The 5-year survival rate of patients with ESCA is still unsatisfactory despite the wide range of contemporary treatments available for malignant tumors (21). ESCA still maintains high morbidity and mortality (21). The prognosis of patients may be improved by searching for molecular markers of ESCA and constructing diagnostic and therapeutic predictive models.
Peptidases are a large class of proteins essential for human beings to complete various life activities. Peptidase is involved in the occurrence and development of various human diseases, such as vascular diseases, rheumatoid arthritis, and neurodegenerative diseases (22). Like here, peptidases also contribute to the development of certain malignant tumors (5, 23).
From the HGNC website, we obtained more than 300 specific human peptidase genes. Then, GEPIA2's differential protein analysis discovered that 60 peptidase genes were expressed differentially in ESCA. Additionally, 7 of the up-regulated peptidase genes in ESCA were significantly associated with patient prognosis. This suggests that peptidase genes may play a vital role in the progression of ESCA. Therefore, we constructed a risk-prognostic model of ESCA based on these 60 peptidase genes. The AUC of its ROC curve was 0.63, 0.64, and 0.84 at 1-year, 2-year, and 4-year. They were additionally verified using the external datasets GSE53624 and GSE53625. We distinguished high-risk and low-risk groups based on the model’s risk score. The results found that the OS of the high-risk group was shorter than that of the low-risk group. Lasso regression analysis and ten-fold cross-validation confirmed that IMMP1L, MAIP1, and UFSP2 genes were significantly associated with the prognosis of ESCA patients. The nomogram integrating IMMP1L, MAIP1, and UFSP2 genes and clinical factors can more accurately predict the OS of ESCA patients and have good clinical applicability.
IMMP1L was identified as an independent predictive factor for ESCA by multivariate Cox proportional hazard regression analysis. One of the mature and functional proteins made by the IMP complex in the mitochondrial intermembrane space is IMMP1L (14). There are, however, not many investigations on IMMP1L's function in malignancies. We found that IMMP1L is highly expressed in most malignancies and at different ESCA clinicopathological stages. In addition, we verified the mRNA expression level of IMMP1L in 15 esophageal cancer tissues. The results showed that the mRNA expression level of IMMP1 in 12 esophageal cancer tissues was significantly increased. This implies that the IMMP1L can be involved in the development of cancer, which may serve as a biomarker for ESCA. The early identification, early diagnosis, and early treatment of ESCA may be made possible by IMMP1L, increasing patient survival.
We conducted GO functional enrichment and KEGG pathway enrichment analyses on the differential genes derived from the single-gene differential analysis to better understand the function of IMMP1L in ESCA. GO functional enrichment analysis showed that IMMP1L was mainly located in the extracellular region, and its function was primarily related to system development. KEGG pathway enrichment analysis showed that IMMP1L targets Neuroactive ligand-receptor interaction, Cytokine-cytokine receptor interaction, and Estrogen signaling pathway. These pathways appear less clearly related to tumors but may still have some intrinsic connection to tumors. Future research will be needed to confirm this. Using STRING and Cytoscape, we identified 13 down-regulated and 17 up-regulated hub genes targeted by IMMP1L. Among them, 11 hub genes KLK7, KLK5, TGM1, CSTA, PPL, SPRR2B, SPRR3, SPRR2A, SPRR2F, IVL, and ALB are differentially expressed in ESCA. Furthermore, KLK5, KLK7, SPRR3, and SPRR2A are currently considered to be genes that can promote tumor growth or survival (15–19). On the other hand, CSTA can inhibit the proliferation of oral squamous cell carcinoma cells (20). We hypothesize that IMMP1L may target these essential genes in ESCA, hence influencing tumor progression. In the future, IMMP1L might be the focus and hotspot of ESCA therapy. However, more research is still required to substantiate it.