Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis
Weiying Zhou1, Miranda Y Fong2, Yongfen Min3
1Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center, Duarte, CA 91010, USA; Department of Pharmacology, College of Pharmacy, The Third Military Medical University, Chongqing, 400038, China.
Abstract:
Cancer-secreted microRNAs (miRNAs) are emerging mediators of cancer-host crosstalk. Here we show that miR-105, which is characteristically expressed and secreted by metastatic breast cancer cells, is a potent regulator of migration through targeting the tight junction protein ZO-1. In endothelial monolayers, exosome-mediated transfer of cancer-secreted miR-105 efficiently destroys tight junctions and the integrity of these natural barriers against metastasis. Overexpression of miR-105 in nonmetastatic cancer cells induces metastasis and vascular permeability in distant organs, whereas inhibition of miR-105 in highly metastatic tumors alleviates these effects. miR-105 can be detected in the circulation at the premetastatic stage, and its levels in the blood and tumor are associated with ZO-1 expression and metastatic progression in early-stage breast cancer.
Insights
Metastatic breast cancer cells secrete miR-105, a microRNA that disrupts endothelial barriers by targeting ZO-1. This promotes cancer cell migration and metastasis, and miR-105 levels correlate with disease progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- MicroRNAs (miRNAs) are key regulators in cell-to-cell communication.
- Cancer cells secrete miRNAs that influence the tumor microenvironment and host interactions.
- The role of specific miRNAs in mediating cancer metastasis is an active area of research.
Purpose of the Study:
- To investigate the role of miR-105, secreted by metastatic breast cancer cells, in regulating cancer cell migration and metastasis.
- To determine the molecular mechanism by which miR-105 affects endothelial barriers.
- To assess the potential of circulating miR-105 as a biomarker for metastatic breast cancer.
Main Methods:
- Analysis of miR-105 expression in metastatic breast cancer cells.
- In vitro studies using endothelial monolayers to assess the impact of exosome-mediated miR-105 transfer on tight junctions.
- In vivo experiments involving overexpression or inhibition of miR-105 in cancer cells to evaluate metastasis and vascular permeability.
- Detection and quantification of miR-105 in patient blood samples and tumor tissues.
Main Results:
- miR-105, secreted by metastatic breast cancer cells, directly targets and degrades the tight junction protein ZO-1.
- Exosomal transfer of miR-105 to endothelial cells disrupts the endothelial barrier integrity, facilitating cancer cell migration.
- Overexpression of miR-105 enhances metastasis and vascular permeability, while inhibition reduces these effects.
- Circulating miR-105 is detectable at the premetastatic stage and correlates with ZO-1 expression and metastatic progression in early-stage breast cancer.
Conclusions:
- miR-105 is a critical mediator of breast cancer metastasis by compromising endothelial barrier function.
- Targeting miR-105 or its downstream effects may offer therapeutic strategies to inhibit metastasis.
- Circulating miR-105 shows promise as a non-invasive biomarker for early detection of metastatic breast cancer.
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