HCC is a worldwide problem because of its high mortality and morbidity. It is crucial to identify new targets for the diagnosis and therapy of HCC. Many E3 ubiquitin-protein ligases have been illustrated to play essential roles and might be potential therapy targets in several carcinomas, including HCC[5, 29–31]. Immunotherapy is a widely used treatment for many malignancies, including HCC. Immune cell infiltration in the immune microenvironment was demonstrated to be associated with immunosurveillance and immunotherapy in HCC[32]. Ubiquitin signalling was demonstrated to be associated with the immune response[33]. The E3 ubiquitin-protein ligase MDM2 was verified to sustain STAT5 stability to control T cell immunity in tumours[34]. However, the association between E3 ubiquitin-protein ligases and immune cell infiltration has not been explored in HCC. Therefore, it was novel and meaningful to identify a hub E3 ubiquitin-protein ligase and analyse its association with immune cell infiltration in HCC.
In this research, we identified CDC20 as a hub E3 ubiquitin-protein ligase in HCC and demonstrated its prognostic value in HCC through data from the TCGA, ICGC, GEO, and TIMER databases. All results showed a strong oncogenic function of CDC20, and the prognosis of HCC patients with high CDC20 expression was poor.
CDC20 is a hub gene in cell cycle progression. CDC20 contributes to the progression or metastasis of several carcinomas, such as pancreatic cancer and breast cancer[35]. Alfarsi et al verified that the expression of CDC20 in oestrogen receptor-positive breast cancer predicted a poor prognosis and no response to endocrine therapy[36]. The high expression of CDC20 cancer also predicts a poor prognosis in patients with gastric cancer, prostate cancer, bladder cancer, and colorectal cancer[37–40]. It has been verified that Cdc20 can induce the radioresistance of bladder cancer by degrading FoxO1[41]. Decreasing the expression level of CDC20 might improve radiosensitivity through Mcl-1/p-Chk1-mediated DNA damage and apoptosis in colorectal cancer[42]. In HCC, Shi et al[43] demonstrated that CDC20 could promote PHD3 ubiquitination and activate HIF-1 signalling to accelerate the proliferation of cancer cells. Additionally, Li et al[44] illustrated that the increased expression of CDC20 was associated with HCC proliferation. We performed GSEA to explore potential biological functions and signalling pathways associated with CDC20 in HCC. The results showed that the major functions and pathways were enriched in the P53 signalling, mTOR signalling, NOTCH signalling, cell cycle, ubiquitin-mediated proteolysis, and T cell receptor signalling pathways. Among these pathways, the P53, mTOR and NOTCH signalling pathways are correlated with HCC metastasis, which is the main reason for a poor prognosis[45, 46]. Furthermore, the NOTCH and T cell receptor signalling pathways are thought to be involved in some cellular elements of the tumour microenvironment[47]. Therefore, the possible associations between CDC20 and certain malignant phenotypes, including metastasis and immune infiltration, should be explored and verified.
All previous studies explored only the prognostic value and oncogenic function of CDC20 in cancers. Nevertheless, the possible association between CDC20 and immune cell infiltration in the tumour environment had not been explored. In this research, we analysed the correlation between CDC20 and immune cell infiltration in HCC and illustrated a possible relation between CDC20 and the immune microenvironment of HCC.
At the beginning of tumour metastasis, tumour cells escape from the anti-tumour immune response and adapt to the microenvironment of the next site of metastasis[48]. Many immune cells in the immune microenvironment play crucial roles in the process of tumour metastasis. For instance, TAMs and neutrophils are promote tumour proliferation and metastasis[49]. Targeting TAMs might be a potential treatment strategy for HCC[50]. In our research, we surveyed the possible correlations between CDC20 expression and immune cell infiltration in HCC. The results suggested significant connections between CDC20 and the infiltration of several immune cell types, including B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and DCs. In addition, the correlations between CDC20 and relative gene biomarkers of 4 types of immune cells were verified through TIMER and GEPIA. These gene markers include several special genes involved in immunotherapy, such as PDCD1 and CTLA4[51]. The correlation analysis indicated that the expression level of CDC20 influences the effect of immunotherapy, which hinted CDC20 as a potential therapeutic target correlated with tumor immunology.