Tribbles Genes in Gastric Cancer: A Tumor-Suppressive Role for TRIB2
Alessia Foscarini1,2, Rossella Tricarico1, Federica Gentile1
1Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, 27100 Pavia, Italy.
Abstract:
Tribbles pseudokinases (TRIB1-3) are important signaling modulators involved in several cancers. However, their function in gastric cancer (GC) remains undefined. GC is still a deadly disease since the lack of sensitive and specific biomarkers for early diagnosis and therapy response prediction negatively affects patients' outcome. The identification of novel molecular players may lead to more effective diagnostic and therapeutic avenues. Therefore, we investigated the role of TRIB genes in gastric tumorigenesis. Data mining of the TCGA dataset revealed that chromosomal instability (CIN) tumors have lower TRIB2 and higher TRIB3 expression versus microsatellite instability (MSI)-high tumors, while TRIB1 levels are similar in both tumor types. Moreover, in CIN tumors, low TRIB2 expression is significantly associated with aggressive stage IV disease. As no studies on TRIB2 in GC are available, we focused on this gene for further in vitro analyses. We checked the effect of TRIB2 overexpression (OE) on MKN45 and NCI-N87 CIN GC cell lines. In MKN45 cells, TRIB2 OE reduced proliferation and colony formation ability and induced G2/M arrest, while it decreased the proliferation and cell motility of NCI-N87 cells. These effects were not mediated by the MAPK pathway. Our results suggest a tumor-suppressive function of TRIB2 in GC with a CIN phenotype.
Insights
Tribbles pseudokinase 2 (TRIB2) shows a tumor-suppressive role in gastric cancer (GC) with chromosomal instability. Lower TRIB2 expression correlates with advanced GC, suggesting its potential as a biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Tribbles pseudokinases (TRIB1-3) are key signaling modulators implicated in various cancers.
- The specific role of TRIB genes in gastric cancer (GC) pathogenesis is largely unknown.
- Gastric cancer lacks sensitive biomarkers for early diagnosis and predicting therapy response, impacting patient outcomes.
Purpose of the Study:
- To investigate the function of TRIB genes, particularly TRIB2, in gastric tumorigenesis.
- To explore the potential of TRIB2 as a diagnostic or therapeutic target in GC.
- To determine the association between TRIB gene expression and GC subtypes (CIN vs. MSI-high).
Main Methods:
- Utilized TCGA dataset for gene expression analysis in GC tumors.
- Performed in vitro experiments involving TRIB2 overexpression (OE) in CIN GC cell lines (MKN45, NCI-N87).
- Assessed cell proliferation, colony formation, cell motility, and cell cycle progression.
Main Results:
- TCGA data indicated lower TRIB2 expression in chromosomal instability (CIN) tumors compared to microsatellite instability-high (MSI-high) tumors.
- Low TRIB2 expression was significantly associated with advanced stage IV disease in CIN tumors.
- TRIB2 OE suppressed proliferation and colony formation in MKN45 cells, inducing G2/M arrest, and reduced proliferation and motility in NCI-N87 cells.
- The observed effects of TRIB2 OE were independent of the MAPK pathway.
Conclusions:
- TRIB2 exhibits tumor-suppressive functions in gastric cancer, particularly within the CIN subtype.
- TRIB2 expression levels may serve as a prognostic biomarker for GC aggressiveness.
- Further research into TRIB2's mechanisms could unveil novel therapeutic strategies for GC.
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