**4. The role of MicroRNAs in NSCLC brain metastasis**

MicroRNAs (miRNAs) are conserved short endogenous RNA molecules (21–25 nt) that play critical roles in gene expression patterning by interfering with target mRNAs [65]. MiRNAs regulate cellular functions including cell growth, cell differentiation, and cell death. About half of the miRNAs participate in tumorigenesis [66]. The expression of miRNAs may lead to the rise of tumors by activating the pathways implicated in carcinogenesis. The function of miRNAs in the development of tumor metastasis to brain has recently attracted attention and various studies have addressed the role of miRNAs in the progression of brain metastases of lung cancers in particular (**Table 1**) [83, 84]. The effects of miRNAs vary widely, depending on the expressional cascades they influence.

In **Table 1**, a summary of currently known miRNA associations with NSCLC and their brain metastases is presented. MiRNA-184 and miRNA-197 are highly expressed in EGFR-mutant NSCLCs of patients with cerebral metastases and may serve as biomarkers for the risk of cerebral seeding [67]. Expression of miRNA-9 and miRNA-1471 has also been found in lung cancer with brain metastasis. Up-regulation of miRNA-145 inhibits the proliferation of human tumor cells in lung adenocarcinomas via targeting of c-Myc and EGFR [79, 85, 86]. MiRNA-146a is overexpressed in NSCLC and is associated with down-regulation of heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 and up-regulation of β-catenin, resulting not only in tumor cell invasion and migration but also in the metastatic potential to brain [87, 88]. Also, MiRNA-95-3p is upregulated in lung adenocarcinoma but overexpression of this MiRNA seems to suppress the formation of brain metastasis via down-regulation of cyclin D1 [75]. MiRNA-378 is overexpressed in NSCLC and their brain metastases and increases tumor growth and metastasis via the upregulation of MMP-7, VEGF, and MMP-9 [74]. Also, MiRNA-328 is overexpressed in NSCLC and allegedly promotes the formation of brain metastases via PRKCA and urokinase-type plasminogen activator (uPA) [71]. PRKCA mediates the expression, resulting in the migration of the cancer cells [89]. Lastly, increased miRNA-21 levels suppress cell death and promote the proliferation and invasion of NSCLC and lung adenocarcinoma cells [68, 90].

Some miRNAs are downregulated in the context of cerebral seeding of lung cancer. MiRNA-768-3p is downregulated in lung cancer cells co-cultured with astrocytes, leading to increased KRAS expression, tumor outgrowth, and propagation of brain metastasis [91]. MiRNA-375 is another miRNA that reportedly is down-regulated in primary NSCLC and reduced levels of miRNA-375 are associated with NSCLC brain metastasis [72]. In tumors in which miRNA-375 was downregulated MMP9 and VEGF were found overexpressed [72]. Reduced miRNA-145 levels also seem to promote brain metastasis in lung adenocarcinoma, while overexpression reduces tumor dissemination [69].


*Non-Small Cell Lung Cancer Brain Metastasis: The Link between Molecular Mechanisms… DOI: http://dx.doi.org/10.5772/intechopen.106385*


*TPD52: tumor protein D52; TRPA1: transient receptor potential ankyrin 1; GRIA3: glutamate receptor, ionotropic, AMPA 3; PRKCA: protein kinase C-α; MMP: matrix metalloprotease; ADAM9: a disintegrin and metalloproteinase 9; PCBP1: poly r(C)-binding protein 1; MTSS1: metastasis suppressor protein 1; FGF9: fibroblast growth factor 9; CCND2: cyclin D2; and TCGA: The Cancer Genome Atlas.*

#### **Table 1.**

*MicroRNAs associated with brain metastasis from NSCLC.*

Taken together, miRNAs appear to have great potential for cancer diagnosis, prognosis, and treatment at the molecular level, but the use of miRNAs for the clinical treatment of brain metastases requires further investigation. Many studies focused on the identification of alterered expression patterens of miRNAs after outgrowth in the brain microenvironment, but validation of data in larger groups of tumor samples is needed [31].
