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Published on: June 12, 2019
lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6
Gabriel Eades1, Benjamin Wolfson1, Yongshu Zhang1
1Greenebaum Cancer Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
Unlabelled:
Triple-negative (ER(-), HER2(-), PR(-)) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth-suppressive activity in some breast cancers; however, these data in TNBC indicate that miR-145 does not affect proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145-regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and affects cell-cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs.
Implications:
The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival.
Insights
Triple-negative breast cancer (TNBC) metastasis is driven by the lincRNA-RoR/miR-145/ARF6 pathway. This pathway, involving upregulated lincRNA-RoR and ARF6, and downregulated miR-145, regulates tumor cell invasion and could be a therapeutic target.
Area of Science:
- Molecular Oncology
- Cancer Genomics
- RNA Biology
Background:
- Triple-negative breast cancer (TNBC) is aggressive with poor prognosis and lacks targeted therapies.
- MicroRNA-145 (miR-145) silencing is a potential TNBC marker.
- Understanding miR-145 downregulation mechanisms is crucial for TNBC treatment.
Purpose of the Study:
- To investigate the molecular mechanism of miR-145 downregulation in TNBC.
- To identify novel therapeutic targets for TNBC metastasis.
Main Methods:
- Molecular profiling and deep sequencing identified miR-145 silencing.
- Overexpression of long intergenic noncoding RNA regulator of reprogramming (lincRNA-RoR) was analyzed.
- Knockdown experiments assessed the impact on miR-145 expression.
- Target validation identified ADP-ribosylation factor 6 (Arf6) as a miR-145 target.
Main Results:
- lincRNA-RoR acts as a competing endogenous RNA sponge, upregulated in TNBC and metastasis.
- Knockdown of lincRNA-RoR restored miR-145 expression.
- miR-145 regulates TNBC cell invasion, not proliferation or apoptosis.
- ARF6 is upregulated in TNBC and metastasis, regulating invasion and cell-cell adhesion via E-cadherin.
Conclusions:
- A novel lincRNA-RoR/miR-145/ARF6 pathway critically regulates TNBC invasion and metastasis.
- This pathway presents potential biomarkers and therapeutic targets for improving TNBC patient survival.
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