Title of the research



Design of EIF6 siRNA and its synergistic effects with apatinib against glioblastoma through regulation of cellular glycolysis





Backgroud


Glioblastoma has a significant impact on patients' lives. Finding new treatment approaches, particularly by targeting cellular metabolism to inhibit tumor growth, would have a profound effect on improving survival rates and quality of life for patients. The project's objectives are directly related to addressing real-world clinical challenges, which makes me feel that the research work has significant social relevance. Participating in a research project like this would provide an opportunity to learn scientific research methods and experimental techniques. This would help cultivate my scientific interests and skills, laying a foundation for future choices in university majors or careers in scientific research.

Studies have reported that apatinib can also inhibit the progression of glioblastoma through various mechanisms, such as promoting cell ferroptosis and enhancing the activity of chemotherapy drugs [1,2]. Animal experiments have shown that apatinib can inhibit tumor growth [3]. Furthermore, clinical studies have reported the use of apatinib in the treatment of recurrent glioblastoma [4]. Apatinib treatment for glioblastoma may be an effective new approach, but currently, its application lacks large-scale clinical trials.

Cellular glycolysis is one of the main metabolic pathways in cancer cells, and inhibiting its normal function is crucial for suppressing cancer cell development. Glycolysis is closely associated with mitochondrial metabolism, and disruptions in mitochondrial metabolism can also impede cancer cell growth [5,6].

A recent study published in Nature Communications revealed that eIF6 autonomously controls fatty acid synthesis and glycolysis in cells, leading to gene expression remodeling and increased levels of lipogenesis and glycolytic enzymes [7]. This suggests that EIF6 promotes cellular glycolysis and improves mitochondrial metabolism in cell function. Results from the TCGA database indicate significantly upregulated expression of EIF6 in glioblastoma. EIF6 has also been shown to play a pro-carcinogenic role in various other tumors [8,9]. In glioblastoma, there is currently only one data analysis article that analyzed EIF6 expression based on TCGA database results, demonstrating its high expression in glioblastoma and its potential correlation with patient prognosis [10].





Inspiration and Innovation


According to the GLOBOCAN report in 2022, brain and nervous system cancer account for more than 30,000 new cases and 25,000 deaths annually [13]. Among these, glioblastoma stands out as the most common malignant primary brain tumor, characterized by its high malignancy and poor prognosis, with a median survival of less than 2 years[14].

Apatinib, a tyrosine kinase inhibitor, has gained approval in recent years as a multi-targeted anti-tumor drug. It has been widely used in the treatment of various cancers, including gastric cancer [11], liver cancer [15], cervical cancer [12], among others.

Several recent studies have reported the application of apatinib in glioblastoma [16]. However, the efficacy and safety of apatinib in the treatment of glioblastoma still require further investigation, a nd the underlying molecular mechanisms of its anti-tumor effects in glioblastoma remain unclear.





Design



1) Discovery of EIF6 as an oncogene and a target of apatinib in glioblastoma.

Eukaryotic translation initiation factor 6 (EIF6) has been identified as an oncogene in various cancers, such as lung cancer and colorectal cancer. However, its role in glioblastoma has been relatively unexplored. In this project, we drew inspiration from both the TCGA database and existing bioinformatic studies to uncover EIF6 as a potential oncogene in glioblastoma and a promising target for apatinib.

a) TCGA database:

The Cancer Genome Atlas (TCGA) is a pivotal cancer genomics program that has comprehensively characterized over 20,000 primary cancer samples across 33 cancer types. In our project, we initiated our investigation by utilizing the TCGA database analysis tool GEPIA (http://gepia.cancer-pku.cn) to evaluate EIF6 expression levels in glioblastoma. Our analysis revealed a significant upregulation of EIF6 in glioblastoma tissue.

Figure 1.EIF6 is remarkably elevated in glioblastoma according to the analysis website of TCGA database GEPIA.

b) Bioinformatic studies:

Building upon our TCGA analysis, we delved into the study conducted by Liang and colleagues[17], which corroborated our findings. Their research demonstrated that EIF6 is notably overexpressed in glioblastoma multiforme and low-grade glioma based on data from TCGA and GTEx databases. Additionally, their study unveiled a correlation between EIF6 expression and overall survival in glioma patients, with higher EIF6 levels predicting shorter overall survival, as per data from TCGA and CGGA databases.

Figure 2.eIF6 expression in tumor tissue and normal counterparts. A. eIF6 in carcinoma tissue and normal counterparts from TCGA database; B. eIF6 in carcinoma tissue and normal counterparts from TCGA and GTEx databases.

Figure 3.Correlation of eIF6 expression with glioma patient’s overall survival. A. Correlation of eIF6 expression with overall survival of GBM patients in TCGA database; B. Time-dependent ROC curve of GBM patients in TCGA database; C. Correlation of eIF6 expression with overall survival of LGG patients in TCGA database; D. Time-dependent ROC curve of LGG patients in TCGA database; E. Correlation of eIF6 expression with glioma patients’ overall survival in TCGA; F. Time-dependent ROC curve in the TCGA database; G. Relationship between eIF6 expression and glioma patients’ overall survival in CGGA; H. Time-dependent ROC curve in the CGGA database.

Furthermore, Scagliola et al. [18] reported a significant role of tyrosine kinase phosphorylation as a key eIF6-regulated event. Given that apatinib is a prototypical tyrosine kinase inhibitor, we speculate that EIF6 may serve as a potential target for apatinib. The interplay between EIF6 and tyrosine kinase phosphorylation could potentially influence the anti-cancer efficacy of apatinib.

Figure 4.Gene Ontology (GO-BP) analysis identifies the most significantly downregulated pro-tumoral pathways in eIF6+/− livers.






References


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