF2 may play a tumor suppressor role through transrepressing gene expression.…”

Section: Discussionmentioning

confidence: 86%

Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer

Zhang

Dai

2021

Front. Mol. Biosci.

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Background: The prognosis of gastric cancer (GC) patients is poor. The effect of aberrant DNA methylation on FOXF2 expression and the prognostic role of FOXF2 methylation in GC have not yet been identified.Methods: The RNA-Seq and gene methylation HM450 profile data were used for analyzing FOXF2 expression in GC and its association with methylation level. Bisulfite sequencing PCR (BSP) was performed to measure the methylation level of the FOXF2 promoter region in GC cell lines and normal GES-1 cells. The cells were treated with the demethylation reagent 5-Aza-dC, and the mRNA and protein expression levels of FOXF2 were then measured by qRT-PCR and western blot assays. The risk score system from SurvivalMeth was calculated by integrating the methylation level of the cg locus and the corresponding Cox regression coefficient.Results: FOXF2 was significantly downregulated in GC cells and tissues. On the basis of RNA-Seq and Illumina methylation 450 data, FOXF2 expression was significantly negatively correlated with the FOXF2 methylation level (Pearson’s R = −0.42, p < 2.2e−16). The FOXF2 methylation level in the high FOXF2 expression group was lower than that in the low FOXF2 expression group. The BSP assay indicated that the methylation level of the FOXF2 promoter region in GC cell lines was higher than that in GES-1 cells. The qRT-PCR and western blot assay showed that FOXF2 mRNA and protein levels were increased in GC cells following treatment with 5-Aza-Dc. The methylation risk score model indicated that patients in the high risk group had poorer survival probability than those in the low risk group (HR = 1.84 (1.11–3.07) and p = 0.0068). FOXF2 also had a close transcriptional regulation network with four miRNAs and their corresponding target genes. Functional enrichment analysis of the target genes revealed that these genes were significantly related to several important signaling pathways.Conclusion: FOXF2 was downregulated due to aberrant DNA methylation in GC, and the degree of methylation in the promoter region of FOXF2 was related to the prognosis of patients. The FOXF2/miRNAs/target genes axis may play a vital biological regulation role in GC.

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Section: Discussionmentioning

confidence: 86%

Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer

Zhang

Dai

2021

Front. Mol. Biosci.

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“…In TGF β induced EMT, FOXF2 upregulation is essential for the transcriptional inhibition of E-cadherin, destruction of cell adhesion, and EMT-related cell migration. On the other hand, TGF β and FOXF2 form a negative feedback loop mediated by miR-182-5p and SMAD3 in BLBC ( Lu et al, 2020 ). Decreased FOXF2 expression promotes TGF β signaling, which conversely silences FOXF2 by upregulating miR-182-5p.…”

Section: Survey Methodologymentioning

confidence: 99%

“…Decreased FOXF2 expression promotes TGF β signaling, which conversely silences FOXF2 by upregulating miR-182-5p. FOXF2 deficiency facilitates the visceral metastasis of BLBC ( Lu et al, 2020 ).…”

Section: Survey Methodologymentioning

confidence: 99%

The regulatory roles and mechanisms of the transcription factor FOXF2 in human diseases

You

2021

PeerJ

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Many studies have focused on the relationship between transcription factors and a variety of common pathological conditions, such as diabetes, stroke, and cancer. It has been found that abnormal transcription factor regulation can lead to aberrant expression of downstream genes, which contributes to the occurrence and development of many diseases. The forkhead box (FOX) transcription factor family is encoded by the FOX gene, which mediates gene transcription and follow-up functions during physiological and pathological processes. FOXF2, a member of the FOX transcription family, is expressed in various organs and tissues while maintaining their normal structural and functional development during the embryonic and adult stages. Multiple regulatory pathways that regulate FOXF2 may also be controlled by FOXF2. Abnormal FOXF2 expression induced by uncontrollable regulatory signals mediate the progression of human diseases by interfering with the cell cycle, proliferation, differentiation, invasion, and metastasis. FOXF2 manipulates downstream pathways and targets as both a pro-oncogenic and anti-oncogenic factor across different types of cancer, suggesting it may be a new potential clinical marker or therapeutic target for cancer. However, FOXF2’s biological functions and specific roles in cancer development remain unclear. In this study, we provide an overview of FOXF2’s structure, function, and regulatory mechanisms in the physiological and pathological conditions of human body. We also discussed the possible reasons why FOXF2 performs the opposite function in the same types of cancer.

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“…The underlying mechanism involves the reciprocal repression loop between FOXF2 and transforming growth factor-β (TGF-β) (Fig. 2 ) 39 . These groundbreaking studies provided theoretical basis for preventing breast cancer metastasis.…”

Section: Tumor Metastasismentioning

confidence: 99%

Progress of Breast Cancer basic research in China

Wang

Guan

et al. 2021

Int. J. Biol. Sci.

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Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.

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FOXF2 deficiency accelerates the visceral metastasis of basal-like breast cancer by unrestrictedly increasing TGF-β and miR-182-5p

Cited by 28 publications

References 47 publications

Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer

Aberrant DNA Methylation-Mediated FOXF2 Dysregulation Is a Prognostic Risk Factor for Gastric Cancer

The regulatory roles and mechanisms of the transcription factor FOXF2 in human diseases

Progress of Breast Cancer basic research in China

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