NAP1L1 Functions as a Novel Prognostic Biomarker Associated With Macrophages and Promotes Tumor Progression by Influencing the Wnt/β-Catenin Pathway in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is regarded as one of the universal cancers in the world. Therefore, our study is based on clinical, molecular mechanism and immunological perspectives to analyze how NAP1L1 affects the progression of HCC. To begin with, the gene expression datasets and clinical data of GSE14520, GSE76427, ICGC, and TCGA are originated from GEO, ICGC, and TCGA databases. Subsequently, DEG screening was performed on data using R studio, and we finally found that 2,145 overlapping DEGs were screened from four datasets at the end. Then, we used R studio to filter the survival-related genes of the GSE76427 and ICGC datasets, and we screened out 101 survival-related genes. Finally, 33 common genes were screened out from 2,145 overlapping DEGs and 101 survival-related genes. Then, NAP1L1 was screened from 33 common genes using the CytoHubba plug-in in Cytoscape software. Furthermore, ground on GEO, ICGC, and TCGA databases, the survival analysis, clinical feature analysis, univariate/multivariate regression analysis, and multiple GSEA were used to study NAP1L1. The Conclusion claimed that HCC patients with higher expression levels of NAP1L1 had a poorer prognosis than those with lower expression levels. Thus, we believe that NAP1L1 is an independent prognostic factor for HCC. In order to shed light on NAP1L1’s molecular mechanism promoting the progression of HCC closely, the GSEA tool was applied to complete the GSEA of the four datasets. Furthermore, the results confirmed that NAP1L1 could promote HCC progression by regulating the G2/M transition of the cell cycle and Wnt signaling pathway. Western blot and flow cytometry were also performed to understand those mechanisms in this study. The result of Western blot showed that NAP1L1 silencing led to downregulation of CDK1 and β-catenin proteins; the result of flow cytometry showed that cell numbers in the G2 phase were significantly increased when NAP1L1 was silenced. Thus, we claimed that NAP1L1 might promote HCC progression by activating the Wnt signaling pathway and promoting cell cycle G2/M transition. In addition, ground on GSE14520 and GSE76427 datasets, and ICGC and TCGA databases, the correlation between NAP1L1 and immune cells was analyzed in HCC patients. At the same time, the TISIDB online database and the TIMER online database were testified to the association between NAP1L1 and immune cells. Hence, the summary shows that NAP1L1 was connected with a certain amount of immune cells. We can speculate that NAP1L1 may influence macrophages to promote HCC progression through some potential mechanisms.

PSC niche develops into immune-responsive blood cells capable of transdifferentiating into lamellocytes inDrosophila

“…Interestingly, the human homologue, NAP1L has been implicated in stress response and apoptosis through control of the NF-kappaB pathway acting on the anti-apoptotic Mcl-1 gene 47 . Recent studies identified NAP1L as a novel prognostic biomarker associated with macrophages promoting hepatocellular carcinoma 48 . High expression of the cytoprotective thioredoxin TrxT against oxidative stress which is also a known conserved marker for inflammatory macrophages further suggests that Spermatid-Marker-PL represents an immune-active plasmatocyte population 49 (Itoh and Bryson, 2018).…”

CircDCAF8 promotes the progression of hepatocellular carcinoma through miR-217/NAP1L1 Axis, and induces angiogenesis and regorafenib resistance via exosome-mediated transfer

“…A number of studies have reported NAP1L1 is upregulated and has a carcinogenic function in various tumors such as breast cancer [ 50 ], pancreatic neuroendocrine neoplasm [ 51 ], colon cancer [ 52 ] and so on. In HCC, NAP1L1 has also been proven to facilitate tumor progression by activating multiple different signaling pathways [ 27 , 53 , 54 ]. Le Y et al [ 55 ] discovered that NAP1L1 is associated with HCC doxorubicin chemotherapy resistance.…”

Evaluation and Application of Drug Resistance by Biomarkers in the Clinical Treatment of Liver Cancer

“…Expression of NAP1L1 (nucleosome assembly protein 1-like 1) is significantly upregulated in tumor tissues compared with adjacent nontumor tissues in many cancers, including liver, colon, ovarian, breast cancer, etc. [ 57 , 58 , 59 , 60 ]. High NAP1L1 expression in HCC tissues is associated with aggressive clinicopathologic features, such as high serum AFP levels, tumor size, and tumor number.…”