Table 2.

MicroRNAs associated with tumor cell extravasation across the blood–brain barrier and the formation of brain metastases

microRNAs	Findings	Primary tumor	Refs
miR-509	Highly expressed in primary tumors, while significantly downregulated in brain metastatic lesions. Regulates two genes: i) RhoC involved in MMP9 expression influencing cancer cell invasion and ii) TNF-α which modifies BBB permeability	Breast cancer	[132]
miR-7	miR profile analysis of cancer stem-like cells revealed that significantly lower level of miR-7 was related to preferential organotropism for the brain, with reduced miR-7 producing greater levels of Kruppel-like factor 4		[131]
miR-105	Identified in the circulation in pre-metastatic cancer patients, reflecting metastatic progression. Suppresses ZO-1, disrupting BBB integrity. Overexpression in non-metastatic tumor cells increases vascular permeability and brain metastases. Inhibition in highly brain metastatic cancer limits metastatic potential. Exosome-mediated miR-105 expression by brain metastatic breast cancer cells is associated with the reprograming of activated microglia, upregulating immune-suppressive cytokines and supporting metastatic niche formation		[78, 133]
miR-19a	Astrocyte-derived exosomes containing miR-19a targeting PTEN in brain metastatic breast cancer cells, which activates the PI3K/Akt pathway, promoting invasion of the brain parenchyma		[134]
miR-181c	Exome-delivered miR-181c facilitates disruption of the BBB in vitro and in vivo by downregulating the gene PDPK1, causing abnormal localization of actin		[79]
miR-122	Freely circulating miR-122 secreted by tumor cells downregulates the glycolytic enzyme pyruvate kinase, suppressing glucose uptake by astrocytes, in vitro and in vivo. Inhibition of miR-122 in vivo restored glucose uptake in the brain, reducing the incidence of metastasis		[81]
miR-1290 and miR-1246	High levels of tumor-secreted EV-mediated miR-1290 and miR-1246, activating astrocytes. Higher circulating EV levels in patients with metastases than without. MiR-1290- or miR-1246-overexpressing astrocytes promote mammospheres. Astrocytes overexpressing miR-1290, but not miR-1246, increase brain colonization and growth of tumor cells		[135]
miR-378	Overexpressed in both primary tumor and associated brain lesions compared to non-brain-metastasizing variants	Lung cancer	[137]
miR-328 and miR-330-3p	Expression pattern able to differentially predict patients positive and negative for brain metastases		[136]
miR-142-3p	EV shuttling of long non-coding RNA LINC00482 to microglia induces microglial M2 polarization by binding to miR-142-3p and upregulating TGF-β1. This in turn facilitates pre-metastatic niche formation in vivo		[80]
miR-150-5p, miR-15b-5p, miR-16-5p, and miR-374b-3p	Identified as a prognostic signature in a retrospective, cohort-based study analyzing genome-wide and targeted miR expression in primary melanoma tissue, improving predictions of brain metastases development	Melanoma	[138]