Globally, well known for the high probability of metastasis and recurrence, glioma is still a leading cause of mortality in brain tumors 20. Despite advances in diagnosis of glioma, most glioma patients can only be diagnosed at the intermediate and advanced stage when surgical resection is not an optimal option 21. Therefore, accurate patient stratification based on reliable prognostic factors is essential for decision of clinical management and determination of subset of glioma patients suitable for personalized treatment. In this study, we first developed a prognostic signature and successfully validated it based on a large combined cohort. Further analysis revealed that patients in two groups of the signature presented significant discrepancy of mutation status and immunity features, which might provide valuable information for predicting the prognosis and treatment of glioma patients, thereby helping physicians predict prognosis and guide treatment for patients.
The kinesin superfamily (KIFs), known as molecular motors with microtubule (MT) class-binding protein superfamily, play pivotal roles in several biological processes, including axonal transport and microtubule stabilization in our body, especially in the brain, that are important for various highly aggressive malignancies including glioma 22. Although several compounds targeting mitotic kinesins including the taxanes, vinca alkaloids, and epothilones, have been successfully used in treatment of a number of hematologic and solid malignancies, the same efficacy does not appear to glioma patients 23. However, there is little share of the literature focused on the potential therapeutic and prognostic role of KIFs in glioma.
Here we identified 22 KIFs closely associated with glioma patients prognosis (6 protective and 16 risk factors) using Cox analysis. Further analysis resulted in the selection of five KIFs (KIF4A, KIF26A, KIF1A, KIF13A and KIF13B) with prognostic values. Among them, KIF4A and KIF13B were risk factors upregulated in the highrisk group, whereas KIF26A, KIF1A and KIF13A were protective factors downregulated in the highrisk group. KIF4A was found to be remarkably upregulated in primary colorectal carcinoma and contributes to proliferation of colorectal carcinoma through modulation of p21-mediated cell cycle progression 24. A recent study reported that low expression of KIF26A had a positive correlation with distal metastasis and poor survival in patients with gastric cancer via regulating the focal-adhesion pathway and repressing the occurrence of epithelial-to-mesenchymal transition 25. De S et al. revealed that overexpression of KIF1A was closely related to the cell resistance to docetaxel in breast cancer 26. In addition, a target of miR-1290, KIF13B is typically involved in activation Wnt pathway and increased the expression of reprogramming-related transcript factors c-Myc and Nanog in colon cancer tissues 27. Given both biological and tumorigenic functions of the five KIFs that were highly consistent with the results from bioinformatics analyses in our study, the prognostic value of five KIFs was demonstrated of valid predictions of clinical outcomes in glioma patients.
We further explored the underlying biological difference between patients in not only high and low risk group, but also in groups of different expression of five KIFs through GSEA and burden analysis. With the Hallmark gene set as a reference set, results of GSEA analysis showed that the E2F target, mitotic spindle, epithelial-mesenchymal translational (EMT), G2M checkpoint and TNFa signaling via NFkB pathways were significantly activated in high risk patients. EMT is the process that epithelial cells transform into motile mesenchymal cells, which is closely related to malignant biological behavior of cancer 28. Recently, EMT has attracted much attention in tumorigenesis and cancer progression of glioma, and a previous study have been reported that the inhibition the process of EMT increased invasion and migration in glioma 29. The mitotic spindle is a fundamental physiological process in cells responsible for the generation of a mitotic spindle with two spindle poles and daughter cells. The abnormal mitotic spindle in cancer cells may be related to the increase of cellular heterogeneity and metastasis as well as facilitation of transformation of cancerous cells 30. G2/M checkpoint, as the DNA-damage in the cell cycle, is a limitation step of cell which is closely correlated with cancer cell growth and migration 31. All these results in our study indicated that the patients in high risk group may aberrantly activate the above pathways, leading to worse genomic and prognosis characteristics.
In addition, we found that patients with high riskscore was significantly positively correlated with immune score, stromal score, and estimate score and revealed a higher level of all main immune checkpoints, implying that patients in high risk group could be considered had a poor response to immunotherapy. Furthermore, mutation anslysis revealed that more somatic mutations including non-synonymous, synonymous mutations and all mutations enriched in patients with high risk, and IDH1 was the most significant hub gene associated with mutation. Then differential expression analysis of five signature KIFs was also conducted between IDH1-mutant group and IDH1-wild group. Finally, we also verified the five signature genes in the Human Protein Atlas (HPA) database, which identified of candidates for relevant biomarkers.
Briefly, we successfully developed a five KIFs based prognostic signature which could be used to stratify patients to further predict clinical outcomes and guide treatment. However, this study had some limitations need to be noted. First, the signature should be further validated in other prospective cohorts. Second, the five signature KIFs need to be further studied, including functional experiments and potential molecular mechanisms.