Overexpressed VDAC1 in breast cancer as a novel prognostic biomarker and correlates with immune infiltrates

Abstract

Background More and more evidence suggests that cancer is a mitochondrial metabolic disease recently and mitochondria dysfunction is critical to tumorigenesis. As a gatekeeper of mitochondria, the voltage-dependent anion channel 1 (VDAC1) is associated with the development of breast cancer (BC). However, its potential mechanism and clinical significance remain unclear; thus, in this research, we aimed to explore it. Methods VDAC1 expression in BC tissues and normal tissues was obtained from The Cancer Genome Atlas (TCGA) and validated by datasets from the gene expression omnibus (GEO) database. Then, the relationships between VDAC1 expression and clinicopathological features were analyzed. Receiver operating characteristics (ROC) curves were used to identify the diagnostic value of VDAC1. The prognostic value was evaluated by Kaplan-Meier survival curves and Cox regression analysis. VDAC1 with its co-expression genes were subjected to enrichment analysis to explore potential mechanisms in BC and the protein-protein interaction (PPI) network was constructed. At last, the association between VDAC1 expression and infiltration levels of immune cell infiltration by various methods, as well as their corresponding markers, was analyzed. We also analyzed the correction between VDAC1 expression and eight immune checkpoint genes and the tumor immune dysfunction and exclusion (TIDE) scores of each BC sample in TCGA were calculated and the differences between high and low VDAC1 expression groups were analyzed. Results VDAC1 expression was remarkably elevated in BC (p < 0.001), and high expression of VDAC1 was associated with the positive expression of ER (p = 0.004), PR (p = 0.033), and HER2 (p = 0.001). ROC analysis suggested that VDAC1 had diagnosed value in BC. The Kaplan-Meier analysis suggested that higher expression of VDAC1 was associated with shorter overall survival (OS), and further Cox regression analysis revealed that VDAC1 was an independent factor of unfavorable prognosis in BC patients. Enrichment analysis of VDAC1 and its co-expression suggested that VDAC1 was related to the regulation of mitochondrial energy metabolism and protein modification, and the HIF-1 singing pathway might be the potential mechanism in BC. Notably, we found that VDAC1 expression was infiltration levels of most types of immune cells, as well as the expression of marker genes of immune cells. The ICGs PDCD1, CTLA4, LAG3, SIGLEC15, and TIGIT were negatively corrected with VDAC1 expression in BC. TIDE scores between the low and high expression groups showed no difference. Conclusion Overexpressed VDAC1 in BC could be severed as a novel biomarker for diagnosis and VDAC1 was an independent factor for adverse prognosis prediction. Our study revealed that VDAC1 might inhibit tumor immunity and might be a novel therapeutic target in BC.

Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology

“…VDAC1 overexpression, its oligomerization and apoptosis induction have been implicated in different diseases [37]. In cancers, VDAC1 is overexpressed [38][39][40], while its oligomerization and, thereby, apoptosis are prevented by the overexpression of anti-apoptotic proteins such as hexokinase and Bcl2, and their detachment from VDAC1 leads to VDAC1 oligomerization and apoptosis [22,37,39].…”

Origin Recognition Complex Subunit 1(ORC1) is a potential biomarker and therapeutic target in cancer

“…ORC1 was highly expressed in different types of tumors tissues and matched normal tissues, as detected from the Cancer Genome Atlas (TCGA) and validated by datasets from the gene expression omnibus (GEO) database [29].To explore the relationship between ORC1 expression and clinicopathological features, analysis of the GEPIA2 and UALCAN databases revealed a signi cant difference in ORC1 expression levels with increasing pathology in ACC, LUAD, OV and SKCM. An analysis of the survival curves of cancer patients found that ORC1 was closely related with poor prognosis in ACC, LIHC, PAAD, READ and THCA.…”

VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference

“…Interestingly, high expression of both VDAC1 and HKs has been observed in many cancer types. 6 , 7 , 9 , 10 , 11 , 12 , 13 This allows cancer cells to maintain a high rate of glycolysis, even under aerobic conditions, which provides a continuous supply of building blocks for rapid cell proliferation. 14 Overall, the altered VDAC1 expression and function appear related to highly metabolically active and energy-demanding cancer cells, suggesting that the channel may act as an oncogene prompting the tumor progression by different molecular mechanisms, including the deregulation of apoptosis.…”