Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Ovarian Cancer | Primary research

FOXD3 may be a new cellular target biomarker as a hypermethylation gene in human ovarian cancer

Authors: Gui-fang Luo, Chang-ye Chen, Juan Wang, Hai-yan Yue, Yong Tian, Ping Yang, Yu-kun Li, Yan Li

Published in: Cancer Cell International | Issue 1/2019

Login to get access

Abstract

Background

FOXD3 is aberrantly regulated in several tumors, but its underlying mechanisms in ovarian cancer (OC) remains largely unknown. The present study aimed to explore the role and associated mechanisms of FOXD3 in OC.

Methods

Microarray data from GEO was used to analyze differential CpG sites and differentially methylated regions (DMR) in tumor tissues and Illumina 450 genome-wide methylation data was employed. The FOXD3 expression level was determined through qRT-PCR and western blot analysis. Wound healing test, colony formation and flow cytometry assay were utilized to analyze cell migration, proliferation abilities, cell cycle and cell apoptosis, respectively. Finally, the effect of FOXD3 on tumor growth was investigated through in vivo xenograft experiments.

Results

GEO data analysis showed that FOXD3 was hypermethylated in OC tissues. Also, qRT-PCR revealed that FOXD3 was low expressed and methylation-specific PCR (MSP) confirmed that the methylation level of FOXD3 was hypermethylated. Combined treatment of 5-aza-2′-deoxycytidine (5-Aza-dC) could synergistically restored FOXD3 expression. Finally, in vitro and in vivo experiments showed that demethylated FOXD3 decreased cell proliferation and migration abilities, and increased the cell apoptosis. In vivo experiment detected that demethylated FOXD3 restrained tumor growth.

Conclusions

FOXD3 could act as a tumor suppressor to inhibit cell proliferation, migration and promote cell apoptosis in OC cells.
Appendix
Available only for authorised users
Literature
1.
2.
Kroeger PT Jr, Drapkin R. Pathogenesis and heterogeneity of ovarian cancer. Curr Opin Obstet Gynecol. 2017;29(1):26–34.CrossRefPubMed
3.
Zhu H, Zhu X, Zheng L, Hu X, Sun L, Zhu X. The role of the androgen receptor in ovarian cancer carcinogenesis and its clinical implications. Oncotarget. 2017;8(17):29395–405.CrossRefPubMed
4.
Koukoura O, Spandidos DA, Daponte A, Sifakis S. DNA methylation profiles in ovarian cancer: implication in diagnosis and therapy (review). Mol Med Rep. 2014;10(1):3–9.CrossRefPubMedCentralPubMed
5.
Chao TK, Huang TS, Liao YP, Huang RL, Su PH, Shen HY, Lai HC, Wang YC. Pyruvate kinase M2 is a poor prognostic marker of and a therapeutic target in ovarian cancer. PLoS ONE. 2017;12(7):e0182166.CrossRefPubMedCentralPubMed
6.
Earp MA, Cunningham JM. DNA methylation changes in epithelial ovarian cancer histotypes. Genomics. 2015;106(6):311–21.CrossRefPubMed
7.
Cardenas H, Vieth E, Lee J, Segar M, Liu Y, Nephew KP, Matei D. TGF-beta induces global changes in DNA methylation during the epithelial-to-mesenchymal transition in ovarian cancer cells. Epigenetics. 2014;9(11):1461–72.CrossRefPubMedCentralPubMed
8.
Vo LT, Thuan TB, Thu DM, Uyen NQ, Ha NT, To TV. Methylation profile of BRCA1, RASSF1A and ER in Vietnamese women with ovarian cancer. Asian Pac J Cancer Prev. 2013;14(12):7713–8.CrossRefPubMed
9.
Zhu L, Zhang S, Jin Y. Foxd3 suppresses NFAT-mediated differentiation to maintain self-renewal of embryonic stem cells. EMBO Rep. 2014;15(12):1286–96.CrossRefPubMedCentralPubMed
10.
Zhao H, Chen D, Wang J, Yin Y, Gao Q, Zhang Y. Downregulation of the transcription factor, FoxD3, is associated with lymph node metastases in invasive ductal carcinomas of the breast. Int J Clin Exp Pathol. 2014;7(2):670–6.PubMedPubMedCentral
11.
Weiss MB, Abel EV, Dadpey N, Aplin AE. FOXD3 modulates migration through direct transcriptional repression of TWIST1 in melanoma. Mol Cancer Res. 2014;12(9):1314–23.CrossRefPubMedCentralPubMed
12.
Kubic JD, Lui JW, Little EC, Ludvik AE, Konda S, Salgia R, Aplin AE, Lang D. PAX3 and FOXD3 promote CXCR4 expression in melanoma. J Biol Chem. 2015;290(36):21901–14.CrossRefPubMedCentralPubMed
13.
Du W, Pang C, Wang D, Zhang Q, Xue Y, Jiao H, Zhan L, Ma Q, Wei X. Decreased FOXD3 expression is associated with poor prognosis in patients with high-grade gliomas. PLoS ONE. 2015;10(5):e0127976.CrossRefPubMedCentralPubMed
14.
Xie MY, Yang Y, Liu P, Luo Y, Tang SB. 5-Aza-2′-deoxycytidine in the regulation of antioxidant enzymes in retinal endothelial cells and rat diabetic retina. Int J Ophthalmol. 2019;12(1):1–7.PubMedPubMedCentral
15.
Joung JG, Kim D, Kim KH, Kim JH. Extracting coordinated patterns of DNA methylation and gene expression in ovarian cancer. J Am Med Inform Assoc. 2013;20(4):637–42.CrossRefPubMedCentralPubMed
16.
Fang F, Munck J, Tang J, Taverna P, Wang Y, Miller DF, Pilrose J, Choy G, Azab M, Pawelczak KS, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res. 2014;20(24):6504–16.CrossRefPubMedCentralPubMed
17.
Koestler DC, Chalise P, Cicek MS, Cunningham JM, Armasu S, Larson MC, Chien J, Block M, Kalli KR, Sellers TA, et al. Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer. BMC Med Genomics. 2014;7:8.CrossRefPubMedCentralPubMed
18.
Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92.CrossRefPubMed
19.
Li D, Mei H, Qi M, Yang D, Zhao X, Xiang X, Pu J, Huang K, Zheng L, Tong Q. FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget. 2013;4(11):2021–44.PubMedPubMedCentral
20.
Li K, Guo Q, Yang J, Chen H, Hu K, Zhao J, Zheng S, Pang X, Zhou S, Dang Y, et al. FOXD3 is a tumor suppressor of colon cancer by inhibiting EGFR-Ras-Raf-MEK-ERK signal pathway. Oncotarget. 2017;8(3):5048–56.PubMed
21.
Yan JH, Zhao CL, Ding LB, Zhou X. FOXD3 suppresses tumor growth and angiogenesis in non-small cell lung cancer. Biochem Biophys Res Commun. 2015;466(1):111–6.CrossRefPubMed
22.
Liu LL, Lu SX, Li M, Li LZ, Fu J, Hu W, Yang YZ, Luo RZ, Zhang CZ, Yun JP. FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. Oncotarget. 2014;5(13):5113–24.PubMedPubMedCentral
23.
Yan F, Shen N, Pang J, Molina JR, Yang P, Liu S. The DNA methyltransferase DNMT1 and tyrosine-protein kinase KIT cooperatively promote resistance to 5-Aza-2′-deoxycytidine (decitabine) and midostaurin (PKC412) in lung cancer cells. J Biol Chem. 2015;290(30):18480–94.CrossRefPubMedCentralPubMed
24.
Shen N, Yan F, Pang J, Wu LC, Al-Kali A, Litzow MR, Liu S. A nucleolin-DNMT1 regulatory axis in acute myeloid leukemogenesis. Oncotarget. 2014;5(14):5494–509.PubMedPubMedCentral
25.
Lin RK, Hsu HS, Chang JW, Chen CY, Chen JT, Wang YC. Alteration of DNA methyltransferases contributes to 5′CpG methylation and poor prognosis in lung cancer. Lung Cancer. 2007;55(2):205–13.CrossRefPubMed
26.
Shang D, Han T, Xu X, Liu Y. Decitabine induces G2/M cell cycle arrest by suppressing p38/NF-kappaB signaling in human renal clear cell carcinoma. Int J Clin Exp Pathol. 2015;8(9):11140–8.PubMedPubMedCentral
27.
Meng F, Sun G, Zhong M, Yu Y, Brewer MA. Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2′-deoxycytidine on ovarian cancer. Br J Cancer. 2013;108(3):579–86.CrossRefPubMedCentralPubMed
Metadata
Title
FOXD3 may be a new cellular target biomarker as a hypermethylation gene in human ovarian cancer
Authors
Gui-fang Luo
Chang-ye Chen
Juan Wang
Hai-yan Yue
Yong Tian
Ping Yang
Yu-kun Li
Yan Li
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0755-8

Other articles of this Issue 1/2019

Cancer Cell International 1/2019 Go to the issue

Primary research

A signature of hypoxia-related factors reveals functional dysregulation and robustly predicts clinical outcomes in stage I/II colorectal cancer patients

Primary research

Relationship between the upregulation of Notch1 signaling and the clinical characteristics of patients with papillary thyroid carcinoma in East Asia: a systematic review and meta-analysis

Primary research

Oncogenic effect of PHLDB2 is associated with epithelial–mesenchymal transition and E-cadherin regulation in colorectal cancer

Primary research

Down-regulation of miR-29c is a prognostic biomarker in acute myeloid leukemia and can reduce the sensitivity of leukemic cells to decitabine

Primary research

AGI-134: a fully synthetic α-Gal glycolipid that converts tumors into in situ autologous vaccines, induces anti-tumor immunity and is synergistic with an anti-PD-1 antibody in mouse melanoma models

Primary research

Sulforaphene induces apoptosis and inhibits the invasion of esophageal cancer cells through MSK2/CREB/Bcl-2 and cadherin pathway in vivo and in vitro
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits