During pregnancy, recurrent spontaneous abortion (RSA) is a prevalent complication that piques the interest of expectant couples and their healthcare providers [27]. The primary mechanism underlying RSA remains poorly understood. Existing literature suggests that repeated miscarriages, pregnancy terminations, diagnostic curettage procedures, and intrauterine infections may result in irreversible harm to the endometrium [28]. Such endometrial damage, along with its thinning, constitutes a significant contributing factor to the development of endometrial carcinoma [29]. Additionally, fluctuations in hormone levels following miscarriages can potentially facilitate the onset of breast cancer [30, 31]. The establishment of novel prognostic markers and therapeutic targets for recurrent spontaneous abortion (RSA) and associated cancer progression is of utmost importance. This study aimed to investigate the characteristics and hub gene of RSA, analyze the underlying relationship between the hub gene and cancers, and predict the response of cancer to immune landscape, immune checkpoint, and targeted therapy.
Initially, a comprehensive approach involving the integration of multiple datasets, differential expression analysis, weighted gene co-expression network analysis (WGCNA), and single-cell analysis was employed to identify key genes that may have substantial implications in the progression of RSA. Through the application of machine learning techniques such as LASSO, random forest (RF), support vector machine (SVM), and XGBoost analysis, our study has identified SLC8A1 as a hub gene associated with RSA. The understanding of the relationship between the SLC8A1 gene and cancer prognosis remains limited. However, recent research has acknowledged the growing importance of gene in the development of cancer. Wang et al. proposed that NCAPG2 could potentially function as a regulatory element and a biomarker for various malignancies [32]. Li et al. demonstrated that EIF4G1 may have the ability to modify the tumor microenvironment and inhibit the metastasis of Breast cancer (BRCA), thus potentially serving as a prognostic biomarker and therapeutic target for BRCA [33]. Similarly, Zhao et al. revealed that CYFIP2 could be considered a potential therapeutic target for both Rheumatoid arthritis (RA) and various types of tumors, offering a new perspective on the treatment of immune-related RA diseases and cancer [34]. Consequently, in order to further explore the association between SLC8A1 expression and tumors, we conducted a comprehensive analysis across multiple cancer types using the TCGA database. The findings of our study indicate a significant expression of SLC8A1 in patients diagnosed with UCEC, which was further validated through the use of ROC curve analysis.
Subsequently, we conducted an extensive analysis encompassing prognostic evaluation, mutational assessment, tumor microenvironment examination, immune checkpoint investigation, and drug sensitivity prediction of SLC8A1 in UCEC. The purpose of this comprehensive analysis was to ascertain the prognostic relevance of SLC8A1. Our study elucidated a correlation between SLC8A1 expression and both clinical outcome and immune cell infiltration in UCEC, thereby suggesting a potential involvement of this biomarker in immunoregulation and prognosis. The endometrium, possessing identical glands to a typical endometrium, serves as the origin of UCEC, an epithelial malignancy. UCEC stands as the primary contributor to cancer among women globally, with its incidence and mortality rates on the rise [35, 36, 37]. Consequently, there is a pressing requirement for reliable biomarkers to address endometrial damage resulting from Recurrent Spontaneous Abortion (RSA), forecast the progression of RSA to UCEC, and facilitate targeted immunotherapeutic interventions for UCEC.
The calcium extrusion regulatory molecule, SLC8A1, encodes a member protein of the NCX1 antiporter that is activated by protein phosphatase 2A. This protein facilitates the transport of calcium out of cells and sodium into cells, thereby regulating calcium homeostasis [38, 39]. Numerous studies have reported an association between SLC8A1 and various diseases. For instance, the deletion of the SLC8A1 gene or the presence of null mutations has been found to result in arrhythmia [40]. Furthermore, SLC8A1 plays a significant role in the pathogenesis of hypertension [41]. Additionally, SLC8A1 has been implicated in the development of diabetes and certain cancers, where it exhibits a reverse function. Long et al. conducted an observation wherein they found that the administration of KB-R7943, a reverse-mode SLC8A1 inhibitor, resulted in a notable increase in cell apoptosis in nude mice with PC3 tumors [42].
Multiple studies have demonstrated the abnormal expression of calcium regulatory molecules in patients with endometriosis, adenomyosis, and UCEC [43, 44, 45]. These calcium extrusion regulatory molecules in the endometrium encompass plasma membrane Ca2+ ATPases (PMCAs) and sodium-calcium exchangers SLC8As, which are secreted into the uterine lumen. In a study conducted by Choi et al it was observed that the expression of SLC8A1 in the uterine endometrium of pregnant pigs suggests a potential association between calcium extrusion molecules and pregnancy [46]. In our own study, we have found that SLC8A1 is significantly decrease in cases of UCEC and RSA compared to normal endometrium. This finding leads us to speculate that dysregulation of Ca2+ homeostasis may contribute to the occurrence and progression of RSA and UCEC. Notably, SLC8A1 is implicated in both sodium-calcium exchange and the alterations in biological behavior induced by Ca2+ in these conditions.
Additionally, our study conducted a comprehensive investigation into the association between SLC8A1 and prognosis through the utilization of Cox regression, survival curve analysis, and prognostic nomogram analysis. The results of our analysis revealed that SLC8A1 exhibited significant prognostic value. Furthermore, a comparative analysis of the survival analysis demonstrated that riskscore and stage were independent prognostic factors. In the scope of our research, we also explored the potential correlation between SLC8A1 mutations in the endometrium and the development and progression of UCEC. Notably, a SLC8A1 mutation was identified in 6% of both the low-risk and high-risk groups.
The genetic heterogeneity of tumors contributes to the intricate tumor structure, which utilizes environmental barriers to enhance its diverse properties and confine the tumor within its microenvironment [47, 48]. In addition to tumor cells and immune cells, the tumor microenvironment (TME) comprises stroma and capillaries, forming a complex system that significantly influences the aggressive behavior of cancerous tumors [49]. Extensive research on the mechanisms driving cancer progression has elucidated the pivotal role played by interactions between genes and immune cells within the TME. Chen et al conducted a comprehensive analysis to elucidate the expression patterns of TRP family genes and their association with the tumor microenvironment (TME) across different types of cancer [50]. In a separate study, Feng et al demonstrated a significant positive correlation between CENPT and infiltration of myeloid-derived suppressor cells (MDSCs), while a significant negative correlation was observed between CENPT and infiltration of T-cell natural killer (NK) cells in the majority of cancer types [51].
The present investigation aimed to examine the relationship between SLC8A1 and immune cell infiltration, as well as the association between SLC8A1 and the immune microenvironment in pan-cancer. We conducted an investigation to determine if there were notable disparities in StromalScore, ImmuneScore, and ESTIMATEScore between immune cell infiltrates categorized as high or low. Intriguingly, our analysis revealed a significant correlation between SLC8A1 and these three scores. Additionally, we proceeded to examine the association between SLC8A1 expression and immune infiltration. Our findings indicate a significant correlation between SLC8A1 expression and T cells CD4 memory resting, T cells CD8, Macrophages M0, and Macrophages M1. These results provide a foundation for further exploration of the underlying mechanisms. The observation of a strong correlation between SLC8A1 expression and M1 macrophages, as well as a negative correlation with M2 macrophages, is of particular interest. It is widely recognized that the infiltration of macrophages is associated with favorable survival outcomes and serves as a prognostic indicator. In addition to the aforementioned survival analysis, the potential utility of SLC8A1 agonists in the treatment of endometrial hyperplasia, endometrial cancer, endometriosis, and abnormal endometrium warrants consideration. Finally, an examination was conducted to determine whether there exists a correlation between SLC8A1 expression and drug sensitivity. Low-risk patients exhibit increased sensitivity to Osimertinib, Dasatinib, Sepantronium bromid, lbrutinib, and other drugs. Our study has demonstrated the promising prognostic potential of the SLC8A1-related prognostic signature in guiding clinical therapeutic decisions.
However, it is imperative to acknowledge the existing limitations within this study that necessitate further investigation. Additional experiments are indispensable to authenticate the exact involvement of SLC8A1 in RSA and elucidate its underlying mechanisms. Furthermore, more extensive research is warranted to acquire a comprehensive comprehension of how SLC8A1 impacts the microenvironment of UCEC. Nonetheless, the outcomes of our study could potentially aid in risk stratification and guide individual treatment options for RSA and UCEC in clinical settings.