Abstract
Neddylation is a process in which a ubiquitin-like molecule NEDD8 is conjugated to a lysine residue of the substrate protein via successive enzymatic cascade reactions. Inactivation of neddylation pathway triggers tumor cell apoptosis or senescence to suppress the tumor growth. So far, there has been limited research on the role of the neddylation pathway (NEDD8-UBE2M-RBX1 axis) in the immune response. In this study, we investigated the association between the neddylation pathway and immune function in HCC by comprehensively analyzing transcriptome and clinical data of HCC samples from TCGA database. The analysis showed that the mRNA expression of neddylation pathway components was up-regulated in HCC and increased with disease severity. Moreover, we observed that activated neddylation pathway was associated with enriched infiltration of T helper 2 (Th2) cells in HCC, while transactivation of STAT5A signaling may mediate this association. On the contrary, no significant correlation between the neddylation pathway and Th1 cells infiltration was identified. Taken together, these findings suggest a potential role of the neddylation pathway in promoting a shift in Th1/Th2 balance toward Th2-dominant immunosuppression. Hence, targeting neddylation pathway could serve as an attractive immunotherapy strategy for suppressing the development of Th2 cells.
Highlights
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third most frequent cause of cancer-related death worldwide [1]
To further validate the neddylation pathway as a promising anti-tumor target, this study investigated the relationship between activated neddylation pathway (NEDD8UBE2M-ring-box 1 (RBX1) axis) and immune cell infiltration by analyzing mRNA transcriptome and clinical data of HCC samples from The Cancer Genome Atlas (TCGA) database
receiver operator characteristic (ROC) curve analysis revealed that all the five neddylation pathway components, especially UBE2M, had a good diagnostic value for HCC (AUC: neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) = 0.963, NAE1 = 0.920, UBA3 = 0.833, UBE2M=0.968, and RBX1 = 0.922) (Figure 1B). These results demonstrate that the neddylation pathway components are transcriptionally up-regulated in HCC and may serve as potential diagnostic markers
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third most frequent cause of cancer-related death worldwide [1]. Due to the high rate of recurrence and metastasis, the five-year survival rate for advanced HCC is very low [2]. HCC is characterized by strong immunosuppressive microenvironment and high immune evasion [3]. Immunotherapy is designed to harness the immune system to attack tumor cells, for reducing the rate of tumor recurrence and metastasis. Immunotherapy has gradually become a promising direction for the treatment of advanced HCC [4, 5]. It is urgent to elucidate the regulatory mechanisms of immune cells infiltration in HCC and identify novel immune-related therapeutic targets
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