This study employed a comprehensive bioinformatics-based omics database exploration strategy to unfold the multi-factorial diagnostic and therapeutic values of LSM5 gene for human brain cancer glioma. Differential gene expression analysis can facilitate the optimum understanding of the functional roles of specific genes in healthy cells and oncogenic development [23–25]. Initially, the DEG analysis revealed that the gene of our interest is significantly upregulated in LGG and GBM tissues compared to the adjacent normal tissues suggesting its possible underlying mechanism in the oncogenic progression of normal brain tissues and subsequent metastasis. Additionally, a disproportionate level of LSM5 expression was observed across different age groups, sex statuses, and histological subtypes of glioma patients. Moreover, the IHC image inspection on the protein level expression of LSM5 in glioma tissues also suggested that the LSM5 gene is also highly expressed in glioma tissues at the protein levels. Therefore, the differential level of LSM5 transcriptional and translational products may be adopted to capture the glioma condition, pathologic stages of glioma, site of metastasis, and metastatic potentials of glioma cells. Also, LSM5-based diagnostic measures could also help to determine the response to any LSM5-targeted therapeutic measures for glioma patients.
Aberrant promoter and gene body methylation patterns are one of the major epigenetic etiological factors for cancer development. Abnormal methylation patterns of different genes can subject healthy cells to tumorigenic transformation by altering the gene expression levels of the gene in question [26]. More specifically, promoter hypomethylation is associated with the upregulation of a particular gene in cancer tissues [27]. In this experiment, we recorded that the LSM5 promoter is hypomethylated in glioma tissues compared to the normal tissues. Later, the hypomethylation pattern of the LSM5 promoter was found to be correlated with its mRNA level overexpression in glioma tissues. Thereby, our analysis suggests that the hypomethylated LSM5 promoter might be accounted for its overexpression in cancerous tissues. Furthermore, the aberrant methylation patterns of different genes can provide a greater sensitive measure for glioma diagnosis and unlike other pathologic testing options, abnormal DNA methylation is observed at an earlier stage of cancer development [28]. Additionally, tracking the gene methylation pattern from the bodily fluid of patients i.e., serum can provide accurate glioma stratification in a non-invasive manner [29]. In this study, the LSM5 gene was found to have a distinct DNA methylation pattern in LGG and GBM tissues. Moreover, a significant variation in the methylation pattern of the LSM5 coding gene was recorded in accordance with advancing age groups of LGG patients justifying the potential of LSM5 methylation status to be an epigenetic diagnostic measure for early stage and non-invasive diagnosis of glioma patients. What’s more, aberrant DNA methylation patterns of different genes can provide an effective therapeutic target for cancer treatment with strategies like regulating DNA methyltransferase activity [30]. In this study, we observed that the lower methylation pattern of LSM5 gene is negatively associated with the OS, DSS and PFS of glioma patients suggesting its methylation pattern to be a potential therapeutic target for individual glioma patient care with epigenetic-based clinical decisions.
Different somatic mutations in specific genes can drive the oncogenic processes in healthy cells and unsurprisingly different CNAs contribute to such deteriorating effects to a greater extent compared to other point mutations [31–33]. Such genetic alterations greatly affect cellular activity by disrupting the normal gene expression levels of the gene in question and other genes (i.e., oncogenes, tumor-suppressor genes) within its interaction networks and thus propel the oncogenic transformation of healthy cells and subsequent metastasis ultimately influencing patient’s survival [34]. In this experiment, we observed that LSM5 genes underwent multiple amplification events in different glioma cohorts. Later the CNAs present in the LSM5 gene was found to be positively associated with its mRNA level expression in glioma tissues. We also found a positive correlation between LSM5 CNAs and the OS, DSS and PFS of LGG and GBM patients which signifies that the LSM5 alterations might further affect the prognosis of glioma patients. From the diagnostic perspective, in vitro studies with clinical specimens suggest that CNAs present in different genes collected from sources like cerebrospinal fluid can predict the condition of glioma patients [35, 36]. Therefore, the observed CNAs in the LSM5 gene can further improve personalized patient care of glioma patients by improving the precision of glioma diagnosis and amplification events in LSM5 genes could be further investigated with studies involving more glioma samples from different demographic regions.
Later on, we discovered that LSM5 overexpression is negatively associated with the unfavorable OS of LGG and GBM patients and RFS of LGG patients suggesting that LSM5 might have an underlying mechanism in the tumorigenic transformation of brain cells and glioma exacerbation. This further justifies the therapeutic potential of LSM5 in LGG and GBM patients. On the contrary, LSM5 overexpression was favorable for the RFS of GBM patients which indicates that therapeutic invention may contribute to improving the GBM prognoses by altering the dosage or activity of LSM5 though such assumption requires further laboratory investigation. Moreover, the impact of LSM5 expression on the survival condition along with its overexpression pattern irrespective of glioma patients’ demographic and clinical condition suggests that the downstream products LSM5 gene might help track the glioma patients throughout the clinical course, identify high-risk groups of patients and recommend necessary follow-up measures.
The immune-cell infiltration analysis revealed that LSM5 expression is disproportionately correlated to the abundance of different immune cells i.e., B cell, T cell, and DC in LGG and GBM patients. Given the functional roles of immune cells in maintaining immunity against cancer cells after getting produced in higher titer in the cancer microenvironment, different immune cells and mediators remain promising targets for glioma diagnosis and treatment [37–39]. For instance, high infiltration levels of CD8 + T cells in glioma patients predicts favorable survival of glioma patients [40]. Therefore, the correlation between the abundance level of different immune cells and LSM5 in glioma patients may guide the propagation of dual diagnosis and combinatorial therapeutic options along with LSM5-targeted ones. Additionally, we also reported that LSM5 expression is correlated with the abundance level of different immunomodulators such as CD48, IL10RB, CD274 in LGG and GBM patients. Previously, IL10RB overproduction has been found to be associated with the unfavorable survival of glioma patients [41]. Moreover, a recent study has systematically grounded that upregulation of CD48 in glioma patients predicts reduced survival [42]. Hence, the association between LSM5 and different immunomodulators could further assist the LSM5-based diagnostic and therapeutic discovery for glioma patients.
After that, the functional enrichment analysis on the top co-expressed genes of LSM5 in LGG and GBM patients revealed that most of the genes were predominantly involved in RNA processing. In recent years, RNA splicing genes have been reported to act as prognostic indicators for glioma patients [43, 44]. Other biological functions of the co-expressed genes of LSM5 included damaged DNA binding, DNA replication, DNA repair and others which can give rise to the tumorigenic transformation of healthy cells upon deregulation [45, 46]. Lastly, the expression pattern and impact of LSM gene on glioma patients’ survival rates were validated using independent glioma microarray datasets i.e., GSE35493, GSE50161, GSE4412. The results obtained from the validation step also supported our initial findings such as LSM5 is highly expressed and negatively impacts the OS of glioma patients.
In summary, the results obtained from the expression, methylation and mutation analysis on LSM5 gene in glioma patients indicate that the selected gene in this study might have an underlying mechanism in glioma development and progression. Moreover, the overexpression pattern and impact on the survival rates of LSM5 gene in glioma patients suggest that the LSM5 gene and its transcriptional and translational products could be potential targets for glioma diagnosis and treatment. Furthermore, the findings from the immunophenotype and neighbor gene analysis of LSM5 should further help develop LSM5-based diagnostic and therapeutic measures for glioma and improve the precision of glioma diagnosis.