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Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer.

ABSTRACT: The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer.

SUBMITTER: Kang MH

PROVIDER: S-EPMC5954140 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer.

Kang Myoung-Hee MH Choi Hyunji H Oshima Masanobu M Cheong Jae-Ho JH Kim Seokho S Lee Jung Hoon JH Park Young Soo YS Choi Hueng-Sik HS Kweon Mi-Na MN Pack Chan-Gi CG Lee Ju-Seog JS Mills Gordon B GB Myung Seung-Jae SJ Park Yun-Yong YY

Nature communications 20180515 1

The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling su ...[more]

PMID: 29765046

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Project description:BACKGROUND:In our previous study, we identified a candidate tumor suppressor gene, testin LIM domain protein (TES), in primary gastric cancer (GC). TES contains three LIM domains, which are specific interacting regions for the cell adhesion and cytoskeleton regulatory proteins. Mena is a known cytoskeleton regulator that regulates the assembly of actin filaments and modulates cell adhesion and motility by interacting with Lamellipodin (Lpd). Therefore, we hypothesized that TES plays a role as tumor suppressor in GC through interacting with Mena. This study aimed to investigate the tumor suppressive functions of TES in GC. METHODS:We explored the tumor suppressive effect of TES in GC by in vitro cell proliferation assay, colony formation assay, cell cycle analysis, Transwell assays, and in vivo tumorigenicity and metastasis assays. The interaction of TES and Mena was investigated through immunoprecipitation-based mass spectrometry. We also analyzed the expression of TES and Mena in 172 GC specimens using immunohistochemistry and investigated the clinicopathological and prognostic significance of TES and Mena in GC. RESULTS:TES suppressed GC cell proliferation and colony formation, induced cell cycle arrest, and inhibited tumorigenicity in vitro. Additionally, it inhibited GC cell migration and invasion in vitro and suppressed metastasis in vivo. TES interacted with Mena, and inhibited the interaction of Mena with Lpd. Transwell assays suggested that TES suppressed migration and invasion of GC cells in a Mena-dependent fashion. In GC patients with high Mena expression, the expression of TES was associated with tumor infiltration (P?=?0.005), lymph node metastasis (P?=?0.003), TNM stage (P?=?0.003), and prognosis (P?=?0.010). However, no significant association was observed in GC patients with low Mena expression. CONCLUSIONS:We believe that TES functions as a Mena-dependent tumor suppressor. TES represents a valuable prognostic marker and potential target for GC treatment.

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Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer.

Publications

Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer.

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