Among all categories of lung cancers, LUAD is one of the most common histological type. Determining the molecular mechanism underlying the occurrence and development of LUAD and the development of new therapeutic targets are essential means for improving its poor prognosis and low survival rate. Therefore, there is an urgent need to obtain comprehensive knowledge about the underlying molecular features of LUAD and identify more potential biomarkers for disease diagnosis and treatment.
In this study, we identified 29 significant genes that exhibited similar trend in their expression in TCGA, GSE8569, and GSE118370 databases by comprehensive bioinformatic analysis. Functional annotation assessment of the ClusterProfiler software package showed that the genes were primarily involved in heart trabecula formation and the regulation of inflammatory response, which are closely related to angiogenesis modulation, survival of endothelial cells, migration, proliferation, cell expansion and adhesion, recombination of the actin cytoskeleton, and maintenance of vascular resting. According to the MCC score of the CytoHubba plug-in, the first 10 genes related to LUAD were screened. It was found that the expression patterns of CDH5, TEK, TIMP3, EDNRB, EPAS1, MYL9, SPARCL1, KLF4, and GFBR3 in LUAD tissues were lower in contrast with those in the non-tumor control group, while the expression pattern of MMP1 in LUAD tissues was higher relative to the non-tumor control group. Among them, the low expression of MYL9 and SPARCL1 was found to be significantly related to patients' poor OS in LUAD. Lastly, the expression patterns of MYL9 and SPARCL1 were verified using the Oncomine database.
MYL9 is a protein-encoding gene 27. The myosin regulatory subunit has an essential role in modulating smooth muscle as well as non-muscle cell contractile activity through its phosphorylation. Reflected in cytokinesis, cell locomotion, receptor capping 28, 29. It is worth noting that myosin is also thought to participate in tumor progression as well as metastasis. MYL9 facilitates airway smooth muscle cell migration and contraction, migration of megakaryocyte and tip cell under pathological conditions such as angiogenesis and tumor growth during development 30–32. MYL9 is modulated by the troponin-related transcription factor-serum response factor (MRTF-SRF) cascade and is necessary for the migration of tumor cells, megakaryocytes, and TIP cells in vivo. The upregulation of MYL9 can also promote the invasive function of tumor-related fibroblasts. Our research shows that the leukocyte transendothelial migration signaling pathway is closely related to MYL9, an essential mechanism for transporting white blood cells to the site of injury, immune response, or infection in the inflammatory response 33. Many researchers have found that MYL9 is expressed in a variety of tumors. Some studies have shown that MYL9 upregulation is remarkably linked to the shorter survival time of patients with colorectal cancer 34–36. Studies by Kruthika et al. have shown that the high expression of MYL9 in patients with glioblastoma is related to poor prognosis and plays an essential role in improving tumor invasiveness 37. Huang et al. found that the downregulation of MYL9 in stroma indicates progression of prostate cancer and poor biochemical recurrence-free survival 38. Our results showed that a higher level of MYL9 in tumor tissue was linked to good disease outcomes LUAD patients. We speculate that MYL9 may be a human tumor suppressor gene.
Glycoprotein SPARCL1 belongs to the SPARC family of matricellular proteins 39. GO analysis showed that the biological process closely related to SPARCL1 was cell-cell adhesion through plasma-membrane adhesion molecules. Cell adhesion molecules are at least partly embedded in the cell membrane. It is related to the modulation of cell adhesion, proliferation, migration 39. Many studies have shown that SPARCL1 has different expression patterns in different types of tumors and plays the tumor suppressor and angiogenesis regulator 40–42. Nelson et al. 43 demonstrated for the first time that the transcriptional level of SPARCL1 is lower in transformed prostate epithelial cell lines and metastatic prostate cancer cells, strongly suggesting the hypothetical role of SPARCL1 in inhibiting the progression and metastasis of prostate cancer. A comprehensive analysis by Wu et al. 44 showed that the downregulated expression of SPARCL1 might be vital for the formation and pathogenesis of cervical cancer. It is also related to precancerous lesions and migration in the occurrence of cervical cancer. Ma et al. 45 found that SPARCL1 protein expression in ovarian cancer tissues is lower in contrast with the neighboring non-tumor tissues, which may suppress the migration along with the proliferative ability of ovarian cancer cells by downregulating the MEK/ERK signaling pathway. The results of Han et al. 46 indicated that the expression of SPARCL1 protein in colorectal tumors was substantially lower compared to corresponding non-tumor tissues, which may be used as a potential tumor suppressor gene and associated with a good prognosis. In our study, relative to non-tumor tissues, SPARCL1 expression was lower in tumor tissues, which was near related to LUAD. The survival analysis data revealed that the higher level of SPARCL1 in tumor tissue was linked to the good prognosis of patients with LUAD.
Although this study screened the DEGs of LUAD tumor tissue and neighboring non-tumor tissue from the publicly downloaded data sets and conducted a comprehensive bioinformatic analysis, the molecular mechanism of survival-related genes influencing the prognosis of LUAD patients should be further verified to validate our findings.