LUAD is one of the significant invasive diseases limiting the life span of humans 32–34. Identifying the molecular mechanisms underlying LUAD carcinogenesis is becoming increasingly instrumental in searching for novel therapeutic targets and biomarkers. Previous studies have confirmed that CAPZA1 elicited pivotal roles in regulating the onset and development of human cancers 35; 36. The role of CAPZA1 in LUAD, however, remains incompletely known and needs to take further study.
Our study first examined that CAPZA1 was significantly overexpressed at mRNA levels in 13 tumors compared with normal tissues, which was validated in the Starbase database. Moreover, survival and prognosis analysis displayed that higher CAPZA1 correlated with worse survival in KIRC, KIRP, LUAD, and LIHC using Starbase database, and only prognosis of CAPZA1 in LUAD had been validated in the PrognoScan database, which might shed light on novel targets for LUAD individualized treatment.
Mechanisms related to ceRNA are modulated by ncRNAs with direct or indirect effects, including gene expression regulation 37. Our study used the Starbase database to find possible miRNAs that interact with CAPZA1 RNA binding proteins, thereby modulating CAPZA1 mRNA stability. The result revealed that 16 miRNAs were finally found. Further analysis shows that only hsa-miR-30d-5p in LUAD was screened since it was low, and its downregulation harbored a better life of patients. Most of the researches related to this miRNA has proved to be tumor-suppressive in many cancers, such as prostate cancer 38, renal cell carcinoma (RCC) 39, non-small cell lung cancer (NSCLC) 40, esophageal squamous cell carcinoma (ESCC) 41, and gallbladder 42. For instance, down-regulated miR-30d-5p has been linked to favorable clinical outcomes in patients with RCC, and overexpression of miR-30d-5p attenuates RCC cell lines proliferation and cell-cycle G1/S transition and facilitated apoptosis, which is denoted as tumor-suppressor 39. Overall, CAPZA1 might be the most potential targeted mRNA of hsa-miR-30d-5 in LUAD.
Recently, lncRNAs have been considered as miRNA sponges to contribute to the regulation of cancers 43. Based on this, 9 possible lncRNAs in LUAD function as the upstream of the hsa-miR-30d-5-CAPZA1 axis. Following survival analysis and correlation analysis, only AC026356.1 was at high activity than normal samples and higher AC026356.1 was reciprocally linked to favorable patients’ OS among all these lncRNAs. More importantly, AC026356.1 lncRNA was positively relevant to CAPZA1 expression whereas negative with hsa-miR-30d-5p, uncovering that AC026356.1 is most likely upstream lncRNAs of hsa-miR-30d-5p-CAPZA1 axis.
Extensive evidence has proved that the tumor-infiltrating immune cells exert a crucial function on patients' prognosis and immunotherapy 44. For example, activating tumor-infiltrating CD8 T cells were able to contribute to antitumor responses 43. In our analysis, CAPZA1 in LUAD was positively relevant to the infiltration of most immune cells, especially for macrophages, CD4 + T cells, CD8 + T cells, dendritic cells, and Neutrophil and purity, which is also validated based on some immune infiltration markers. Also, we further confirmed that CAPZA1 in LUAD was significantly positively correlated with the TMB, MSI, immune score and stromal score, indicating that CAPZA1 could participate in regulating immune infiltration function in LUAD. Apart from this, immunotherapy, mainly represented by immune checkpoint inhibitors (ICIs), has shown promising efficacy in treating many types of cancers 45. Thus, the link immune checkpoints like PD1, PD-L1, and CTLA-4 with CAPZA1 were assessed in LUAD. Similarly, this correlation had the same trend, indicating that CAPZA1 might serve as a new tumor immunotherapy target in LUAD.
Nevertheless, some restrictions are supposed to be highlighted in our investigations. Firstly, considering tissue specificity, we fail to enable our conclusions to replant to other tumors. Next, we need to validate the roles of CAPZA1 in LUAD on antitumor immunotherapy and tumor immunity based on more basic experiments. Finally, it is imperative to gather more robust data or samples of LUAD due to the lack of available public datasets.
For the first time, collectively, we comprehensively determine the CAPZA1 serve as an oncogene in pan-cancers and higher CAPZA1 expression process unfavorably prognostic value in LUAD based on Starbase database and PrognoScan database. Our findings also uncovered that CAPZA1 might play an essential role in tumor immunity during the development of LUAD, such as immune infiltration cells, immune infiltration markers, TMB, MSI, immune score, stromal score, and immune checkpoints, and maybe a reliable therapeutic target for immunological antitumor strategy.