The occurrence and development of HCC is a multi-factor and multi-stage complex pathogenesis, involving the aberrant expression of many genes and changes in the immune microenvironment . HCC is a cancer with a high fatality rate in the world, and there is currently not effective diagnosis and treatment method [11, 12]. Increasing experimental evidences demonstrated that the ceRNAs can regulate the interaction between invading immune cells and tumor cells and influence tumor proliferation, metastasis, drug resistance and the prognostic outcome of patients [8, 13, 14]. Therefore, it is extremely urgent to find potential novel therapeutic targets and prognostic markers.
In our study, we identified two survival-related critical genes (NDC80 and BUB1B) by WGCNA, PPI network construction, centrality analysis and survival analysis. Generally, NDC80 (nuclear division cycle 80) is a core component of the NDC80 kinetochore complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25 . A previous study showed that NDC80 complexes plays important roles in chromosome segregation, and spindle assembly checkpoint function . In the tumorigenesis, overexpression of NDC80 leads to the hyper-activation of spindle assembly checkpoint and finally causes chromosome instability, which is generally considered to be landmark events of tumor growth . Furthermore, higher expression level of NDC80 have been reported in HCC tissues, compared to adjacent tissues, which is insistent with our research result. Previous researches manifested that higher levels of NDC80 in tumor tissues promote HCC progression by anti-apoptotic effects and overcoming cell cycle arrest. BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) is an essential component of the spindle checkpoint . Increasing studies indicate overexpression of BUB1B promotes the tumor proliferation and invasion by BUB1B/mTORC1 signaling pathway in HCC . The TICs, as a component of the tumor microenvironment, exert enormous influence on tumor growth, invasion, and metastasis . The tumor microenvironment has different abilities to induce adverse and beneficial consequences of tumorigenesis . In this study, we suggested that the high expression level of NDC80 and BUB1B was significantly related with the patients’ short OS time and high immune infiltrates.
In the current study, we found that the HCC-related T cells CD4 memory resting is negatively associated with AL021453.1 (R = − 0.44, P = 4.9e-4) and CCDC137 (R = − 0.47, P = 2e − 04) by correlation analysis, which suggested that AL021453.1 and CCDC137 may play a role in immune landscapes of HCC.
AL021453.1 is an endogenous lncRNAs, has so far been reported to aberrant expression in the Pheochromocytoma and Paraganglioma . But its function entirely unknown in cancer. This study is the first to show AL021453.1 as an independent biomarker high expression associated with poor overall survival and and high risk scores in HCC patients. CCDC family proteins can participate in intracellular signal transduction, genetic signal transcription, molecular recognition and cell cycle regulation [23, 24]. Similar to AL021453.1, the CCDC137 as an independent signature was highly expressed in HCC tissue, and HCC patients with high expression possessed poor overall survival rate and prognosis. Some previous studies showed that the CCDC137(coiled-coil domain containing 137) is the member of CCDC family proteins contributing to various diseases and may contribute to elevated infiltration of tumor microenvironment and was associated with tumor immunosuppressive status . Besides, it had been reported to involve in the human immunodeficiency virus type 1 (HIV-1) regulating immune cell death . Meanwhile, accumulating studies identified that metabolic changes in the tumor microenvironment may impact immune metabolism, thus promoting or damaging anti-cancer immunity . For example, Van et al found thatnon-alcoholic fatty liver disease (NAFLD) cause apoptosis of intrahepatic CD4 + T cells and promote the tumorigenesis . In adition, Brown et al further certified that down-regulated expression of Carnitine palmitoyltransferase gene induces CD4 + T cell apoptosis, thereby facilitating the HCC development through in vivo experiments . In our study, T cells CD4 memory resting in high risk groups possessed lower fraction than in the lower risk groups. In clinical and survival analysis, high expression of T cells CD4 memory resting showed higher survival probability, and higher overall survival [30, 31]. Thus, T cells CD4 memory resting may function as HCC suppressors. After a systematic literature review, we found no direct reports on AL021453.1 association with dendritic cells and tumor immunity. However, the hypothesis that ceRNAs are involved in immune regulation and affecting HCC tumorigenesis and development have been validated by various experiments . Meanwhile, the hypergeometric testing and correlation analysis results of the ceRNAs network revealed that CCDC137 (protein-coding RNA), hsa-miR-93-5p (miRNA), and AL021453.1 (LncRNA) were significantly correlated. Thus, we infered that AL021453.1 might indirectly regulate CCDC137 by interacting with hsa-miR-93-5p, and further regulate T cells CD4 memory resting. We had such a conserved discussion because of the lack of literature. Further studies to explore the relationship between the ceRNAs and T cells CD4 memory resting are needed.