Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer
Loss of GATA6 expression promotes lymphatic metastasis in bladder cancer
复制标题
GATA6表达缺失促进膀胱癌淋巴转移
DOI：
10.1096/fj.201903176r
复制
发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Chen Xu
中科院分区：
文献类型：
--
作者：
Wang Chanjuan;Liu Qinghua;Huang Ming;Zhou Qianghua;Zhang Xiaoyu;Zhang Jingtong;Xie Ruihui;Yu Yanqi;Chen Shang;Fan Jianbing;Chen Xu
膀胱癌淋巴结转移与肿瘤复发和患者预后不良相关。然而，膀胱癌细胞诱导淋巴管生成并进一步促进淋巴系统转移的机制仍不清楚。在这里，我们表明，转录因子加塔-结合因子6（GATA 6）在膀胱癌中通过启动子高甲基化显著下调。低水平GATA 6表达与淋巴结转移阳性显著相关，并且能够预测膀胱癌的早期复发和较短的生存期。GATA6的重建抑制GATA6低膀胱癌细胞中的淋巴管生成和淋巴结转移，而GATA6的沉默导致GATA6高膀胱癌细胞中的淋巴转移。此外，我们证明了GATA 6与血管内皮生长因子（VEGF）-C（一种淋巴管生成因子）的启动子结合，并作为转录抑制因子。该GATA6/VEGF-C轴对于GATA6介导的淋巴转移是必需的。在膀胱癌患者中，低GATA 6与高VEGF-C和总生存率降低相关。这些发现表明GATA 6是膀胱癌淋巴转移的关键调节因子，并为该疾病提供了新的治疗靶点。
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.
登录
查看更多内容
影响因子：
50.3
作者：
De Carvalho DD;Sharma S;You JS;Su SF;Taberlay PC;Kelly TK;Yang X;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
--
作者：
Faleiro I;Leão R;Binnie A;de Mello RA;Maia AT;Castelo-Branco P
通讯作者：
Castelo-Branco P
影响因子：
24.5
作者：
Martinelli P;Carrillo-de Santa Pau E;Cox T;Sainz B Jr;Dusetti N;Greenhalf W;Rinaldi L;Costello E;Ghaneh P;Malats N;Büchler M;Pajic M;Biankin AV;Iovanna J;Neoptolemos J;Real FX
通讯作者：
Real FX
影响因子：
82.9
作者：
Skobe, M;Hawighorst, T;Detmar, M
通讯作者：
Detmar, M
GATA6通过调节miR-520b/CREB1轴抑制胃癌迁移和转移
影响因子：
9
作者：
Liu, Hao;Du, Feng;Zhao, Xiaodi
通讯作者：
Zhao, Xiaodi