Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer.
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Cell Proliferation
GATA6 Transcription Factor
/ genetics
Humans
Lymphangiogenesis
Lymphatic Metastasis
Mice
Mice, Inbred BALB C
Mice, Nude
Prognosis
Survival Rate
Tumor Cells, Cultured
Urinary Bladder Neoplasms
/ genetics
Xenograft Model Antitumor Assays
GATA6
VEGF-C
bladder cancer
lymphangiogenesis
metastasis
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
18
12
2019
revised:
06
02
2020
accepted:
18
02
2020
pubmed:
28
2
2020
medline:
20
1
2021
entrez:
28
2
2020
Statut:
ppublish
Résumé
Lymph node metastasis is associated with tumor relapse and poor patient prognosis in bladder cancer. However, the mechanisms by which bladder carcinoma cells induce lymphangiogenesis and further promote metastasis in the lymphatic system remain unclear. Here, we show that the transcription factor GATA-binding factor 6 (GATA6) was substantially downregulated in bladder cancer via promoter hypermethylation. Low-level GATA6 expression significantly correlated with lymph node metastasis positivity and was able to predict earlier relapse and shorter survival of bladder cancer. Reconstitution of GATA6 inhibited lymphangiogenesis and lymph node metastasis in GATA6-low bladder cancer cells, while silencing of GATA6 rendered lymphatic metastasis in GATA6-high bladder cancer cells. Additionally, we demonstrated that GATA6 bound to the promoter of vascular endothelial growth factor (VEGF)-C, a lymphangiogenic factor, and acted as a transcriptional repressor. This GATA6/VEGF-C axis was essential for GATA6-mediated lymphatic metastasis. In bladder cancer patients, low GATA6 correlated with high VEGF-C and reduced overall survival. These findings indicate GATA6 as a pivotal regulator in the lymphatic dissemination of bladder cancer and suggest a new therapeutic target for the disease.
Identifiants
pubmed: 32103545
doi: 10.1096/fj.201903176R
doi:
Substances chimiques
Biomarkers, Tumor
0
GATA6 Transcription Factor
0
GATA6 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5754-5766Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
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