This study presents a novel and comprehensive approach to examining non-apoptotic cell death pathways in the context of cancer. By integrating gene sets representing 11 distinct non-apoptotic cell death mechanisms, the authors calculated a composite "death enrichment score" that provided valuable insights. The strong positive correlations observed between this integrated score and the enrichment of specific non-apoptotic death modalities, such as pyroptosis, ferroptosis, and necroptosis, highlight the utility of this innovative methodology. This multifaceted assessment of non-apoptotic cell death allows a more holistic understanding of how these diverse pathways may collectively influence cancer biology. The application of WGCNA enabled the identification of a specific gene module (the blue module) that was closely associated with the computed death enrichment score. The significant correlations observed between this module and the death score underscore the biological relevance of this gene set. By using the blue module genes as input for further statistical analyses, the authors uncovered the potential prognostic significance of these genes, with the ENO2 gene emerging as a prominent candidate. The subsequent dimensionality reduction techniques, including Random Forest and LASSO regression, further corroborated the role of ENO2 as a key player in the context of non-apoptotic cell death and cancer progression.
ENO2, also known as neuron-specific enolase (NSE), is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate during glycolysis[16]. ENO2 is often upregulated in various types of cancer[17], including neuroendocrine tumors[18], small-cell lung cancer[19], and breast cancer[20]. In cancer cells, increased expression of ENO2 can promote several hallmarks of cancer, such as enhanced glycolytic metabolism, cell proliferation, and survival[16]. ENO2 overexpression has been associated with more aggressive tumor phenotypes, increased metastatic potential, and poor patient prognosis in some cancer types. The mechanisms by which ENO2 contributes to cancer progression are not fully elucidated. It may involve its role in facilitating glycolytic energy production, which can support the rapid growth and division of cancer cells[21]. ENO2 may also have non-metabolic functions, such as modulating signaling pathways or interacting with other proteins to promote cancer cell survival and invasion[22]. In our study, ENO2 is upregulated in colorectal cancer, a common characteristic observed in many types of cancer. The increased expression of ENO2 in the tumor samples compared to normal tissues indicates that ENO2 may play an important role in the cancer phenotype and tumor progression. Besides, the level of ENO2 expression or the presence of ENO2-related factors can influence the survival outcomes of COAD patients. Specific details on how the patients were categorized into different ENO2-related groups and the corresponding survival differences would be needed to interpret this finding further. Our in vitro validation proved that overexpression of ENO2 in COLO 320DM colon adenocarcinoma cells promotes their proliferation and cell cycle progression. The increased expression of key cell cycle regulators, such as Cyclin D1 and Cyclin B1, and the upregulation of the proliferation marker Ki67, suggest that ENO2 overexpression can enhance the proliferative capacity of colon cancer cells.
Targeting ENO2 or its associated metabolic pathways has been explored as a potential therapeutic strategy in some cancers, though clinical applications are still under investigation[23]. In our study, high expression of ENO2 in COAD tumors may sensitize the cancer cells to certain therapeutic agents, such as chemotherapies (e.g., Vinblastine, Cisplatin, Fludarabine) and targeted therapies (e.g., Dasatinib, Leflunomide, Entospletinib, AZD8186, AMG-319). The enhanced drug sensitivity observed in the high ENO2 group could be attributed to the metabolic alterations or other cellular changes associated with increased ENO2 expression in the cancer cells. This information may have implications for personalized treatment approaches, where ENO2 expression levels could guide the selection of more effective drug regimens for COAD patients. Further research is needed to fully understand the complex role of ENO2 in the various aspects of cancer biology and to evaluate its utility as a biomarker or therapeutic target.
Emerging evidence suggests that ENO2 plays a role in cancer immune evasion. Cancer cells can release ENO2 into the tumor microenvironment, where it can interact with and inhibit the function of immune cells, such as T cells and natural killer (NK) cells. ENO2 can inhibit the activation and proliferation of T cells, reducing their ability to mount an effective anti-tumor immune response[16]. Besides, ENO2 can interfere with the cytotoxic function of macrophages, limiting their capacity to recognize and destroy cancer cells[24]. ENO2 can also contribute to the expansion and activation of MDSCs, which are known to suppress anti-tumor immune responses[25]. In line with these findings, our study proved that higher expression of ENO2 is linked to increased infiltration or activation of these components in the tumor microenvironment. This relationship may have important implications for understanding the role of ENO2 in shaping the immune landscape of the tumor and potentially influencing the overall immune response and tumor progression. The modulators, such as CD274 (PD-L1), VTCN1 (B7-H4), and CD276 (B7-H3), are known to play critical roles in immune checkpoint regulation and can influence the ability of the immune system to recognize and attack the tumor cells. The positive correlation between ENO2 and these modulators suggests that ENO2 expression may be associated with the upregulation or activation of these immune checkpoint molecules, which could potentially contribute to the tumor cells' evasion of the immune system.
Overall, these findings provide insights into the complex interactions between the ENO2 gene and COAD, highlighting the potential involvement of ENO2 in promoting tumor growth, affecting drug sensitivity, shaping the immune landscape, and influencing the overall immune response against the tumor. Further investigation into the mechanistic links between ENO2 and the oncogenesis of COAD could yield valuable information for understanding tumor biology and potentially identifying therapeutic targets.