Search

Background: Metastasis is a major factor associated with high recurrence and mortality in hepatocellular carcinoma patients while the underlying mechanism of metastasis remains elusive. In our study, PLOD2 was shown to be involved in the process of metastasis in HCC. Methods: TCGA database and HCC tissue microarrays were used to evaluate the expression of genes. In vitro migration, invasion, in vivo subcutaneous tumor model and in vivo lung metastasis assays were used to determine the role of PLOD2 in tumor growth and metastasis in HCC. RNA sequencing and gene set enrichment analysis were performed to uncover the downstream factor of PLOD2 in HCC cells. A luciferase reporter assay was performed to evaluate the interaction between PLOD2 and IRF5.Results: The expression of PLOD2 in HCC tissues was higher than that in adjacent tissues, and increased PLOD2 expression was often found in advanced tumors and was correlated with poor prognosis in HCC patients. In vitro experiments, knockdown of PLOD2 reduced the migration and invasion of human HCC cells. Loss of PLOD2 suppressed human HCC growth and metastasis in a subcutaneous tumor model and a lung metastasis model. BIRC3 was proven to be the downstream factor of PLOD2 in human HCC cells. In addition, PLOD2 was transcriptionally regulated by IRF5 in HCC cells. Conclusion: High expression of PLOD2 was regulated by IRF5, which was correlated with the poor survival of HCC patients. PLOD2 enhanced HCC metastasis via BIRC3, suggesting that PLOD2 might be a valuable prognostic biomarker for HCC treatment.

Background & aims: The application of immunotherapy in hepatocellular carcinoma has been hindered by resistance to therapeutics. Cancer cell-induced CD8+ T cell malfunction may account for the failure of tumor immunotherapies. The crucial regulators in HCC that mediate resistance to CD8+ T cell-based cancer immunotherapy are still obscure. Methods: Three independent CRISPR genome-wide screening was constructed. HCC cell-CD8+T cell co-culture model and mouse HCC models were performed to explore the effect of cancer USP14 in vitro and in vivo. Metabolomics, glucose up-take analysis and immune co-precipitation were performed for mechanismstudy. scRNA-seq, HCC PDO and PDX models were used to validate the therapeutic potential of targeting cancer USP14. Results: USP14 was identified as an essential driver of HCC cells tolerating to CD8+ T cells. Cancer USP14 was upregulated and positively correlated with resistance to anti-PD1 therapy and poor prognoses in HCC patients. Inhibition of cancer USP14 reduced the growth of HCC cell with CD8+ T cell co-culturing and enhanced the function of co-cultured CD8+ T cells. Targeting cancer USP14 inhibited HCC tumor growth and boosted anti-PD1-induced tumor immunity in vivo. USP14 highly-expressed HCC cells were avidly consumed and outcompeted CD8+ T cells for glucose by stabilizing GLUT1, resulting in CD8+ T cells starving and malfunction. These HCC cells also lead to acidification in the TME, causing CD8+ T cell dysfunction. The PDO and PDX models confirmed the above results. Conclusions:Our data defined a pro-immunoevasiverole for cancer USP14 in CD8+ T cell-based tumor immunity. Combining USP14 inhibition and PD1 blockade constitutes a potential therapy for HCC. Lay summary: Cancer USP14 sever as a potential therapeutic target for HCC.