Estrogen-related receptor-gamma influences Helicobacter pylori infection by regulating TFF1 in gastric cancer
Introduction
Gastric cancer (GC) is the most common cancer globally and predominantly in Eastern Asia [1]. While surgical resection is the standard regimen for early-stage GC, use of standard treatment in the advanced and late stages is very limited [2]. Several molecular therapeutic options using monoclonal antibodies, such as trastuzumab and bevacizumab, have been widely used for GC patients [3]. Recently developed immune therapies modulating T-cell activation have emerged as a new therapeutic option [4]. However, immunotherapy has minimal success rate, demonstrating that effective new molecular targets for treatment are urgently required [[4], [5], [6]].
Since the detailed molecular mechanism of GC development is poorly understood, the development of therapeutic targets is delayed, suggesting that a biological understanding of GC is crucial for treatment regimens [7,8]. Of the many factors contributing to GC, Helicobacter pylori infection, classified as a class I carcinogen by the WHO, is a causative agent of GC [9]. Helicobacter pylori infection leads to chronic inflammation, which eventually promotes GC [10]. However, the molecular mechanisms governing the relationship between H. pylori infection and GC development are not clearly understood.
The imbalance between tumor suppressors and oncogenes influences GC development. For example, conventional tumor suppressors TP53 and PTEN play a crucial role in tumorigenesis [8] and RUNX3 [11] and ESRRG [12] act as gastric-specific tumor suppressors due to their restricted expression patterns. Deregulation of tumor suppressors is a critical step in tumorigenesis, although the molecular mechanisms of tumor suppression vary. Thus, modulation of tumor-suppressive transcription factors is well recognized as an effective therapeutic strategy for cancer [12].
Helicobacter pylori infection is a major contributing factor to GC [13]. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB), a well-known transcriptional regulator of inflammation, is induced by H. pylori and is involved in GC development [14]. However, the relationship between tumor suppressors and H. pylori infection is not well established in GC. Previously, we identified that ESRRG suppresses the Wnt pathway as a new tumor suppressor in GC [12]. Since ESRRG inhibits GC development by suppressing the Wnt pathway, which positively influences H. pylori infection, we can assume that ESRRG can modulate H. pylori infection.
In the current study, we identified that ESRRG protects gastric cells from H. pylori infection and inhibits GC cell growth by regulating TFF1 and NF-κB. ESRRG is positively correlated with TFF1 and negatively correlated with NF-κB. Our study provides new molecular insights into the correlation between ESRRG and H. pylori infection, and suggests that ESRRG can be a therapeutic target for the treatment of GC.
Section snippets
Gene expression data analysis
Gene expression data from the NCBI Gene Expression Omnibus (GEO) database are publicly available. All data were downloaded and processed using Biometric Research Branch (BRB) array tools and used for further analysis.
Cell lines and reagents
GC cell lines were purchased from the American Type Culture Collection. Cells were grown in Dulbecco's modified essential medium or RPMI1640 supplemented with 10% fetal bovine serum. The cells were incubated at 37 °C in a humidified incubator with 5% CO2. DY131 (#2266; TOCRIS,
ESRRG has protective roles against H. pylori infection in gastric cells
Previously, we found that ESRRG functions as a tumor suppressor by antagonizing the Wnt pathway in GC, and ESRRG expression was found to be predominant in normal gastric tissues [12]. In addition, gene expression profiling data revealed that H. pylori infection suppresses ESRRG expression [17]. Since ESRRG antagonizes tumor growth and is influenced by H. pylori infection, we hypothesized that the tumor-suppressive activity of ESRRG is correlated with H. pylori infection.
To investigate how
Discussion
In the current study, we identified a novel tumor suppressor, ESRRG, that prevents H. pylori infection-induced GC. Previous reports have demonstrated that ESRRG is a tumor suppressor that regulates the Wnt pathway in GC. Although ESRRG harbors tumor suppressive properties by inhibiting the Wnt pathway, the detailed mechanisms of the contributions of ESRRG as tumor suppressors are poorly understood. Since H. pylori infection is a well-characterized contributing factor to GC [18], we hypothesized
Conclusion
We identified a novel role for ESRRG as a potent tumor suppressor in GC by modulating H. pylori infection. We also provide mechanistic insights into GC promotion and development, as well as novel therapeutic targets for the treatment of GC.
Funding statement
This research was supported by a National Research Foundation (NRF-2020R1A2C1003216 to Y–Y.P; NRF-2013R1A1A2064367, NRF-2017R1A6A3A03004244 to M-H.K).
Author contributions
M.-H.K. and Y.-Y.P. generated the hypothesis, designed the experiments, and wrote the manuscript. M.-H.K. performed the experiments. M.-H.K. S.-i.E, and Y.-Y.P. interpreted the data.
Declaration of competing interest
The authors declare no Conflict of Interest.
References (29)
- et al.
Gastric cancer
Lancet
(2009) - et al.
Causal relationship between the loss of RUNX3 expression and gastric cancer
Cell
(2002) - et al.
Organoid cultures for the analysis of cancer phenotypes
Curr. Opin. Genet. Dev.
(2014) - et al.
Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network
Cell
(2006) - et al.
The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: fifth Edition American Joint Committee on Cancer staging, proximal disease, and the "different disease" hypothesis
Cancer
(2000) - et al.
Targeted therapy for upper gastrointestinal tract cancer: current and future prospects
Histopathology
(2021) - et al.
Novel systemic therapies for advanced gastric cancer
J Gastric Cancer
(2018) - et al.
A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: evidence does not translate?
Canc. Biol. Ther.
(2015) - et al.
Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers
Expet Rev. Mol. Med.
(2014) - et al.
Gene expression signature-based prognostic risk score in gastric cancer
Clin. Canc. Res.
(2011)
Gastric cancer-molecular and clinical dimensions
Nat. Rev. Clin. Oncol.
Cure of Helicobacter pylori infection and resolution of gastritis by adoptive transfer of splenocytes in mice
Infect. Immun.
Helicobacter pylori and gastric cancer: a state of the art review
Gastroenterol Hepatol Bed Bench
Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer
Nat. Commun.
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