Background The biological significance of MAF1, a tumor suppressor, in carcinogenesis and immune response of hepatocellular carcinoma (HCC) remains unreported. Understanding the underlying mechanisms by which MAF1 enhances anti-tumor immunity in HCC is crucial for developing novel immunotherapy strategies and enhancing clinical responses to treatment for patients with HCC. Methods Mice were subjected to hydrodynamic tail vein injections of transposon vectors to overexpress AKT/NRas, or c-Myc, with or without wild-type (WT) or mutant-activated (−4A) MAF1, or short-hairpin MAF1 (shMAF1). Liver tissues and tumors were harvested and analyzed using histology, immunohistochemistry, immunoblotting, quantitative reverse-transcription PCR, and flow cytometry. MAF1 was overexpressed or knocked down in HCC cells via lentiviral transfection. Cell lines were analyzed using RNA sequencing, immunoblotting, dual luciferase reporter, and chromatin precipitation assays. Results Both MAF1-WT and MAF1-4A proteins significantly inhibit hepatocarcinogenesis in mice, with the mutant form exhibiting a stronger suppressive effect. Although MAF1 knockdown alone does not induce abnormalities in the mouse liver, it accelerates c-Myc-induced carcinogenesis. Our results provide the first in vivo evidence that MAF1 plays a tumor suppressor role by activating PTEN to suppress the AKT-mammalian target of rapamycin signaling pathway during hepatocarcinogenesis in physiologically relevant tumor models. More importantly, we found that MAF1 not only enhances the intratumoral infiltration of CD8 + T cells by increasing CXCL10 secretion but also enhances their functional activity by inhibiting PDL1 transcription in mouse liver cancer, which were confirmed in human HCC or in vitro experiments. Furthermore, PDL1 overexpression accelerates mouse hepatocarcinogenesis by antagonizing the tumor-suppressive role of MAF1. Conclusions Our study uncovers a novel anti-tumor immunity of MAF1 in hepatocarcinogenesis and human HCC. These findings suggest that the stimulated MAF1 could potentially improve immunotherapy in combination with immune checkpoint inhibitors in HCC patients, especially in those with an absence of T cells in HCC tissues.
[Objective] To investigate the mutation of latent membrane protein 1(LMP1) distal promoter L1-TR in nasopharyngeal carcinoma(NPC) tissue and the influence on promoter activity.[Methods] The L1-TR fragments of Epstein-Barr virus(EBV) genome in B95.8 cells and fresh NPC tissue cells were amplified by using polymerase chain reaction(PCR) and the difference between their nucleotides sequence were compared by direct sequencing.The luciferase reporter containing mutant or prototype L1-TR promoter was constructed and transfected into the HaCat,B95.8,and C666-1 cells respectively to compare the transcriptional activity.[Results] The nucleotides insertion,deletion and point mutations were found in L1-TR promoter derived from NPC tissue compared with B95.8 prototype,and activity of the mutant L1-TR promoter was reduced markedly(P 0.05).[Conclusions] The activity of the LMP1 promoter in NPC tissue is significantly lower than that of B95.8 prototype L1-TR,which might contribute to the immune evasion mechanism of EBV.
Abstract The androgen receptor ( AR ) plays an important role in male-dominant hepatocellular carcinoma, and specific acquired somatic mutations of AR have been observed in HCC patients. Our previous research have established the role of AR wild type as one of the key oncogenes in hepatocarcinogenesis. However, the role of hepatic acquired somatic mutations of AR remains unknown. In this study, we identify two crucial acquired somatic mutations, Q62L and E81Q , situated close to the N-terminal activation function domain-1 of AR . These mutations lead to constitutive activation of AR , both independently and synergistically with androgens, making them potent driver oncogene mutations. Mechanistically, these N-terminal AR somatic mutations enhance de novo lipogenesis by activating sterol regulatory element-binding protein-1 and promote glycogen accumulation through glycogen phosphorylase, brain form, thereby disrupting the AMPK pathway and contributing to tumorigenesis. Moreover, the AR mutations show sensitivity to the AMPK activator A769662. Overall, this study establishes the role of these N- terminal hepatic mutations of AR as highly malignant oncogenic drivers in hepatocarcinogenesis and highlights their potential as therapeutic targets for patients harboring these somatic mutations.
Abstract Repositioning approved antitumor drugs for different cancers is a cost-effective approach. Gilteritinib was FDA-approved for the treatment of FLT3-mutated acute myeloid leukaemia in 2018. However, the theraputic effects and mechanism of Gilteritinib on other malignancies remains to be defined. In this study, we identified that gilteritinib has an inhibitory effect on lung cancer cells (LCCs) without FLT3 mutation in vitro and in vivo. Unexpectedly, we found that gilteritinib induces cholesterol accumulation in LCCs via upregulating cholesterol biosynthetic genes and inhibiting cholesterol efflux. This gilteritinib-induced cholesterol accumulation not only attenuates the antitumor effect of gilteritinib but also induces gilteritinib-resistance in LCCs. However, when cholesterol synthesis was prevented by squalene epoxidase (SQLE) inhibitor NB-598, both LCCs and gilteritinib-resistant LCCs became sensitive to gilteritinib. More important, the natural cholesterol inhibitor 25-hydroxycholesterol (25HC) can suppress cholesterol biosynthesis and increase cholesterol efflux in LCCs. Consequently, 25HC treatment significantly increases the cytotoxicity of gilteritinib on LCCs, which can be rescued by addition of exogenous cholesterol. In a xenograft model, the combination of gilteritinib and 25HC showed significantly better efficacy than either monotherapy in suppressing lung cancer growth, without obvious general toxicity. Thus, our findings identify an increase in cholesterol induced by gilteritinib as a mechanism for LCC survival, and highlight the potential of combining gilteritinib with cholesterol-lowering drugs to treat lung cancer.
Abstract Background and Aims Androgen receptor (AR) has been reported to play an important role in the development and progression of man’s prostate cancer. Hepatocellular carcinoma (HCC) is also male‐dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis. Approach and Results In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high AR S96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease‐free survival, which has been proven as an independent survival predictor for patients with HCC. Conclusions AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man‐biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.
To compare the detection rates of Epstein-Barr virus (EBV) DNA in the serum/plasma between apparently healthy adults (AHAs) and nasopharyngeal carcinoma (NPC) patients in attempt to evaluate the efficiency of EBV DNA assay for serodiagnosis of NPC.The plasma and serum were obtained from 58 AHAs and 66 untreated NPC patients. EBV DNA W-fragment was detected using nested ploymerase chain reaction (PCR). Immunoenzymatic assay for titration of IgA-VCA was also adopted.EBV DNA detection rate (84.85%) in the plasma/serum of 66 NPC patients was significantly higher than that (10.34%) in 58 AHAs. The sensitivity of plasma/serum EBV DNA assay (0.8485) was higher than that (0.8030) of titrating IgA-VCA (positive criterion >/= 1:40) though the specificities of these two tests were the same (0.8966). The correct rate, predictive value of a positive test, and Odds ratio of dual positivity (0.8387, 0.9792 and 141.0, respectively) were higher than those of single positivity either to plasma/serum EBV assay (0.5242, 0.7333 and 1.1423, respectively) or to IgA-VCA >/= 1:40 test (0.4839, 0.5385 and 1.0480, respectively).The EBV DNA detection in the plasma/serum using nested PCR may be a useful indicator for serodiagnosis of NPC.
Abstract Background Bladder cancer (BLCA) is one of the most diagnosed cancers in humans worldwide. Recently, immunotherapy has become a main treatment option for BC. However, most BLCA patients do not respond to immune checkpoint inhibitors or relapse after immunotherapy. Therefore, it is very important to identify novel biomarkers for the prediction of immunotherapy response in B patients. Methods Pancancer single‐cell RNA sequencing (scRNA‐seq) data were used to identify the clusters of CD4 + T cells in the tumour microenvironment (TME). The clinical significance of key CD4 + T‐cell clusters was evaluated based on the survival data of two independent immunotherapy bladder cancer (BLCA) cohorts. We also investigated the function of key clusters of CD4 + T cell in the TME of BC cells in vitro. Results This study identified two novel exhausted CD4 + T‐cell subpopulations with the expression of PD1 hi CD200 hi or PD1 hi CD200 low in BC patients. Moreover, BLCA patients with a high level of PD1 hi CD200 hi CD4 + exhausted T cell showed immunotherapy resistance. Cell function analysis demonstrated that PD1 hi CD200 hi CD4 + exhausted T cell can promote epithelial–mesenchymal transition (EMT) and angiogenesis in BLCA cells. In addition, PD1 hi CD200 hi CD4 + exhausted T cells were shown to communicate with malignant BLCA cells through the GAS6–AXL axis. Finally, we also found that GAS6 expression is upregulated in B cells by METTL3‐mediated m6A modification. Conclusions PD1 hi CD200 hi CD4 + exhausted T cell may serve as a novel biomarker for poor prognosis and immunotherapy resistance in B. Targeted inhibitors of PD1 hi CD200 hi CD4 + exhausted T cells may help improve the efficacy of immunotherapy.
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