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Published on: June 26, 2016
miR-29c plays a suppressive role in breast cancer by targeting the TIMP3/STAT1/FOXO1 pathway
Wan Li1,2, Jie Yi3, Xiangjin Zheng1,2
11The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, China.
Background:
miR-29c has been associated with the progression of many cancers. However, the function and mechanism of miR-29c have not been well investigated in breast cancers.
Methods:
Real-time quantitative PCR was used to assess expression of miR-29c and DNMT3B mRNA. Western blot and immunochemistry were used to examine the expression of DNA methyltransferase 3B (DNMT3B) protein in breast cancer cells and tissues. The functional roles of miR-29c in breast cancer cells such as proliferation, migration, invasion, colony formation, and 3D growth were evaluated using MTT, transwell chambers, soft agar, and 3D Matrigel culture, respectively. In addition, the luciferase reporter assay was used to check if miR-29c binds the 3'UTR of DNMT3B. The effects of miR-29c on the DNMT3B/TIMP3/STAT1/FOXO1 pathway were also examined using Western blot and methyl-specific qPCR. The specific inhibitor of STAT1, fludarabine, was used to further check the mechanism of miR-29c function in breast cancer cells. Studies on cell functions were carried out in DNMT3B siRNA cell lines.
Results:
The expression of miR-29c was decreased with the progression of breast cancers and was closely associated with an overall survival rate of patients. Overexpression of miR-29c inhibited the proliferation, migration, invasion, colony formation, and growth in 3D Matrigel while knockdown of miR-29c promoted these processes in breast cancer cells. In addition, miR-29c was found to bind 3'UTR of DNMT3B and inhibits the expression of DNMT3B, which was elevated in breast cancers. Moreover, the protein level of TIMP3 was reduced whereas methylation of TIMP3 was increased in miR-29c knockdown cells compared to control. On the contrary, the protein level of TIMP3 was increased whereas methylation of TIMP3 was reduced in miR-29c-overexpressing cells compared to control. Knockdown of DNMT3B reduced the proliferation, migration, and invasion of breast cancer cell lines. Finally, our results showed that miR-29c exerted its function in breast cancers by regulating the TIMP3/STAT1/FOXO1 pathway.
Conclusion:
The results suggest that miR-29c plays a significant role in suppressing the progression of breast cancers and that miR-29c may be used as a biomarker of breast cancers.
Insights
MicroRNA-29c (miR-29c) suppresses breast cancer progression by inhibiting DNA methyltransferase 3B (DNMT3B) and regulating the TIMP3/STAT1/FOXO1 pathway. Lower miR-29c levels correlate with poorer patient survival, suggesting its potential as a breast cancer biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MicroRNA-29c (miR-29c) is implicated in various cancers, but its specific role in breast cancer remains under-explored.
- Understanding miR-29c's function is crucial for developing novel breast cancer diagnostics and therapeutics.
Purpose of the Study:
- To investigate the expression, function, and mechanism of miR-29c in breast cancer.
- To determine the relationship between miR-29c and DNA methyltransferase 3B (DNMT3B) in breast cancer progression.
Main Methods:
- Quantitative PCR and Western blotting to assess miR-29c, DNMT3B, and pathway protein expression.
- Cell proliferation, migration, invasion, and colony formation assays to evaluate miR-29c function.
- Luciferase reporter assays to confirm miR-29c binding to DNMT3B 3'UTR.
Main Results:
- miR-29c expression decreased with breast cancer progression and correlated with patient survival.
- Overexpression of miR-29c inhibited breast cancer cell proliferation, migration, and invasion, while knockdown promoted these processes.
- miR-29c directly targets and inhibits DNMT3B, subsequently affecting the TIMP3/STAT1/FOXO1 pathway.
Conclusions:
- miR-29c acts as a tumor suppressor in breast cancer by inhibiting DNMT3B and regulating key signaling pathways.
- miR-29c holds potential as a prognostic biomarker for breast cancer patients.
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