Colorectal cancer is one of the most common malignant tumors worldwide[23]. With the change of people's living habits and the aging of the population, the incidence of colorectal cancer is increasing year by year[24], and the proportion of local progression of colorectal cancer is the highest, which is the focus and difficulty of treatment[25]. At present, the main treatment for colorectal cancer is surgery combined with radiotherapy and chemotherapy, but the efficacy is not satisfactory[26]. This study aims to explore the occurrence factors of colorectal cancer and find more appropriate molecular markers, so as to improve the diagnosis and treatment effect of colorectal cancer patients.
Previous studies have reported that in colorectal cancer, tumor bud-derived C-C chemokine ligand 5 (CCL5) can recruit fibroblasts through the CCR5-SLC25A24 signaling pathway, further promote angiogenesis and collagen synthesis through the recruited fibroblasts, and finally form a tumor-promoting microenvironment[27]. Moreover, SLC25A24 has been reported that to act as a negative feedback control between cellular Ca(2+) overload and mPT (mitochondrial permeability transition) - dependent cell death, suggesting that SLC25A24 may represent a novel target for cancer therapy[28]. In this study, clinical case analysis and bioinformatics methods were used to explore the value of SLC25A24 in colorectal cancer, including gene expression, KM survival analysis, univariate and multivariate Cox analysis. Next, we identified SLC25A24 as a prognostic gene and validated it in clinical cases. qRT-PCR analysis showed that SLC25A24 was expressed in colorectal cancer cell lines. In addition, immunohistochemical analysis showed that SLC25A24 expression was higher in colorectal cancer tissues than in normal tissues. Interestingly, high SLC25A24 expression was associated with better survival. These results suggest that SLC25A24 can be used as a potential prognostic marker in colorectal cancer patients. The enriched GO items in BP included endomembrane system organization, proteasomal protein catabolic process and vesicle organization, etc. The enriched GO items in CC included endosome membrane, trans-Golgi network and midbody, etc. The enriched GO items in MF included cell adhesion molecule binding, guanyl ribonucleotide binding and nucleoside binding, etc. In KEGG pathway analysis, we observed that most of the multiple pathways were related to immune responses, including Ras signaling pathway[29], Rap1 signaling pathway[30], Endocytosis[31] and Ubiquitin mediated proteolysis[32], etc.
A series of different solute carrier family members play an important role in the development of tumor. SLC16A1 was up-regulated in urinary tumors and it might promote tumor development by regulating the epigenetic process of urinary cancer[33]. SLC25A1 was significantly upregulated in colorectal cancer, and knockdown of SLC25A1 can significantly inhibit the growth of colorectal cancer cells by inhibiting G1/S cell cycle progression and inducing apoptosis in vitro and in vivo[34]. In our study, SLC25A24A is highly expressed in colorectal cancer and indicates a better prognosis. To determine the biological role of SLC25A24 in colorectal cancer cells, apoptosis assay was performed. Apoptosis assay confirmed that the apoptosis ability of colorectal cancer cells was significantly promoted after transfection with SLC25A24 siRNA. However, we cannot rely solely on clinical parameters to predict clinical outcomes in patients after surgery, as the biological aggressiveness of each disease is characterized by its potential for metastasis and resistance to anticancer therapies. Therefore, the identification of important molecular prognostic factors may help to predict clinical outcomes more accurately and may also reveal new predictors and therapeutic targets.
The infiltration of immune cells into solid tumors is a hallmark of cancer and plays a key role in disease progression[35]. Recognition of the importance of tumor microenvironment (TME) in inhibiting antitumor immunity has led to significant advances in tumor immunotherapy, and tumor microenvironment can promote tumor development, metastasis, and resistance to chemotherapy and immunotherapy[36, 37]. In colorectal cancer, the infiltration of immune cells plays an important role in immune regulation[38]. In a study of colorectal cancer, features of immune infiltration were a better predictor of clinical outcome than classical TNM staging[39]. In some solid tumors, low levels of immune infiltration have worse outcomes compared with high immune infiltration[40]. Most tumors that disrupt antitumor immunity lack CD8 + T-cell infiltration and tend to be resistant[41]. The presence of CD8 + T cells in the tumor is beneficial to the prognosis of colorectal cancer patients[42]. In this study, we explored the correlation between SLC25A24 and immune cell infiltration. SLC25A24 was found to be significantly positive associated with the infiltration of various immune cells, such as CD8 + T cells, CD4 + T cells, neutrophils and macrophages, etc. The high SLC25A24 mRNA expression group had a higher proportion of antitumor immune cells, such as: CD8 + T cells, CD4 + T cells, aDC (activated dendritic cells). The results indicated that SLC25A24 was correlated with antitumor immunity in colorectal cancer, which partially explained the correlation of SLC25A24 with a better prognosis. The same gene may play different roles at different stages of cancer, such as the roles of TGF-β and INPP4B in cancers[43, 44]. In addition, there are genes that are beneficial for the body, but once a tumor has formed, tumor cells may hijack the gene to protect them, such as SCAL1[45]. Taken together, these results suggest that SLC25A24 might affect immune cell infiltration, making SLC25A24 become a novel immune-related therapeutic target in colorectal cancer patients. It has been demonstrated that the expression of immune checkpoint molecules limits immune surveillance in the tumor microenvironment[46]. Studies have confirmed that therapeutic antibodies against immune checkpoint molecules, including CTLA-4, CD274, and PDCD1, can enhance antitumor T-cell activity and improve clinical outcomes in various tumor types[47]. Our results confirmed that SLC25A24 was positively associated with multiple immune checkpoint molecules (such as CTLA-4, CD274, HAVCR2, PDCD1LG2 and TIGIT) in colorectal cancer and was associated with microsatellite instability and immunotherapy sensitivity, suggesting an important role of SLC25A24 in regulating the expression of immune checkpoints molecules and immunotherapy. These results suggested that SLC25A24 played an extremely important role in the immunotherapy of colorectal cancer.