ALOXE3 表达预测结肠腺癌不良预后并调节免疫浸润

Lipoxygenase family proteins (LOXs) are involved in various stages of tumor development, however, their specific roles in tumor-infiltrating lymphocytes (TILs) within colon adenocarcinoma (COAD) remain poorly defined. This study aims to comprehensively examine LOXs expression in COAD and evaluate their potential associations with immune cell infiltration and clinical outcomes.

We analyzed transcriptomic and clinical data from 477 tumor and 41 adjacent normal tissue samples in the TCGA-COAD dataset to evaluate the expression levels of LOX family genes and their associations with overall survival. To validate ALOXE3 expression, we performed RT-qPCR on fresh tumor and the corresponding matched adjacent tissues from six human colon carcinoma patients. Additionally, immune cell infiltration associated with LOX expression was explored using the TIMER and TISIDB databases. For functional validation, ALOXE3 was either overexpressed or silenced via shRNA in colon cancer cell lines, and its effects on tumor progression were assessed through in vitro proliferation assays and in vivo xenograft models.

Among all LOX family members, only ALOXE3 expression was significantly associated with survival outcomes in COAD patients (overall survival: HR = 1.56, p < 0.05; disease-specific survival: HR = 2.12, p < 0.01; progression-free interval: HR = 1.55, p < 0.05). Functional assays showed that ALOXE3 overexpression significantly promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo, whereas shRNA-mediated knockdown of ALOXE3 markedly suppressed cell proliferation. KEGG pathway analysis of genes co-expressed with ALOXE3 revealed a remarkable enrichment in mitogen-activated protein kinase (MAPK) signlaing pathway. Consistently, ALOXE3 overexpression resulted in activation of the ERK1/2 signaling pathway, as confirmed by Western blot analysis (p < 0.05). Furthermore, treatment with the ERK inhibitor SCH772984 effectively suppressed ALOXE3-induced tumor cell proliferation, suggesting that ALOXE3 may drive tumor growth via activation of the ERK1/2 signaling pathway.

ALOXE3 promotes tumor progression in COAD through activation of the ERK1/2 signaling pathway and exhibits a strong association with the immune cell infiltration of the tumor microenvironment. It may serve as a prognostic biomarker and a potential therapeutic target in COAD. Further studies are warranted to validate its clinical applicability and explore its role in immunotherapeutic approaches. [Image: see text]