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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. BRAFV600E 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.

SUBMITTER: Smith E

PROVIDER: S-EPMC6557614 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Smith Eric E Tomita Yoko Y Palethorpe Helen M HM Howell Stuart S Nakhjavani Maryam M Townsend Amanda R AR Price Timothy J TJ Young Joanne P JP Hardingham Jennifer E JE

Epigenetics 20190220 2

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 ...[more]

PMID: 30739527

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Project description:BackgroundSmad interacting protein-1 is a transcription factor that is implicated in transforming growth factor-?/bone morphogenetic protein signaling and a repressor of E-cadherin and human telomerase reverse transcriptase. It is also involved in epithelial-mesenchymal transition and tumorigenesis. However, genetic and epigenetic alterations of SIP1 have not been fully elucidated in cancers. In this study, we investigated mutations and promoter hypermethylation of the SIP1 gene in human hepatocellular carcinomas.MethodsSIP1 expression was analyzed in HCC cell lines and primary tumors in comparison to normal and non-tumor liver tissues by using semi-quantitative RT-PCR, quantitative real-time RT-PCR and immunohistochemistry. Mutation and deletion screening of the SIP1 gene were performed by direct sequencing in HCC-derived cells. Restoration of SIP1 expression was sought by treating HCC cell lines with the DNA methyl transferase inhibitor, 5-AzaC, and the histone deacetylase inhibitor, TSA. SIP1 promoter methylation was analyzed by the combined bisulfite restriction analysis assay in in silico-predicted putative promoter and CpG island regions.ResultsWe found that the expression of SIP1 was completely lost or reduced in five of 14 (36%) HCC cell lines and 17 of 23 (74%) primary HCC tumors. Immunohistochemical analysis confirmed that SIP1 mRNA downregulation was associated with decreased expression of the SIP1 protein in HCC tissues (82.8%). No somatic mutation was observed in SIP1 exons in any of the 14 HCC cell lines. Combined treatment with DNA methyl transferase and histone deacetylase inhibitors synergistically restored SIP1 expression in SIP1-negative cell lines. Analysis of three putative gene regulatory regions revealed tumor-specific methylation in more than half of the HCC cases.ConclusionsEpigenetic mechanisms contribute significantly to the downregulation of SIP1 expression in HCC. This finding adds a new level of complexity to the role of SIP1 in hepatocarcinogenesis.

Dataset Information

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

Publications

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

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