**5. Role of lncRNAs in NSCLC brain metastasis**

Long non-coding RNAs (lncRNAs) are non-coding transcripts comprising > 200 nucleotides that have substantial functions in various physiological and pathological pathways. Similar to miRNAs, lncRNAs also regulate a variety of molecular targets by various mechanisms. Recently, the effective role of lncRNAs in tumorigenesis was shown [92]. lncRNAs are important regulators of lung cancer progression. Some lncRNAs serve different functions in various types of cells [93]. MALAT1 (Metastasisassociated lung adenocarcinoma transcript 1) is a large non-coding RNA gene that is highly conserved in mammals and regulates gene expression via splicing-independent mechanisms in NSCLC metastasis [94]. MALAT1 is located on chromosome 11q13 and increased MALAT1 levels were recently discovered in patients with NSCLC who had developed cerebral metastasis, while not in patients without brain locations [95, 96]. In addition, functional studies revealed that overexpression of MALAT1 leads to overexpression of vimentin in highly invasive metastatic lung cancer cell lines while silencing MALAT1 affects EMT programming and suppresses metastasis of the lung cancer cells [96]. Moreover, RNAi-mediated repression of MALAT1-RNA has a negative impact on the migration and outgrowth of human NSCLC cell lines. Overexpression of MALAT1 in NIH/3T3 fibroblasts significantly enhanced migration [97] and stimulated cell motility via the regulation of related genes [98]. The oncogene c-MYC influences cerebral metastasis of NSCLC by inducing the overexpressing of Non-coding RNA BCYRN1 (brain cytoplasmic RNA 1) in NSCLC cells [99, 100]. c-MYC-activated BCYRN1 induces NSCLC metastasis by the expression of MMP9 and MMP13, members of the matrixin subfamily that behave as ECM-degrading enzymes [101–103]. HOTAIR (HOX transcript antisense RNA) is a lncRNA that is highly expressed in NSCLCs with brain seeding [104]. *In vitro* studies have revealed that HOTAIR expression enhances

tumor cell migration and outgrowth [105]. At this point, the relationship between MALAT1 and HOTAIR in NSCLC brain metastasis is still unknown [104].
