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miR-141 is a key regulator of renal cell carcinoma proliferation and metastasis by controlling EphA2 expression
Xuanyu Chen1, Xuegang Wang1, Anming Ruan1
1Authors' Affiliations: Department of Urology, Union Hospital; Department of Pathogen Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Cancer Biology Program, Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Department of Neurology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
Purpose:
Although microRNAs (miRNA) have been revealed as crucial modulators of tumorigenesis, our understanding of their roles in renal cell carcinoma (RCC) is limited. Here we sought to identify human miRNAs that act as key regulators of renal carcinogenesis.
Experimental Design:
We performed microarray-based miRNA profiling of clear cell RCC (ccRCC) and adjacent normal tissues and then explored the roles of miR-141 both in vitro and in vivo, which was the most significantly downregulated in ccRCC tissues.
Results:
A total of 74 miRNAs were dysregulated in ccRCC compared with normal tissues. miR-141 was remarkably downregulated in 92.6% (63/68) ccRCC tissues and would serve as a promising biomarker for discriminating ccRCC from normal tissues with an area under the receiver operating characteristics curve of 0.93. Overexpression of miR-141 robustly impaired ccRCC cell migratory and invasive properties and suppressed cell proliferation by arresting cells at G0-G1 phase in vitro and in human RCC orthotopic xenografts. Significantly, the antitumor activities of miR-141 were mediated by its reversal regulation of erythropoietin-producing hepatocellular (Eph) A2 (EphA2), which then relayed a signaling transduction cascade to attenuate the functions of focal adhesion kinase (FAK), AKT, and MMP2/9. In addition, a specific and inverse correlation between miR-141 and EphA2 expression was obtained in human ccRCC samples. Finally, miR-141 could be secreted from the ccRCC donor cells, and be taken up and function moderately in the ccRCC recipient cells.
Conclusion:
miR-141 serves as a potential biomarker for discriminating ccRCC from normal tissues and a crucial suppressor of ccRCC cell proliferation and metastasis by modulating the EphA2/p-FAK/p-AKT/MMPs signaling cascade.
Insights
MicroRNA-141 (miR-141) is significantly downregulated in clear cell renal cell carcinoma (ccRCC). Restoring miR-141 suppresses ccRCC growth and metastasis by targeting EphA2 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- MicroRNAs (miRNAs) are key regulators of tumorigenesis.
- Understanding miRNA roles in renal cell carcinoma (RCC) is crucial for developing targeted therapies.
Purpose of the Study:
- Identify human miRNAs regulating renal carcinogenesis.
- Investigate the function of miR-141 in clear cell RCC (ccRCC).
Main Methods:
- Microarray profiling of ccRCC and normal tissues.
- In vitro and in vivo functional studies of miR-141.
- Analysis of miR-141 expression correlation with EphA2 in human ccRCC samples.
Main Results:
- 74 miRNAs were dysregulated in ccRCC; miR-141 was significantly downregulated.
- miR-141 acts as a biomarker for ccRCC detection (AUC=0.93).
- Overexpression of miR-141 inhibited ccRCC cell proliferation, migration, and invasion via the EphA2/FAK/AKT/MMP2/9 pathway.
Conclusions:
- miR-141 is a potential biomarker for ccRCC diagnosis.
- miR-141 functions as a tumor suppressor in ccRCC by inhibiting proliferation and metastasis.
- The EphA2/p-FAK/p-AKT/MMPs signaling cascade is modulated by miR-141 in ccRCC.
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