Promoter hypermethylation of LGALS4 correlates with poor prognosis in patients with urothelial carcinoma
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Meei-Maan Wu1, Ching-Fei Li2, Li-Fang Lin2, Alexander Sheng-Shin Wang3, Yeong-Shiau Pu3, Hsiu-Hua Wang2, Ai-Chung Mar2, Chien-Jen Chen4, Te-Chang Lee2
1Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
3Department of Urology, National Taiwan University Hospital, Taipei, Taiwan
4Genomics Research Center, Academia Sinica, Taipei, Taiwan
Meei-Maan Wu, email: [email protected]
Te-Chang Lee, email: [email protected]
Keywords: urothelial carcinoma, galectin-4, promoter methylation, prognosis, biomarkers
Received: July 04, 2016 Accepted: February 13, 2017 Published: March 03, 2017
Galectine-4 (gal-4), encoded by the LGALS4 gene, was recently shown to exhibit a tumor suppressive effect in colorectal carcinoma and pancreatic adenocarcinoma, although how the expression of this gene is regulated remains unknown. No reports describe the significance of gal-4 in the malignant potential of urothelial tumors. Thus, we analyzed LGALS4 methylation and gene expression and their clinical relevance and biological function in urothelial carcinoma (UC). LGALS4 methylation was initially identified as a progression biomarker for UC patients through genome-wide DNA methylation profiling of 16 tumor samples. Bisulfite sequencing PCR and immunohistochemistry were performed to validate the promoter methylation and expression of LGALS4. We used quantitative methylation-specific PCR to determine the methylation levels of LGALS4 normalized to ACTB in the tumor samples of 79 UC patients and compared the levels between patients with different clinicopathological characteristics. The association with survival probability was analyzed with the Kaplan-Meier method and Cox regression analysis. The ectopic expression of gal-4 in cancer cell lines was used to address its biological function in UC in vitro. The promoter hypermethylation of LGALS4 (>2.51, log10 scale) revealed a positive correlation with high levels of both histological grade and tumor T category and with lymph node metastasis (all P≤0.001). In addition, LGALS4 hypermethylation was an independent predictor of inferior survival in UC patients (P<0.05). The ectopic expression studies demonstrated that gal-4 suppressed urothelial cancer cell growth, migration, and invasion. Thus, LGALS4 may function as a tumor suppressor gene in UC progression. Our findings provide evidence that methylation-mediated LGALS4 gene repression may be involved in urothelial tumor progression.
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