Estrogen enhances mismatch repair by induction of MLH1 expression via estrogen receptor-β
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Jun-Yu Lu1,2, Peng Jin2, Wei Gao3, De-Zhi Wang2 and Jian-Qiu Sheng2
1Third Military Medical University, Chongqing, China, 400038
2Department of Gastroenterology, PLA Army General Hospital, Beijing, China, 100700
3Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, Dalian, China, 116044
Jian-qiu Sheng, email: firstname.lastname@example.org
Keywords: colorectal cancer, estrogen, estrogen receptor beta, mismatch repair, MLH1
Received: July 22, 2016 Accepted: January 03, 2017 Published: March 18, 2017
Epidemiological data demonstrated that hormone replace treatment has protective effect against colorectal cancer (CRC). Our previous studies showed that this effect may be associated with DNA mismatch repair. This study aims to investigate the mechanism of estrogen induction of MLH1, and whether colorectal tumor proliferation can be inhibited through induction of MLH1 by estrogen signal pathway. Human CRC cell lines were used to examine the regulation of MLH1 expression by over-expression and depletion of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ), under the treatment with 17β-estradiol or β-Estradiol 6-(O-carboxy-methyl)oxime:BSA, followed by a real-time Q-PCR and Western blotting analysis. Luciferase reporter and chromatin immunoprecipitation assays were used to identify the estrogen response elements in the proximal promoter of MLH1 gene. Then, the influence of estrogen-induced MLH1 on CRC tumor growth were determined in vitro and in vivo. We found that mismatch repair ability and microsatellite stability of cells were enhanced by estrogen via induction of MLH1 expression, which was mediated by ERβ, through a transcriptional activation process. Furthermore, we identified that ERβ exerted an inhibitory effect on CRC tumor proliferation in vitro and in vivo, combined with 5-FU, through up-regulation of MLH1 expression. Finally, we concluded that estrogen enhances mismatch repair ability and tumor inhibition effect in vitro and in vivo, via induction of MLH1 expression mediated by ERβ.
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