Reduced aquaporin-1 transcript expression in colorectal carcinoma is associated with promoter hypermethylation

Abstract

Aquaporin-1 (AQP1) is a homo-tetrameric transmembrane protein that facilitates rapid movement of water and ions across cell membranes. The clinical significance of AQP1 expression in colorectal carcinoma (CRC) is controversial. The aim of this study was to investigate the prognostic significance of AQP1 transcript expression and the association between expression and promoter methylation in normal colonic mucosa, CRC tissues and cell lines. Analysis of publicly available datasets from The Cancer Genome Atlas revealed that AQP1 expression was significantly decreased in CRC compared to normal mucosa (12.7 versus 33.3 respectively, P < 0.0001). However, expression increased with advanced disease, being significantly higher in stage IV (17.6) compared to either stage I (11.8, P = 0.0039) or II (10.9; P = 0.0023), and in patients with lymph node metastasis compared to those without (13.9 versus 11.3 respectively, P = 0.0023). Elevated expression was associated with decreased overall survival with univariate (Cox Proportional Hazard Ratio 1.60, 95% confidence interval 1.05-2.42, P = 0.028), but not multivariable analysis when considering the confounders stage and age. Analysis of HumanMethylation450 data demonstrated that AQP1 promoter methylation was significantly increased in CRC compared to normal mucosa. Analysis of CRC tissues and cell lines strongly suggested that methylation was associated with decreased expression. BRAF V600E mutation alone did not explain the increase in methylation. In conclusion, AQP1 transcript expression was decreased in CRC compared to normal mucosa, and this was associated with AQP1 promoter hypermethylation. AQP1 transcript expression increased with advanced disease but was not an independent prognostic indicator.

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

“… Forest plots compiled for aquaporin (AQP) classes, with hazard ratio and confidence interval (CI) data extracted from the published literature, based on analyses of levels of protein, RNA or both. References listed in the figure as [ref] for data sources are as follows: [ 1 ] Angelico, 2018 [ 45 ]; [ 2 , 24 ] Bellezza, 2017 [ 46 ]; [ 3 ] Kang, 2015 [ 47 ]; [ 4 ] Kao, 2012 [ 48 ]; [ 5 ] Luo, 2017 [ 44 ]; [ 6 ] Otterbach, 2010 [ 49 ]; [ 7 ] Park, 2017 [ 50 ]; [ 8 ] Qin, 2016 [ 51 ]; [ 9 , 20 , 23 , 29 ] Sato, 2018 [ 52 ]; [ 10 ] Sekine, 2014 [ 53 ]; [ 11 ] Smith, 2019 [ 54 ]; [ 12 , 14 , 15 , 21 , 22 , 25 , 26 , 27 , 30 ] Thapa, 2018 [ 55 ]; [ 13 ] Yoshida, 2013 [ 56 ]; [ 16 ] Chae, 2015 [ 57 ]; [ 17 ] Liu, 2013 [ 58 ]; [ 18 , 28 ] Peng, 2016 [ 59 ]; [ …”

Integrative Analysis Reveals Comprehensive Altered Metabolic Genes Linking with Tumor Epigenetics Modification in Pan-Cancer

“…Among these genes, we found numerous genes whose function in tumorigenesis and their expression associated with promoter hypermethylation or hypomethylation were well-documented in the literature. ZNF154 and AQP1 , whose hypermethylated patterns are biomarkers for distinguishing tumor from normal samples [41, 42], are downregulated and hypermethylated in BRCA and LUAD in our study. In addition, hypermethylation and downregulation of PPP2R2B, whose mRNA expression is in a DNMT-dependent manner [43], were found in BRCA.…”

Stereoselective Anti-Cancer Activities of Ginsenoside Rg3 on Triple Negative Breast Cancer Cell Models

“…In particular, our aim was to investigate whether these two epimers have effects on different functions on TNBC in cell line models, including proliferation, apoptosis, cell cycle, migration and invasion. Furthermore, in line with our previous research focus [28,34,35,36,37], we investigated the interaction of Rg3 epimers with AQP1 in in silico models.…”