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Updated: Jun 6, 2025
In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
Gremlin-2 is a novel tumor suppressor that negatively regulates ID1 in breast cancer
Jiwoo Jung1, Na Hui Kim2, Jayeon Park1
1Department of Medical Sciences, Graduate School, Soonchunhyang University, Asan-si, 31538, Republic of Korea.
Background:
Breast cancer is one of the most common cancers in women and is closely associated with obesity. Gremlin-2 (GREM2), an antagonist for bone morphogenetic proteins (BMPs), has been considered an inhibitor of adipogenic differentiation in adipose-derived stromal/stem cells. However, the role of GREM2 in breast cancer cells remains largely unknown, and its signaling mechanism has yet to be clarified.
Methods:
Bioinformatics analysis was conducted using public databases. Breast cancer cells overexpressing mock or GREM2 were used for in vitro and in vivo studies. Cell viability, colony formation, migration, and animal studies were performed to investigate the role of GREM2 in breast cancer cells. Screening of target genes affected by GREM2 overexpression in breast cancer cells was performed through RNA sequencing (RNA-seq) analysis.
Results:
The expression level of GREM2 mRNA was significantly reduced in both breast cancer tissues and cell lines. Kaplan-Meier analysis showed that low expression of GREM2 and high methylation of the GREM2 promoter were each associated with poor patient survival. The low mRNA expression of GREM2 in breast cancer cells was increased by the demethylating agent decitabine. Breast cancer cells overexpressing GREM2 decreased cell proliferation when compared to control cells, both in vitro and in vivo. Through comparison of RNA-seq analysis between cell lines and tissue samples, gene ontologies that were consistently upregulated or downregulated by GREM2 in breast cancer were identified. In particular, the expression of inhibitor of DNA-binding-1 (ID1) was repressed by GREM2. BMP2 is one of the upstream regulators that increases the expression of ID1, and the expression of ID1 reduced by GREM2 was restored by overexpression of BMP2. Also, the migration ability of breast cancer cells, which had been suppressed by GREM2, was restored by BMP2 or ID1.
Conclusions:
Low expression of GREM2 in breast cancer cells is associated with hypermethylation of the GREM2 promoter, which may ultimately contribute to poor patient survival. GREM2 participates in regulating the expression of various genes, including ID1, and is involved in suppressing the proliferation of breast cancer cells. This suggests that GREM2 has the potential to act as a novel tumor suppressor in breast cancer.
Insights
Gremlin-2 (GREM2) is downregulated in breast cancer, and its low expression correlates with poor survival. Overexpressing GREM2 suppresses tumor growth, suggesting it acts as a tumor suppressor.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer is a prevalent malignancy in women, often linked to obesity.
- Gremlin-2 (GREM2), a bone morphogenetic protein (BMP) antagonist, inhibits adipogenic differentiation but its role in breast cancer is unclear.
Purpose of the Study:
- To investigate the role and signaling mechanism of Gremlin-2 (GREM2) in breast cancer.
Main Methods:
- Bioinformatics analysis of public databases.
- In vitro and in vivo studies using breast cancer cells with GREM2 overexpression.
- RNA sequencing (RNA-seq) to identify GREM2 target genes.
- Analysis of cell viability, proliferation, and migration.
Main Results:
- GREM2 mRNA expression is significantly reduced in breast cancer tissues and cell lines.
- Low GREM2 expression and high promoter methylation correlate with poor patient survival.
- GREM2 overexpression suppressed breast cancer cell proliferation in vitro and in vivo.
- GREM2 repressed inhibitor of DNA-binding-1 (ID1) expression; BMP2/ID1 signaling influenced cell migration.
Conclusions:
- Reduced GREM2 expression in breast cancer, linked to promoter hypermethylation, contributes to poor survival.
- GREM2 suppresses breast cancer cell proliferation by regulating genes like ID1.
- GREM2 shows potential as a novel tumor suppressor in breast cancer.
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