Abstract
ObjectiveNatural killer (NK) cells play a critical role in the innate antitumor immune response. Recently, NK cell dysfunction has been verified in various malignant tumors, including hepatocellular carcinoma (HCC). However, the molecular biological mechanisms of NK cell dysfunction in human HCC are still obscure.MethodsThe expression of circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in HCC tissues, exosomes, and cell lines was detected by qRT-PCR. Exosomes were isolated from the culture medium of HCC cells and plasma of HCC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit and then characterized by transmission electronic microscopy, NanoSight and western blotting. The role of circUHRF1 in NK cell dysfunction was assessed by ELISA. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the molecular mechanisms of circUHRF1 in NK cells. In a retrospective study, the clinical characteristics and prognostic significance of circUHRF1 were determined in HCC tissues.ResultsHere, we report that the expression of circUHRF1 is higher in human HCC tissues than in matched adjacent nontumor tissues. Increased levels of circUHRF1 indicate poor clinical prognosis and NK cell dysfunction in patients with HCC. In HCC patient plasma, circUHRF1 is predominantly secreted by HCC cells in an exosomal manner, and circUHRF1 inhibits NK cell-derived IFN-γ and TNF-α secretion. A high level of plasma exosomal circUHRF1 is associated with a decreased NK cell proportion and decreased NK cell tumor infiltration. Moreover, circUHRF1 inhibits NK cell function by upregulating the expression of TIM-3 via degradation of miR-449c-5p. Finally, we show that circUHRF1 may drive resistance to anti-PD1 immunotherapy in HCC patients.ConclusionsExosomal circUHRF1 is predominantly secreted by HCC cells and contributes to immunosuppression by inducing NK cell dysfunction in HCC. CircUHRF1 may drive resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for patients with HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer death in the world [1]
We examined the levels of 14 circular RNAs derived from UHRF1 by qRT-PCR
The results showed that the number of metastatic tumor nodules induced by PLC/PRF/5 cells transfected with pLO5-ciR-circUHRF1 was significantly increased compared with that induced by HCC cells transfected with pLO5-ciR-Mock (Fig. 6c)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer death in the world [1]. Despite the rapid advancements in diagnosis, surgical techniques, targeted therapy, and immunotherapy, the 5-year overall survival rate of HCC patients remains unsatisfactory due to relapse with distant metastasis and resistance to antitumor agents [2,3,4]. The underlying biological molecular mechanisms of HCC tumorigenesis, metastasis, and resistance to anti-HCC agents remain obscure [5,6,7]. T cell immunoglobulin and mucin domain 3 (TIM-3) is an immunomodulatory receptor that engages with ligands on tumor cells and the microenvironment to inhibit antitumoral immunity in a variety of cancers, including HCC [8,9,10]. Blockade of TIM-3 may represent a novel strategy to increase NK function in cancer patients [11]. Research on NK cells in HCC has been relatively scarce despite considerable evidence showing that they have an important role in malignancy
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