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miR-148a downregulates the expression of transforming growth factor-β2 and SMAD2 in gastric cancer
1Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.
Abstract:
The effects of miR-148a in regulating the expression of TGFβ2 and SMAD2 in MNNG-initiated gastric cancer rats and the mechanism of action in GC cells were determined. Effects of miR-148a on the proliferation, migration, and invasion of GC cell lines were demonstrated. We used Wistar rats, Balb/c nude mice, and GC cell lines. Rats were treated with MNNG to establish a GC rat model. Levels of miR-148a, TGFα, TGFβ2, SMAD2, SMAD3, and SMAD4 were tested in gastric tissues from different groups. In GC cell lines, we constructed and transfected a primary miR-148a plasmid to determine the expression patterns of TGFβ2, SMAD2, and SMAD4. A luciferase activity assay was used to monitor the effects of miR-148a on the TGFβ2- and SMAD2-3'UTRs. We identified nude mouse models bearing BGC-823-miR-148a or BGC-823-vector cells. Tumor volumes were detected, and TGFβ2, SMAD2 expression levels were determined in tumor tissues. The in vivo study demonstrated an increase in the mRNA and protein levels of TGFβ2, SMAD2, and SMAD4 in the MNNG-treated group compared with the control group. However, there were no differences in the mRNA and protein levels in either TGFα or SMAD3. The in vitro study demonstrated that overexpression of miR-148a reduced TGFβ2 and SMAD2 significantly in GC cells. The results of the luciferase activity assay showed that miR-148a could bind to the 3'UTRs of TGFβ2 and SMAD2 and inhibited their activity. Overexpression of miR-148a inhibited proliferation, migration, and invasion significantly in GC cell lines. In vivo, tumor volume of BGC-823-miR-148a was smaller than that of BGC-823-vector. Overall, miR-148a inhibited the proliferation, migration, invasion, and expression of TGFβ2 and SMAD2 in GC cells. It was concluded that miR-148a might play an important role in gastric cancer, and is a potential candidate for GC treatment.
Insights
MicroRNA-148a (miR-148a) suppresses gastric cancer (GC) progression by inhibiting the expression of TGFβ2 and SMAD2. This microRNA demonstrates potential as a therapeutic target for treating GC.
Area of Science:
- Molecular Biology
- Oncology
- Gene Regulation
Background:
- Gastric cancer (GC) remains a significant global health challenge with complex molecular underpinnings.
- MicroRNAs (miRNAs) are emerging as critical regulators in cancer development and progression.
- Understanding the role of specific miRNAs, like miR-148a, in GC is crucial for therapeutic advancements.
Purpose of the Study:
- To investigate the regulatory role of miR-148a in the expression of transforming growth factor beta 2 (TGFβ2) and SMAD2 in gastric cancer.
- To elucidate the mechanism by which miR-148a affects gastric cancer cell proliferation, migration, and invasion.
- To evaluate the therapeutic potential of miR-148a in preclinical models of gastric cancer.
Main Methods:
- Establishment of a MNNG-induced gastric cancer rat model and utilization of GC cell lines (BGC-823).
- Quantification of miRNA and gene expression levels (miR-148a, TGFβ2, SMAD2, SMAD4) in tissues and cells.
- In vitro studies involving miR-148a overexpression, luciferase reporter assays, and assessment of cell proliferation, migration, and invasion.
- In vivo studies using nude mouse xenograft models to evaluate tumor growth and gene expression.
Main Results:
- MNNG treatment in rats led to increased TGFβ2, SMAD2, and SMAD4 expression, while miR-148a overexpression in GC cells significantly reduced TGFβ2 and SMAD2 levels.
- miR-148a directly targets the 3' untranslated regions (3'UTRs) of TGFβ2 and SMAD2, inhibiting their activity.
- Overexpression of miR-148a markedly inhibited GC cell proliferation, migration, and invasion, and reduced tumor volume in vivo.
Conclusions:
- miR-148a acts as a tumor suppressor in gastric cancer by downregulating TGFβ2 and SMAD2 expression.
- The findings highlight miR-148a's significant role in inhibiting GC cell aggressiveness.
- miR-148a represents a promising therapeutic candidate for gastric cancer treatment.
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