Many lncRNAs showed in epigenetic changes like gene imprinting, modifications, and regulations. Beyond lncRNA, there is yet another type of non-coding RNA with much less information associated with cancer biology. Small-non coding RNA (snoRNA) has 60 to 300 nucleotides. Recent studies have shown the migration and progression of lung cancer tumours mainly through EMT and MMPs regulated by lncRNAs. Additionally, the immune system has cytotoxic CD8 + T cells to restrict tumour cell growth in cancers. Furthermore, overexpression of tumour-promoting lncRNAs can manage immune evasion of LC cells 24. However, this paper will focus on cancer-related lncRNAs and mRNAs.
XLOC_l2_000941 third up-regulated lncRNA gene in DEGs results, with Log FC = 2.68 (Table 1), is related to MYC transcription factor (TF) based on Peng-ran Sun et al. studies 25. MYC, also known as c-myc, is a multifunctional TF that plays a vital role in cell cycle progression, apoptosis, and cellular transformation 26. c-myc expression is also up-regulated in ovarian endometriotic cyst stromal cells, and its expression can be suppressed by miR-196b 27. The expression of c-MYC–regulated genes are associated with a higher risk for brain metastasis in breast cancer patients 28. This paper demonstrates the different expressions of XLOC_l2_000941 in BM SCLC individuals.
MYOM2, a fourth high expression gene with Log FC = 2.60 in BM patients with the highest rate of missense mutations, is a protein-coding gene that usually plays a role in synthesising titin-associated protein fibronectin type III and immunoglobulin C2 domains 29. Fibronectin is a cell adhesion protein that could affect metastasis 30. MYOM2 may associate with the pharmacology of Tumor necrosis factor (TNF) blockers 31, a multifunctional cytokine that plays critical roles in diverse cellular events such as cell survival, proliferation, differentiation, and death alter cancer metastasis 32. As we show in Table 2, MYOM2 is associated with LINC01511 and LINC00448 lncRNAs. LINC01511 is up-regulated in triple-negative breast cancer and might play a fundamental role in the mechanism of EGFR exon 19 deletions in lung adenocarcinoma 33.
WHAMMP2 (WAS protein homolog associated with actin, Golgi membranes, and microtubules pseudogene 2) is a pseudogene highly expressed in BM SCLC similar to Thymocytes in Thymus in brain metastasis patients mentioned in table S4.
TMEM176B and TMEM176A have an extensive correlation with different lncRNAs, as shown in Table 2. Some of these lncRNAs get involved in cancers; for instance, LINC00501 prohibits lung cancer development and metastasis by mediating miR-129-5p/HMGB1 and up-regulated in non-small cell lung cancer (NSCLC) patients 34. Contrariwise, LBX2-AS1 promotes cell proliferation and metastasis through Notch signalling in NSCLC 35. Also, we find that these two genes have Physical interactions, Co-expression relations, and shared protein domains, demonstrated in Fig. 3B. Transmembrane proteins (TMEMs) are membrane proteins with at least one transmembrane structure; They are also known as integral membrane proteins. TMEM176 plays diverse functions in distinct malignancies. A range of membrane protein functions Is intimately associated with the proliferation, invasion, and metastasis of malignant tumours 36,37. In human hepatocellular carcinoma, epigenetic silencing of TMEM176A promotes ERK signalling 38. Similarly, high expression of TMEM16A plays a role in gastrointestinal stromal tumours 39. TMEM176A in glioblastoma can inhibit Bcl2 expression and cause apoptosis 40,41. Increased TMEM176B protein levels have been found in various tumours, and inhibition of TMEM176B has been shown to increase CD8 + T cell-mediated tumour growth control, improving cancer therapy effectiveness 42. TMEM176B represses adenosine triphosphate (ATP) and nigericin-induced NLRP3 inflammasome activation in dendritic cells and macrophages through ionic mechanisms. Targeting TMEM176B can emphasise anti-tumoral CD8+ T cell responses in an inflammasome-dependent manner while directly killing malignant cells 43,44.
Phosphatidylinositol glycan anchor biosynthesis class C and W, respectively (PIGC and PIGW), are critical genes in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, encode an endoplasmic reticulum (ER)-associated protein that is significant for the biosynthesis of glycosylphosphatidylinositol (GPI) 45. This process happens in the endoplasmic reticulum and is a step in the glycosylphosphatidylinositol (GPI) biosynthesis, anchoring many cell surface proteins to the membrane. Defects in the PIGW gene cause the age-dependent epileptic encephalopathy West syndrome and a syndrome exhibiting hypophosphatasia and cognitive disability (HPMRS5) 46. PIGC was up-regulated and associated with the transferase activity of cancer cells such as Hepatocellular carcinoma (HCC) 45. Since cell adhesion can be altered in metastasis, it can indicate that in SCLC brain metastasis, GPI binding changes because of the high expression of PIGC and PIGW.
We indicate that ABCA13, an ATP-binding cassette (ABC) transporter, has the most mutations (9%) in lung cancer patients, as shown in figure S2, Suggesting that alteration of this gene can affect lung cancer state.
AMFR is a gene that encodes ubiquitin-protein ligase. It also correlates with lncRNAs, including FGF10-AS1, LINC02115, and LINC01716 (Table 2). Overexpression of gp78/AMFR in human cancers is related to low survival and the high stage of the tumours 47,48. Thus, It can attribute narrow expression of AMFR in non-BM SCLC despite BM SCLC to a biomarker of this type of cancer metastasis. CRAT encodes an acetyltransferase and has involved in specific pathways among Beta-oxidation of very-long-chain fatty acids, Beta-oxidation of pristanoyl-CoA, and Peroxisomal lipid metabolism (Table S3). CRAT is required to transport acetyl-CoA from peroxisomes or mitochondria into the cytoplasm to activate calcium/calmodulin-dependent kinase II (CaMKII). A decrease in CRAT protein levels reduces cell proliferation and low cell migration; it also is necessary for CaMKII activation 49. OCLN is the most downregulated gene in DEGs results, with Log FC = -3.56 (Table 1); naturally encoded transmembrane proteins play an essential role in regulating cell permeability barriers formed by protein tight junctions and Are an Integral Component of the blood-brain barrier (BBB)50. We demonstrate that low expression of this gene may affect brain metastasis since prior studies reveal that CeRNA regulates OCLN mRNA, which plays a vital function in the BBB. PIK3CG is a component of the PI3K-Akt signalling pathway, controlling essential cell functions such as cell proliferation, differentiation, and metabolism 51,52. OCLN also has a relation with three lncRNAs such as ARHGEF2-AS1, NKX2-1-AS1, and LINC01806 (Table 2). Two hub genes, including CAT and APP, are involved in different cancers; for Instance, CAT, positioned specially in peroxisomes, decomposes H2O2, a spinoff of fatty acid oxidation, to oxygen and water. Thus, CAT confers safety in opposition to the deadly consequences of H2O2 without producing intermediate unfastened radicals, and the ensuing oxygen is applied to different metabolic processes 53. Catalase is likewise often downregulated in tumour tissues like non-small-cell lung cancer than in normal tissues of the exact origin 54. H2O2 is a mediator of several physiological processes, including cell differentiation and proliferation, cellular metabolism, survival, and immune response, through ROS (reactive oxygen species) intracellular signalling (Fig. 1)55. Amyloid precursor protein (APP) is a protein known to have a role in the progression of Alzheimer's disease. Its cytoplasmic region contains numerous phosphorylation sites. APP has also been suggested as a molecule involved in cell proliferation and invasion in various human cancers, including non-small-cell lung cancer 56–58. Our study reveals that these genes are downregulated In brain metastasis SCLC and suggests that they can Influence the cancer stage and survival rate, as shown in Fig. 5. We suggest these genes mentioned above can be associated with brain metastasis in SCLC and might be employed as new therapeutic targets and potential prognosis biomarkers. However, considering these genes as a Biomarker require deep and comprehensive studies yet clinical validations. Since we performed only bioinformatical analysis, deficiencies still demand clinical experiments and data validation. Furthermore, these candidates' metastasis genes' functions and mechanisms are still to be investigated.
In conclusion, brain metastasis SCLC shows a different gene expression than non-BM SCLC. We demonstrated up and down-regulation of specific lncRNAs and mRNAs and their networks to evaluate their predictive values. Preventing cancer metastasis with reliable biomarkers can be considered vital; however, it is yet unknown to find the exact role of these distinct lncRNAs and how They influence cancer metastasis.