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Digestive Diseases and Sciences
Published in: Digestive Diseases and Sciences 10/2022

07-01-2022 | Metastasis | Original Article

KISS-1, Mediated by Promoter Methylation, Suppresses Esophageal Squamous Cell Carcinoma Metastasis via MMP2/9/MAPK Axis

Authors: Houyu Duan, Xiang Ding, Hesheng Luo

Published in: Digestive Diseases and Sciences | Issue 10/2022

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Abstract

Background and Aims

KISS-1 is an established tumor suppressor that inhibits metastases in various malignancies. However, little is known regarding its role in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to identify the possible mechanisms of KISS-1 in ESCC metastasis.

Methods

The expression levels of KISS-1 mRNA and protein in ESCC samples and cell lines were analyzed by qRT-PCR, IHC, and western blotting. Bisulfite sequencing PCR (BSP) and methylation-specific PCR (MSP) were used to analyze the methylation pattern of KISS-1 promoter in ESCC cells with or without 5-Aza-dC treatment. The role of KISS-1 in the progression and metastasis of ESCC was analyzed through in vitro functional assays.

Results

KISS-1 mRNA and protein were markedly downregulated in ESCC tissues and cell lines compared to the respective controls. Hypermethylation of KISS-1 promoter correlated to its lower expression levels in ESCC, and KISS-1 demethylation inhibited tumor progression. Ectopic KISS-1 overexpression inhibited tumor cell metastasis in vitro. In addition, KISS-1 overexpression downregulated the matrix metalloproteinase 2 and 9 (MMP2 and 9) and inhibited epithelial–mesenchymal transition (EMT). Finally, KISS-1 downregulated phosphorylated extracellular regulated protein kinase 1/2 (ERK1/2) and phosphorylated p38 mitogen-activated protein kinase (MAPK) without affecting their total expression levels in the ESCC cells. MAPK/ERK and p38 MAPK agonists reversed the suppressive effects of KISS-1.

Conclusions

The hypermethylation of KISS-1 promoter partly contributed to its downregulation in ESCC. KISS-1 inhibits the metastasis of ESCC cells by targeting the MMP2/9/ERK/p38 MAPK axis.
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Metadata
Title
KISS-1, Mediated by Promoter Methylation, Suppresses Esophageal Squamous Cell Carcinoma Metastasis via MMP2/9/MAPK Axis
Authors
Houyu Duan
Xiang Ding
Hesheng Luo
Publication date
07-01-2022
Publisher
Springer US
Keyword
Metastasis
Published in
Digestive Diseases and Sciences / Issue 10/2022
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-021-07335-1

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