Article ; Online: Epigenetic silencing of the dual-role signal mediator, ANGPTL4 in tumor tissues and its overexpression in the urothelial carcinoma microenvironment.
2017 Volume 37, Issue 5, Page(s) 673–686
Abstract: Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 ( ... ...
| Abstract | Urothelial carcinoma (UC) carcinogenesis has been hypothesized to occur through epigenetic repression of tumor-suppressor genes (TSGs). By quantitative real-time polymerase chain reaction array, we found that one potential TSG, angiopoietin-like 4 (ANGPTL4), was expressed at very low levels in all bladder cancer cell lines we examined. Previous studies had demonstrated that ANGPTL4 is highly expressed in some cancers, but downregulated, by DNA methylation, in others. Consequently, owing to these seemingly conflicting functions in distinct cancers, the precise role of ANGPTL4 in the etiology of UC remains unclear. In this study, using methylation-specific PCR and bisulfite pyrosequencing, we show that ANGPTL4 is transcriptionally repressed by DNA methylation in UC cell lines and primary tumor samples, as compared with adjacent noncancerous bladder epithelium. Functional studies further demonstrated that ectopic expression of ANGPTL4 potently suppressed UC cell proliferation, monolayer colony formation in vitro, and invasion, migration, and xenograft formation in vivo. Surprisingly, circulating ANGPTL4 was significantly higher in plasma samples from UC patients than normal control, suggesting it might be secreted from other cell types. Interestingly, our data also indicated that exogenous cANGPTL4 could promote cell proliferation and cell migration via activation of signaling through the Erk/focal adhesion kinase axis. We further confirmed that mouse xenograft tumor growth could be promoted by administration of exogenous cANGPTL4. Finally, immunohistochemistry demonstrated that ANGPTL4 was downregulated in tumor cells but overexpressed in tumor adjacent stromal tissues of muscle-invasive UC tissue samples. In conclusion, our data support dual roles for ANGPTL4 in UC progression, either as a tumor suppressor or oncogene, in response to microenvironmental context. |
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| MeSH term(s) | Aged ; Aged, 80 and over ; Angiopoietin-like 4 Protein/blood ; Angiopoietin-like 4 Protein/genetics ; Angiopoietin-like 4 Protein/metabolism ; Animals ; Carcinogenesis/genetics ; Carcinoma, Transitional Cell/genetics ; Carcinoma, Transitional Cell/pathology ; Carcinoma, Transitional Cell/surgery ; Case-Control Studies ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation/genetics ; Cystectomy ; DNA Methylation/genetics ; Down-Regulation ; Epigenesis, Genetic/genetics ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Genes, Tumor Suppressor ; Humans ; Male ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Middle Aged ; Oncogenes/genetics ; Promoter Regions, Genetic/genetics ; Signal Transduction ; Tumor Microenvironment ; Urinary Bladder/pathology ; Urinary Bladder/surgery ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology ; Urothelium/pathology ; Xenograft Model Antitumor Assays |
| Chemical Substances | ANGPTL4 protein, human ; Angiopoietin-like 4 Protein |
| Language | English |
| Publishing date | 2017-10-16 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639046-8 |
| ISSN | 1476-5594 ; 0950-9232 |
| ISSN (online) | 1476-5594 |
| ISSN | 0950-9232 |
| DOI | 10.1038/onc.2017.375 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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