In the comprehensive study, our goal was to elucidate the potential significance of ABCD2 in pan-cancer research. Our investigation commenced with a fundamental transcriptomic analysis aimed at exploring the variations in ABCD2 expression across diverse cancer types. This analysis unveiled noteworthy differences in ABCD2 expression, with low expression detected in 25 different tumors.Subsequently, we conducted Kaplan-Meier survival analysis on cancer patients, revealing intriguing findings. The survival analysis plots clearly indicate that heightened ABCD2 expression is linked to favorable outcomes in terms of Overall Survival, Disease-Specific Survival. Notably, this positive correlation was particularly evident in specific cancers such as breast cancer, sarcoma, and cutaneous melanoma.Furthermore, We explored the relationship between ABCD2 expression and patient demographics, including age and clinical stage. Our findings revealed a significant correlation between ABCD2 expression and age in specific tumor types, providing valuable insights into the role of ABCD2 in cancer. In GBMLGG, LAML, LGG, and LUAD, ABCD2 expression tended to be lower in younger patients, while in BRCA, STAD, and THCA, it exhibited lower expression in older patients. These findings carry potential implications for tailoring immunotherapy strategies based on patient age, highlighting the need for personalized treatment approaches.Additionally, our study uncovered a significant correlation between ABCD2 expression and tumor stages across various malignancies, particularly notable in the transitions from stages I to II and I to III, where ABCD2 expression exhibited significant differences. These observations align with the current consensus that tumor progression is a consequence of both aggressive tumor growth and disruptions in the host immune balance. This disruption is often manifested through immune cell infiltration within the tumor microenvironment (TME), presumably as a mechanism to hinder tumor development[21–23]. Tumor-infiltrating lymphocytes (TILs) are widely recognized as the primary effector cells in the host's anti-tumor immune response, and assessing the extent of their infiltration has demonstrated prognostic significance across various cancer types[24]. Our GSEA enrichment analysis results highlighted a significant association between dysregulated ABCD2 expression and the infiltration levels of immune cells, including B cells and CD4 + T cells. These findings strongly suggest that ABCD2 holds potential as both a biomarker and an immune target for prognostic assessment in diverse cancer types. Furthermore, our enrichment analysis also unveiled the possibility that ABCD2 may influence tumorigenesis and progression through diverse immune pathways, encompassing lymphocyte activation and cell adhesion.
Prior research has established an association between ABCD2 and X-linked adrenoleukodystrophy (ALD)[25].While previous studies have explored the association between ABCD2 and X-linked adrenoleukodystrophy (ALD), there has been limited investigation into the relationship between ABCD2 and tumorigenesis. Our innovative discoveries suggest that ABCD2 alterations, such as mutations and deep deletions, can be detected across a spectrum of tumor types. Additionally, we observed notable disparities in the methylation degree of ABCD2 between normal and cancer tissues.Utilizing single-cell sequencing data, we uncovered potential regulatory roles of ABCD2-related genes in various tumor-related biological processes, such as DNA damage and apoptosis. As widely acknowledged, the presence of immune cells within the tumor microenvironment (TME) is a crucial factor in tumor progression and has substantial implications for the clinical outcomes of individuals with tumor. Consequently, conducting a thorough analysis of immune cell infiltration within tumors can unveil the mechanisms behind immune evasion in cancer, opening up prospects for the innovation of novel therapeutic approaches[26]. For example, immunoglobulins such as IgG, IgM, and IgA play crucial roles. Depletion of effector B cells and T cells can assist tumor cells in evading immune surveillance, ultimately diminishing the overall survival prospects of cancer patients[27]. Our results demonstrate a significant correlation between ABCD2 expression and the infiltration levels of immune cells, including B cells and CD4 + T cells. These findings suggest that ABCD2 holds the potential to serve as an attractive immune target for immunotherapy, thereby offering innovative prospects for clinical treatment.Finally, we predicted the efficacy of chemotherapy in BRCA patients, and screened two potential ABCD2 targeting drugs, which can replace anthracycline and taxane to produce better therapeutic effects in BRCA patients.
Microglia/macrophages have been identified as critical contributors to the Nerve inflammation research progress. Notably, human monocytes, characterized by minimal ABCD2 expression, exhibit significant impairment in very-long-chain fatty acid (VLCFA) metabolism, a hallmark of (X-ALD). In contrast, murine macrophages lacking Abcd1 but with moderate endogenous expression of Abcd2 show a milder metabolic phenotype compared to human X-ALD monocytes, which lack substantial ABCD2 expression. Highlighting the therapeutic promise of enhancing ABCD2 expression as a viable approach in X-ALD management[28]. However, our study yielded contrasting results as glioblastoma patients exhibiting high ABCD2 expression displayed lower survival rates compared to those with low ABCD2 expression. This discrepancy may be attributed to the distinct distribution of abcd2 mRNA within the brain. Notably, abcd2 mRNA was primarily detected in the pyramidal and granular cell layers of the dentate gyrus and cerebral cortex. Additionally, strong labeling for abcd2 was observed in the inner granular and Purkinje cell layers of the cerebellum. ABCD2 transcript RNA was found in the cerebral cortex, and this expression pattern of ABCD2 may be associated with glioblastomas[29]. However, our survival analysis of glioblastoma showed that patients with low expression had a higher survival rate, so we hypothesized that ABCD2 may be associated with tumors, but not affect and alter cancer progression through metabolism.
The reported study investigates the feature of ABCD2 in tumor, specifically focusing on ovarian cancer cell line SKOV-3. The experiment involved knocking down ABCD2 expression using siRNA. The results revealed that reducing ABCD2 expression led to an increase in cell apoptosis following cisplatin treatment, indicating that ABCD2 plays a role in modulating the sensitivity of ovarian cancer cells to cisplatin[30, 31]. However, our PFI (Progression-Free Interval) survival analysis (Fig. 5K) showed a contrasting result. It indicated that patients with lower ABCD2 expression had lower survival rates in ovarian cancer compared to those with high ABCD2 expression. This finding appears to contradict the earlier experiment's results. The discrepancy may be attributed to differences in treatment regimens, as the experiment specifically examined cisplatin therapy. While the experiment highlighted ABCD2's involvement in cisplatin sensitivity in ovarian cancer cells, our survival analysis suggests that the impact of ABCD2 expression on patient outcomes may vary depending on the treatment administered.
Our study systematically elaborated the pan-cancer analysis of ABCD2 from the differential expression of ABCD2 in cancer to the infiltration of tumor environment and finally screened for potential targeted drugs. However, our study also had some limitations. However, the relationship with protein levels needs to be further verified in future studies. At the same time, as public databases are being further updated, there are few data for some tumors, so for some tumors with less data, further research can be conducted.
In summary, our study employed a range of bioinformatics analysis techniques to comprehensively investigate ABCD2 in pan-cancer research. We conducted analyses of its expression levels, clinical prognosis, promoter methylation status, genetic alterations, single-cell sequencing, and GSEA enrichment. Notably, we unveiled, for the first time, that ABCD2 exhibits differential expression between tumor and normal tissues. Furthermore, we established robust correlations between ABCD2 expression, clinical prognosis, and immune cell infiltration levels.Our findings not only highlight ABCD2 as a novel potential biomarker for prognostic and immune-related assessments across various cancers but also underscore its significance as an independent prognostic factor in multiple tumor types. The varying expression patterns of ABCD2 hold the potential to impact prognosis diversely across different cancers. Therefore, further research is warranted to elucidate the specific roles of ABCD2 in each tumor type.