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In Vivo Inhibition of MicroRNA to Decrease Tumor Growth in Mice
Published on: August 23, 2019
MicroRNA-146a suppresses metastatic activity in brain metastasis
Su Jin Hwang1, Ho Jun Seol, Young Mi Park
1Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 135-710, Korea.
Abstract:
Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower β-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased β-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of β-catenin and downregulation of hnRNPC.
Insights
MicroRNA-146a is absent in brain metastases, and its restoration suppresses tumor cell migration and invasion. This suggests a potential therapeutic target for reducing brain metastasis spread.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Brain metastases from primary lung, breast, and melanoma tumors are challenging to treat with surgery and radiation.
- Understanding the molecular mechanisms driving brain metastasis is crucial for developing new therapies.
Purpose of the Study:
- To investigate the molecular basis of brain metastasis using a mouse model.
- To identify key molecular players, including microRNAs, involved in the brain-trophic metastatic process.
Main Methods:
- Isolated brain-trophic metastatic cells (MDA-MB-435-LvBr2) by injecting MDA-MB-435 cells into immunodeficient mice.
- Analyzed differences in gene and microRNA expression between parental and metastatic cells.
- Manipulated microRNA-146a levels to assess its impact on cell behavior and molecular targets.
Main Results:
- Metastatic cells exhibited altered morphology, lower β-catenin, and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels compared to parental cells.
- MicroRNA-146a was significantly downregulated in brain metastatic cells.
- Restoring microRNA-146a suppressed cell migration and invasion, increased β-catenin, and decreased hnRNPC, MMP-1, uPA, and uPAR expression.
Conclusions:
- MicroRNA-146a is virtually absent in brain metastases and acts as a suppressor of metastatic potential.
- Upregulation of β-catenin and downregulation of hnRNPC are associated with the metastatic phenotype driven by low microRNA-146a.
- MicroRNA-146a represents a potential therapeutic target for inhibiting brain metastasis.
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