Vitamin D receptor gene methylation in hepatocellular carcinoma

Abdalla, Mai; Khairy, Eman; Louka, Manal L.; Ali-Labib, Randa; Ibrahim, Eman

doi:10.1016/j.gene.2018.02.024

Cited by 19 publications

(20 citation statements)

References 39 publications

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“…Hepatocellular carcinoma, the most predominant type of primary liver cancer, is one of the leading causes of cancer-related death and arouses global concern in recent years ( Abdalla et al, 2018 ; Hu et al, 2018 ; Jin et al, 2018 ). Because most (more than 80%) of patients with HCC are diagnosed at a late stage of the disease, potentially curative therapies (including ablation, chemotherapy, proton beam therapy, chemoembolization, and targeted drug therapy) are often less effective and only extend the overall survival by a short time ( Llovet et al, 2008 ; Gao et al, 2014 ; Xiang et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma

et al. 2018

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Cancer immunotherapy has made unprecedented breakthrough in the fields of chimeric antigen receptor-redirected T (CAR T) cell therapy and immune modulation. Combination of CAR modification and the disruption of endogenous inhibitory immune checkpoints on T cells represent a promising immunotherapeutic modality for cancer treatment. However, the potential for the treatment of hepatocellular carcinoma (HCC) has not been explored. In this study, the gene expressing the programmed death 1 receptor (PD-1) on the Glypican-3 (GPC3)-targeted second-generation CAR T cells employing CD28 as the co-stimulatory domain was disrupted using the CRISPR/Cas9 gene-editing system. It was found that, in vitro, the CAR T cells with the deficient PD-1 showed the stronger CAR-dependent anti-tumor activity against native programmed death 1 ligand 1-expressing HCC cell PLC/PRF/5 compared with the wild-type CAR T cells, and meanwhile, the CD4 and CD8 subsets, and activation status of CAR T cells were stable with the disruption of endogenous PD-1. Additionally, the disruption of PD-1 could protect the GPC3-CAR T cells from exhaustion when combating with native PD-L1-expressing HCC, as the levels of Akt phosphorylation and anti-apoptotic protein Bcl-xL expression in PD-1 deficient GPC3-CAR T cells were significantly higher than those in wild-type GPC3-CAR T cells after coculturing with PLC/PRF/5. Furthermore, the in vivo anti-tumor activity of the CAR T cells with the deficient PD-1 was investigated using the subcutaneous xenograft tumor model established by the injection of PLC/PRF/5 into NOD-scid-IL-2Rγ-/- (NSG) mice. The results indicated that the disruption of PD-1 enhanced the in vivo anti-tumor activity of CAR T cells against HCC, improved the persistence and infiltration of CAR T cells in the NSG mice bearing the tumor, and strengthened the inhibition of tumor-related genes expression in the xenograft tumors caused by the GPC3-CAR T cells. This study indicates the enhanced anti-tumor efficacy of PD-1-deficient CAR T cells against HCC and suggests the potential of precision gene editing on the immune checkpoints to enhance the CAR T cell therapies against HCC.

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Section: Introductionmentioning

confidence: 99%

Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma

et al. 2018

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“…27,28 Several studies have suggested that VDR gene methylation alterations may have a role in the pathogenesis of infectious and malignant diseases. [29][30][31][32][33][34] Vitamin D plays an important regulatory role in immune system 6 function and its deficiency has been introduced in the etiology of autoimmune diseases. 19,35 It affects many aspects of the innate and adaptive immune system.…”

Section: Introductionmentioning

confidence: 99%

The expression and methylation status of vitamin D receptor gene in Behcet's disease

Shirvani

Nouri

Sakhinia

et al. 2019

Immunity Inflam & Disease

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Introduction Vitamin D has important roles as a natural immune modulator via regulating the expression of genes which have been implicated in the pathophysiology of autoimmune diseases. Vitamin D function and its deficiency have been linked to a wide range of metabolic disorders including disorders of calcium metabolism, malignant, cardiovascular, infectious, neuromuscular, and inflammatory diseases. Environmental factors, genetic factors, and epigenetic changes contribute to Behcet's disease (BD) development. The aim of our study was to analyze the expression level and methylation status of the vitamin D receptor (VDR) gene promoter in the peripheral blood mononuclear cells (PBMCs) of patients with BD. Methods In a case‐control study, 48 Iranian Azeri patients with BD and 60 age‐, sex‐ and ethnically‐matched healthy controls were included. Venous blood samples were collected and PBMCs were isolated by Ficoll protocol. The DNA and RNA were subsequently extracted. Promoter methylation levels were evaluated by MeDIP‐quantitative polymerase chain reaction (qPCR). The expression of VDR was evaluated by real‐time PCR. Results The results of quantitative real‐time PCR analysis showed that the level of VDR expression in patients with BD was significantly lower than the control group (P = .013). There was no significant difference in the level of DNA methylation in the BD and control groups (P > .05). As the results show, the expression level of VDR gene was significantly different between female and male in the patient group (P = .001). VDR gene expression was significantly higher in subjects with phlebitis. No correlation was observed between VDR gene expression rate and BD activity. Conclusion VDR gene expression decreased in patients with BD. However, there is no suggestion evidence that the expression level of VDR is regulated by a unique DNA methylation mechanism. No correlation exists between VDR gene expression and BD activity.

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“…Intercellular adhesion molecule 1 (ICAM1) was considered closely related to occurrence, development, metastasis and invasion process of HCC 21. VDR gene promoter methylation was significantly higher in the HCC group compared to both CLD and control groups,22 and the reduced expression of VDR mRNA decreased the bioavailability of 1,25-(OH) 2 D 3 , providing an escape mechanism from the antitumor effect 23. TNF receptor-associated factor 1 (TRAF1) as a unique TRAF protein interacts with multiple TNFR family members, regulatory proteins, kinases and adaptors to perform diverse functions in multiple tumors 24.…”

Section: Discussionmentioning

confidence: 99%

<p>Apolipoprotein M could inhibit growth and metastasis of SMMC7721 cells via vitamin D receptor signaling</p>

Yu¹,

Pan²,

Sang³

et al. 2019

CMAR

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Objective: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality-to-incidence ratios. Apolipoprotein M (ApoM), a member of the apolipoprotein family, is mainly synthesized in the liver, whereas its role in HCC has not been elucidated. Here, we examined the effect of ApoM on the biological behavior of HCC cells and the possible mechanisms. Methods: We used CRISPR/Cas9 technology to knock out ApoM in SMMC7721 cells. Differentially expressed genes before and after ApoM knockout (KO) were analyzed by GeneChip microarrays and confirmed by qRT-PCR. Cell assays of proliferation, apoptosis, migration and invasion were performed in SMMC7721 cells, and the expression of epithelialmesenchymal transition (EMT) markers was performed by western blot. And we performed functional recovery experiments by overexpressing vitamin D receptor (VDR) in SMMC7721. Results: The ApoM-KO SMMC7721 cell line was successfully constructed using the CRISPR/ Cas9 technology. Our results showed that silencing ApoM suppressed apoptosis and promoted proliferation, migration, invasion and EMT of SMMC7721 cells. The microarray data revealed that a total of 1,868 differentially expressed genes were identified, including VDR. The qRT-PCR and western blot verification results demonstrated that knocking out ApoM could significantly reduce the expression of VDR. The functional recovery experiments indicated that VDR overexpression could offset the inhibition of cell apoptosis and the promotion of cell proliferation, migration, invasion and EMT caused by knocking out ApoM in SMMC7721 cells. Conclusion: ApoM could function as a tumor suppressor to inhibit the growth and metastasis of SMMC7721 cells via VDR signaling in HCC.

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Vitamin D receptor gene methylation in hepatocellular carcinoma

Cited by 19 publications

References 39 publications

Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma

Disruption of PD-1 Enhanced the Anti-tumor Activity of Chimeric Antigen Receptor T Cells Against Hepatocellular Carcinoma

The expression and methylation status of vitamin D receptor gene in Behcet's disease

<p>Apolipoprotein M could inhibit growth and metastasis of SMMC7721 cells via vitamin D receptor signaling</p>

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