Abstract
Hepatocellular carcinoma (HCC) is one of the most common carcinomas worldwide. Our study aims to analyze how NUSAP1 affects progression of HCC from clinical, molecular mechanism and immune perspectives. Firstly, we downloaded GSE62232, GSE102079, GSE112790, and GSE121248 gene expression profile datasets from GEO database. R studio was used to screen DEGs of each dataset, and 86 overlapping DEGs of the four datasets were screened at last. Then, CytoHubba plug-in in Cytoscape software was used to screen out NUSAP1 from the 86 DEGs. Subsequently, survival analysis, clinical correlation analysis, independent prognostic analysis, and GSEA enrichment analysis of NUSAP1 were analyzed using HCC patients from GSE76427 dataset, ICGC database, and TCGA database. The results revealed that HCC patients with higher expression level of NUSAP1 had a worse prognosis. NUSAP1 was an independent prognostic factor of HCC, and it may promote HCC progress by regulating cell cycle. To further elucidate its underlying molecular mechanism, we used cBioProtal online data analysis tool to screen all co-expression genes of NUSAP1 and used top 300 co-expression genes to accomplish KEGG and GO enrichment analysis; the results confirmed that NUSAP1 accelerated progression of HCC by regulating cell cycle. We continued to draw KEGG pathway map of cell cycle using co-expression genes enriched in cell cycle pathway by KEGG online tool. The map depicted that most of co-expression genes of NUSAP1 were located in S phase and G2/M phase of the cell cycle, and they could regulate the genes in G1 phase. To further understand the mechanism of cell cycle, we also did qRT-PCR, Western blot, and flow cytometry; the results showed that NUSAP1 was closely associated with CDK4, CDK6, and cyclinD1, which could regulate G1 to S phase transition. Besides, we also analyzed correlation between NUSAP1 and immune cells using HCC patients from GSE76427 dataset, ICGC database, and TCGA database. NUSAP1 was associated with some immune cells, and we speculated that NUSAP1 could also promote HCC progression by influencing T cell CD4 memory resting and macrophage M0 through some underlying mechanism.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common and the fourth deadliest malignant tumors globally (Bray et al, 2018)
We continued to conduct univariate (Figure 5F) and multivariate regression analysis (Figure 5G) using clinical information of 374 HCC patients; the results showed Nucleolar and spindle-associated protein 1 (NUSAP1) was statistically significant in univariate regression analysis (p < 0.001, HR = 1.034) and multivariate regression analysis (p < 0.002, HR = 1.028), which once again verified that NUSAP1 was an independent prognostic factor of HCC
We continued to conduct univariate (Figure 6F) and multivariate regression analysis (Figure 6G) using clinical information of 732 HCC patients; the results showed NUSAP1 was statistically significant in univariate regression analysis (p < 0.001, HR = 1.072) and multivariate regression analysis (p < 0.002, HR = 1.068), which demonstrated that NUSAP1 was an independent prognostic factor of HCC again
Summary
Hepatocellular carcinoma (HCC) is the sixth most common and the fourth deadliest malignant tumors globally (Bray et al, 2018). It is prevalent in China, Asia, and Africa (Forner et al, 2012). About 60% new HCC cases occur in China every year, and the 5-year survival rate is approximately 12% (Chen et al, 2016; Zeng et al, 2018). Despite so many treatment options available, the overall survival (OS) of HCC patients remains poor due to its extremely high rates of postoperative recurrence and metastasis (Villanueva et al, 2011). There is an urgent need to investigate underlying molecular mechanism of HCC occurrence, development, and poor prognosis in order to explore better strategies of prevention, diagnosis, and treatment in HCC
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