Tumor metastasis is a hallmark of tumor, with distant metastasis frequently developing in lung cancer, even at initial diagnosis, resulting in poor prognosis and high mortality. and potential miRNA-targeted treatments for lung cancer with the expectation that further exploration of miRNA-targeted therapy may establish a new spectrum of lung cancer treatments. BEC HCl = 10) from lung cancer with that of primary lung cancers (= 24) identified and validated a candidate viral miRNA, Hsv2-miR-H9-5p, encoded by herpes simplex virus type 2 latency-associated transcript [155]. Hsv2-miR-H9-5p expression is significantly higher in bone metastasis lesions than primary lung cancers. Hsv2-miR-H9-5p increases lung cancer cell migration and invasion in vitro by directly targeting suppressor of cytokine signaling 2 (SOCS2), inhibiting Jak2 kinase activity and Jak2-signal transducer and activator of transcription 3 (STAT3) binding [156]. SOCS2 expression is down-regulated in lung cancer [157]. MiR-139-5p serum levels from patients with lung adenocarcinoma and osteolytic bone metastasis are lower than those in patients with other organ metastasis. MiR-139-5p expression in mesenchymal stem cells (MSCs) significantly increases during osteogenic differentiation. Notch homolog 1, translocation-associated (Drosophila) (Notch1), a direct miR-139-5p target, exhibits significant down-regulation during MSC osteogenesis [159]. Tumor transfer of miR-192-enriched exosome-like vesicles to the endothelial compartment of the osseous milieu in vivo reduced bone metastases burden. MiR-192 overexpression confers anti-osseous metastatic activity in vivo and limits tumor-induced angiogenesis [160]. MiR-203/TGF-/Smad2 expression represents an important tumor suppressor signaling pathway for bone metastasis in NSCLC, as patients with bone metastasis exhibited lower tumor tissue miR-203 expression than those without bone metastasis [161]. 4.2. Role of miRNAs in Lung Cancer Brain Metastasis Brain metastasis affects approximately 25% of patients with NSCLC during their lifetime [162]. However, no molecular biomarkers or effective indices are available to reduce brain metastasis risk. The mechanism of brain metastasis is also not completely clear due to the limited obtainable cells specimens. Table 3 lists lung cancer brain metastasis-related miRNAs. Table 3 Brain metastasis-related microRNAs in NSCLC. = 7) and without (= 8) brain CD80 metastasis. MiR-328 overexpression in A549 cells significantly promotes cell migration concomitant with protein kinase C alpha (PRKCA) up-regulation [171]. Overexpression of mir-423-5p, selected using microarray analysis of brain metastasis-related miRNAs and validated by quantitative PCR, promotes NSCLC cell colony formation, cell motility, migration, and invasion by direct targeting metastasis suppressor 1 (MTSS1). In clinical samples, lung adenocarcinoma tissues without brain metastasis exhibit positive staining for MTSS1 expression [176]. Microarray analysis between patients with and without brain metastasis revealed that a three-miRNA (including miR-210, miR-214, and miR-15a) signature predicts the brain metastasis of patients with lung adenocarcinoma with high sensitivity and specificity [170]. Recently, increasing evidence BEC HCl revealed that exosomes play important roles in the tumor microenvironment and the mechanism of malignant tumor metastasis. Exosomes, consist of a phospholipid bilayer, which is composed mainly of proteins, lipids, carbohydrates, and nucleic acids [181,182]. Exosome carries miRNAs, termed exomiRs, to acceptor cells to promote nonadjacent intercellular communication, which involves in cell differentiation, immune response, antigen presentation, and cell invasion/migration [183,184,185]. The transfer of exosomal miRNA can modulate gene expression in acceptor cancer cells to facilitate metastasizing cancer cell settlement in pre-metastatic organs, suggesting these exosomal miRNAs prepare the pre-metastatic niche [186]. Astrocytes oppose brain metastasis via exosome-delivered miR-142-3p, which directly binds to the suppressing transient receptor potential ankyrin-1 (TRPA1) 3UTR. TRPA1 also directly targets the FGF receptor 2 C-terminal proline-rich motif, thereby constitutively activating the receptor and increasing lung adenocarcinoma progression and metastasis [168]. Transferring miR-142-3p from astrocytes to lung cancer cells suppresses TRPA1 in the latter, promoting brain metastasis. MiR-184 and miR-197 are also overexpressed in patients carrying EGFR mutation with brain metastasis; their expression level BEC HCl may serve to stratify the brain metastasis risk in this subpopulation [169]. 4.3. Role of miRNAs in Lung Cancer Lymph Node Metastasis Lymphatic metastasis comprises an important mechanism in tumor.