Abstract
PurposeTo unravel the oncogenic role of CDCA4 in different cancers from the perspective of tumor immunity.MethodsRaw data on CDCA4 expression in tumor samples and paracancerous samples were obtained from TCGA and GTEX databases. In addition, we investigated pathological stages and the survival analysis of CDCA4 in pan-cancer across Gene Expression Profiling Interactive Analysis (GEPIA) database. Cox Proportional Hazards Model shows that high CDCA4 levels are associated with several vital indicators in oncology. On the one hand, we explored the correlation between CADA4 expression and tumor immune infiltration by the TIMER tool; On the other hand, we utilized the methods of CIBERSORT and ESTIMATE computational to evaluate the proportion of tumor infiltrating immune cells (TIIC) and the amounts of stromal and immune components based on TCGA database. The use of antineoplastic drugs and the expression of CDCA4 also showed a high correlation via linear regression. Protein–Protein Interaction analysis was performed in the GeneMANIA database, and enrichment analysis was performed and predicted signaling pathways were identified by using Gene Ontology and Kyoto Encyclopedia of Genes. The correlation between CDCA4 expression with Copy number variations (CNV) and methylation is detailed, respectively. Molecular biology experiments including Western blotting, flow cytometry, EDU staining, Transwell and Wound Healing assay to validate the cancer promoting role of CDCA4 in hepatocellular carcinoma (HCC).ResultsMost tumors highly expressed CDCA4. Elevated CDCA4 expression was associated with poor OS and DFS. There was a significant correlation between CDCA4 expression and TITCs. Moreover, markers of TIICs exhibited distinct patterns of CDCA4 associated immune infiltration. In addition, we pay attention to the association between the expression of CDCA4 and the use of the anti-tumor drugs. CDCA4 is related to biological progress (BP), cellular component (CC) and molecular function (MF). Dopaminergic Synapse, AMPK, Sphingolipid, Chagas Disease, mRNA Surveillance were significantly enriched pathways in positive and negative correlation genes with CDCA4. CNV is thought to be a positive correlation with CDCA4 expression. Conversely, methylation is negative correlation with CDCA4 expression. Molecular biology experiments confirm a cancer promoting role for CDCA4 in HCCConclusionCDCA4 may serve as a biomarker for cancer immunologic infiltration and poor prognosis, providing a new way of thinking for cancer treatment.
Highlights
CDCA4 (Cell division cycle-associated protein 4), known as HEPP/SEI3/TRIPBr3, was discovered to be a gene expressed only in hematopoietic progenitor cells rather than hematopoietic stem cells [1]
When overexpressed in mammalian cell lines, CDCA4 was found to have the same biological function as the SEI-3 protein, which has recently been shown to interact with CBP (CREB-binding protein) and stimulate the transactivating function of tumor suppressor p53 as well as induce p53-independent growth inhibition [23]
CDCA4 differential expression was shown to be greater in a number of human malignancies, including breast cancer [3], non-small cell lung cancer [4], osteosarcoma [5], head and Neck squamous cell carcinoma (HNSC) [6], and ovarian cancer [6, 7]
Summary
CDCA4 (Cell division cycle-associated protein 4), known as HEPP/SEI3/TRIPBr3, was discovered to be a gene expressed only in hematopoietic progenitor cells rather than hematopoietic stem cells [1]. The chenodeoxycholic acid (CDCA) family genes were shown to be tightly co-expressed with known cell cycle genes such as CDC2 (cell division cycle 2 gene), CDC7 (cell division cycle 7 gene), and cyclins, according to gene-based research [2]. CDCA4 has been studied from the perspectives of physiology and clinical pathology in several species, and it was thought to have a critical role in cell cycle regulation [3]. There was a plethora of cell or animal experiment-based data linking CDCA4 to several forms of malignancies. CDCA4 was shown to be upregulated in breast cancer [3], non-small cell lung cancer [4], osteosarcoma [5], head and neck squamous cell carcinoma [6], and ovarian cancer [6, 7]. CDCA4 is a potential biomarker and a key mediator in a variety of human malignancies, the link between CDCA4 function and carcinogenesis remains unclear
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