HCC is considered to be one of the most prevalent malignant tumors that threatens human health, in recent years, the age of onset tends to be younger, mainly concentrated between 40–60, in our data, the mean age of patients with HCC was 50.6 years old, the younger the age at onset of HCC, the worse the prognosis[19, 20].
Using samples from HCC patients admitted to Guangxi Medical University Cancer Hospital, we performed next-generation sequencing and validated our findings using qRT-PCR and the TCGA database. Consistently, in both the Guangxi cohort and the TCGA-validated cohort, ESPL1 was highly expressed in tumor tissues compared to adjacent tissues. As described in previous studies, it showed that overexpression of ESPL1 was associated with tumor progression, such as endometrial cancer, glioma, chronic myeloid leukemia, and breast cancer. However, the opposite trend was reported in gastric carcinoma . It demonstrated that the expression of ESPL1 varies among different tumors, but was frequently expressed in most tumor tissues. Clinically, ESPL1 overexpression is correlated with poor outcomes and advanced tumor stages, suggesting that ESPL1 could be used in predicting tumor malignancy. In addition, the results of multivariate and univariate survival analysis exhibited that the ESPL1 was probably a promising biomarker for the prognosis of HCC.
The enriched analysis of co-expressed genes associated with the ESPL1 gene showed that they might be involved in the cell cycle pathways, mitotic sister chromatid segregation, and cell division of HCC. Cancer cells often have upregulated levels of CDKs for progression through the cell cycle, therefore, the development of drugs inhibiting CDKs has become a novel strategy for treating the tumors[23, 24]. After selecting the top 10 co-expression genes, prognostic analyses were performed, and the results suggested that ESPL1, GTSE1, BUB1B, PRC1, KIF23 and TOP2A genes might be unfavorable for the prognosis of HCC. GTSE1 is expressed specifically during the G2 and S phases of the cell cycle , A previous study has identified that GTSE1 is a key regulator involved in mitosis [26, 27]. Lai et al found that the GTSE1 promoted cell proliferation by upregulating FOXM1 expression in prostate cancer and was associated with an unfavorable prognosis. The mechanism of the GTSE1 gene has also been reported in bladder cancer, according to Liu et al, high GTSE1 levels may induce the transfer of p53 to the cytoplasm, thus regulating FOXM1/CCNB1 expression. . As for breast cancer and hepatocellular carcinoma, GTSE1 is associated with poor prognosis, study also suggested that it can improve the ability of proliferative and metastatic through upregulating the expression of EMT markers.[30–32]. Another research has shown that knockdown GTSE1 increases the sensitivity of non–small-cell lung cancer to radiation through a DNA damage repair pathway . BUB1B, a member of the BUB1 proteins, plays a critical role in chromosome segregation, and aberrant expression of BUB1B had been reported in various cancers including lung adenocarcinoma, glioblastoma and ductal breast carcinoma. Tang et al indicated that the expression of BUB1B increased in multiple myeloma patients, and was closely correlated with poor outcomes . Additionally, BUB1B can upregulate the mTORC1 signaling pathway and participate in proliferation, migration, invasion, EMT, and metastases in HCC . Additionally, Jiao et al. reported that BUB1B promotes cholangiocarcinoma proliferation and invasion via JNK-c-Jun signaling . PPRC1, a microtubule-associated protein, is involved in cytokinesis. It has already been documented that PRC1 is overexpressed in different cancers, including pancreatic cancer , breast cancer and bladder cancer. A study of hepatocellular carcinoma has been reported that PRC1 exerts an oncogenic effect by promoting cancer proliferation, stemness, metastasis and oncogenesis. Mechanistically, PRC1 can reinforce Wnt signaling pathway to promote early HCC recurrence . Zhan et al. also demonstrate a similar description that PRC1 facilitates the progression of lung cancer through the activation of Wnt signaling pathway . As for oral squamous cell carcinoma, PRC1 is strikingly related to low differentiation, metastasis and high-clinical stage. The data indicated that it can significantly promote cell cycle transition and diffusion via the signaling pathway of p53/PRC1/EGFR . KIF23 is a type of nuclear protein that exerts a critical effect in modulating cytokinesis [47, 48] and its dysregulated expression has been observed in diverse cancers, which leads to poor outcomes, such as Glioma, gastric cancer, Hepatocellular carcinoma[51, 52], renal cell carcinoma, pancreatic ductal adenocarcinoma, lung cancer, colorectal cancer, ovarian cancer[57, 58]and breast cancer[59, 60], these studies demonstrated that KIF23 overexpression is widely involved in tumor progression. TOP2A is an essential nuclear enzyme that regulates the state of DNA during transcription and is participated in the processes of chromatid separation . Increasingly researches have been suggested that TOP2A is evidently expressed in tumor tissues. Kim et al confirmed that elevated expression of TOP2A was indicative of progression and a high rate of recurrence in non-muscle-invasive bladder cancer . In addition, TOP2A is also involved in many other important biological behaviors, such as proliferation and invasion, which play pivotal roles in tumor initiation and progression, including bladder urothelial carcinoma, pancreatic cancer, ovarian cancer and hepatocellular carcinoma[67, 68]. In general, the prognostic model established by six genes has a good prediction potential for the overall survival of patients with HCC.
More and more reports suggest that the interaction and signaling between liver malignant cells and the immune microenvironment contribute to tumorigenesis and progression. This immunosuppressive microenvironment can induce tolerance and promote tumor proliferation, invasion as well as metastasis [69–73]. In this study, we also assessed the correlation between ESPL1 expression and immune cell infiltration in HCC, The results showed that ESPL1 gene expression was positively correlated with B cells, CD8 naïve cells, dendritic cells (DCs), effector memory cells, Tr1, iTreg and nTreg cells. Numerous studies have revealed that TME in cancer patients is associated with a raised Treg cells number in circulation [74, 75], increased FOXP3-Tregs have been found in concordance with cancers prognosis and progression in ovarian cancer and uveal melanoma.
In conclusion, this research evaluated the ESPL1 expression, prognostic value and its correlation with the infiltration of immune cells in HCC. Even so, we must consider our results in the light of certain limitations, the data utilized in this study were based only on the genetic perspective and lacked validation at the protein level. In addition, increasingly in vitro and in vivo experiments should be considered to demonstrate the molecular function of ESPL1 and further mechanistic exploration.