The Role And Mechanism Of Loss Expression Of GATA6 In Promoting Lymphatic Metastasis In Bladder Cancer

Human bladder cancer is one of the most aggressive and lethal malignancies.Over the past decades,despite the advances in diagnosis and surgery,little progress had been made in the treatment of bladder cancer.Notably,bladder carcinoma cells were prone to metastasize to regional lymph nodes,with up to 25%of patients were found to harbor metastatic lymph node deposits at the time of cystectomy.The positivity and number of regional lymph node metastases were considered a crucial step in the development of distant metastasis and were significantly associated with the recurrence of bladder cancer,with an average patient survival rate of only 35%.Thus,there is an urgent need to investigate the underlying mechanisms of the lymphatic dissemination in the context of bladder cancer.Tumor-induced lymphangiogenesis,a process to generate new lymphatic vessels around the tumors,is thought to be an important step in the lymphatic spread of cancer.The process of lymphangiogenesis can be effectively provoked by tumor-secreted lymphangiogenic growth factors,such as those in the vascular endothelial growth factor(VEGF)receptor family(VEGF-C and VEGF-D),which bind to their cognate VEGFR-3 receptor and induce its activation to stimulate proliferation and migration of lymphatic endothelial cells.While VEGF-D factor is the newly identified member in lymphangiogenesis,VEGF-C is the first identified putative lymphangiogenic growth factor,and has been constantly shown upregulated and correlated with lymph node metastasis and poor survival rates of cancer patients.Importantly,the recognition of VEGF-C/VEGFR3 axis function in tumor-associated lymphangiogenesis has suggested that blocking the VEGF-C/VEGFR3 signaling might be a useful therapeutic strategy to restrict lymphatic spread.Further investigation of the mechanisms that modulate the expression of VEGF-C in bladder cancer is necessary for discovering potential therapeutic molecules to control disease progression.GATA6,a member of the GATA family(GATA1?6),is a zinc finger transcription factor that regulates the transcription of target genes by regulating the assessments of transcriptional co-factors and RNA polymerase ? on proximal promoters.The GATA6 gene is highly expressed in the embryonic endoderm and mesoderm,which plays an important role in the regulation of cellular differentiation and organogenesis during vertebrate development.Dysregulation of GATA6 has been implicated in many human diseases including cancers.Although high expression of GATA6 was found in several types of cancer,GATA6 was downregulated and played tumor-suppressive roles by inhibiting cell proliferation,migration,invasion,epithelial-mesenchymal transition,stem cell-like properties and metastasis in pancreatic,lung,liver,ovarian and gastric cancers.However,the role of GATA6 in bladder cancer remains unknown.In this study,we found that GATA6 was remarkably decreased in bladder cancer by frequent promoter methylation.Overexpression of GATA6 substantially suppressed bladder cancer cell-associated lymphangiogenesis and lymphatic metastasis,while the silencing of GATA6 showed opposite effects.We also found that GATA6 directly inhibited the transcription of VEGF-C in vitro,which was required for low GATA6-mediated lymphatic metastasis.Furthermore,we showed that the GATA6/VEGF-C axis was clinically relevant and correlated with poor prognosis in bladder cancer patients.Taken together,these findings provide a novel mechanism for the regulation of VEGF-C to facilitate lymphatic metastasis in bladder cancer and suggest that GATA6 may serve as a potential marker or therapeutic target.