Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Relationship between histone demethylase LSD family and development and prognosis of gastric cancer.

Objective: to elucidate the correlation between histone demethylase and gastric cancer. Research object: histone demethylase and gastric cancer. Results: As one of the important regulatory mechanisms in molecular biology and epigenetics, histone modification plays an important role in gastric cancer including downstream gene expression regulation and epigenetics effect. Both histone methyltransferase and histone demethylases are involved in the formation and maintaining different of histone methylation status, which in turn through a variety of vital molecules and signaling pathways involved in the recognition of histone methylation modification caused by the downstream biological process, eventually participate in the regulation of chromatin function, and with a variety of important physiological activities, especially closely related to the occurrence of gastric cancer and embryonic development. Conclusion: This paper intends to review the research progress in this field from the aspects of histone methylation modification and the protein structure, catalytic mechanism and biological function of the important histone demethylases LSD1 and LSD2, in order to provide the theoretical reference for further understanding and exploration of histone demethylases in development and prognosis of gastric cancer.

The profile and prognostic value of circulating lymphocyte subsets in metastatic colon cancer.

OBJECTIVE: Colon cancer (CC) are the most common malignant cancer in human digestive system, however, the profile and prognostic value of circulating lymphocyte subsets in CC patients has not been systemically clarified. METHODS: In this study, 158 patients with metastatic CC were enrolled. Chi-square test was used to analyze the relationship between baseline peripheral blood lymphocyte subsets and clinicopathological parameters. Kaplan-Meier and Log-rank tests were used to analyze the relationship between clinicopathological parameters and baseline peripheral lymphocyte subsets and overall survival (OS) of patients with metastatic CC. Univariate/multivariate COX regression analysis was used to identify the independent factors in metastatic CC. RESULTS: The baseline peripheral blood CD3+T cells, CD4+T cells, NK cells and B cells of BRAF mutant patients were significantly lower than those in BRAF wild-type patients; The baseline CD8+T cells of KRAS mutation group was lower than that in KRAS wild type group. Peripheral blood CA19-9 > 27, left-sided colon cancer (LCC), KRAS and BRAF mutation were poor prognostic factors, and ALB > 40, NK cells were protective prognostic factors for metastatic CC. In patients with liver metastases subgroup, higher NK cells also indicated a longer OS. Finally, LCC (HR = 0.56), CA19-9 (HR = 2.13), ALB (HR = 0.46) and circulating NK cells (HR = 0.55) were independent prognostic factors for metastatic CC. CONCLUSION: LCC, higher level of ALB and NK cells at baseline are protective factors, and higher CA19-9, KRAS/BRAF gene mutation are adverse prognostic factors. Sufficient circulating NK cells are independent prognostic factor for metastatic CC patients.

Sesamin promotes apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma.

Sesamin is a lignan compound in plants that has various pharmacological effects, including reducing diabetes-associated injuries, regulating fatty acid and cholesterol metabolism, and exerting antiinflammatory and antitumour effects. Previous studies have reported that sesamin can inhibit the proliferation of several types of tumour cells and exert antitumour effects. However, the antitumour effect of sesamin on T-cell lymphoma is still unknown. In this study, we selected a T-cell lymphoma mouse model to investigate the mechanism of sesamin against T-cell lymphoma via programmed cell death in vivo and in vitro. We found that sesamin could significantly inhibit the growth of EL4 cells in a tumour-bearing mouse model. Sesamin markedly inhibited the proliferation of EL4 cells by inducing apoptosis, pyroptosis and autophagy. Autophagy occurred earlier than apoptosis and pyroptosis in EL4 cells after sesamin treatment. Blocking autophagy inhibited apoptosis and pyroptosis in EL4 cells after sesamin treatment. Taken together, these results suggested that sesamin promoted apoptosis and pyroptosis via autophagy to enhance antitumour effects on murine T-cell lymphoma. This study expands our knowledge of the pharmacological effects of sesamin on T-cell lymphoma, and provides a theoretical basis for the development of new antitumour drugs and treatments for T-cell lymphoma.

Expression and Gene Regulation Network of Adenosine Receptor A2B in Lung Adenocarcinoma: A Potential Diagnostic and Prognostic Biomarker.

Adenosine receptor A2B (ADORA2B) encodes a protein belonging to the G protein-coupled receptor superfamily. Abnormal expression of ADORA2B may play a pathophysiological role in some human cancers. We investigated whether ADORA2B is a potential diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD). The expression, various mutations, copy number variations, mRNA expression levels, and related network signaling pathways of ADORA2B were analyzed using bioinformatics-related websites, including Oncomine, UALCAN, cBioPortal, GeneMANIA, LinkedOmics, KM Plotter, and TIMER. We found that ADORA2B was overexpressed and amplified in LUAD, and a high ADORA2B expression predicted a poor prognosis for LUAD patients. Pathway analyses of ADORA2B in LUAD revealed ADORA2B-correlated signaling pathways, and the expression level of ADORA2B was associated with immune cell infiltration. Furthermore, ADORA2B mRNA and protein levels were significantly higher in human LUAD cell lines (A549 cells and NCl-H1299 cells) than in normal human bronchial epithelial (HBE) cells, and the transcript levels of genes positively or negatively correlated with ADORA2B were consistent and statistically significant. siRNA transfection experiments and functional experiments further confirmed these results. In vitro results were also consistent with those of bioinformatics analysis. Our findings provide a foundation for studying the role of ADORA2B in tumorigenesis and support the development of new drug targets for LUAD.

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.

New Aspect of Liver IL-17+γδ T Cells.

Liver is a critical organ where comprehensive immune regulation or defense occurs. γδ T cells in liver represent indispensable population and are found to be regulating a variety of diseases including autoimmunity, cancer, fibrosis, and infections. IL-17+ γδ T cells in liver is a functional subset which has been found to have pro-inflammatory effect or anti-infection ability. However, how their function is activated or maintained, isn't well understood. Microbiota in the intestine provide continual source of metabolites to the liver, through at least the portal vein. The interaction between intestinal microbiota and liver γδ T cells has not been well studied. Li et al found that lipid antigen derived from intestinal microbiota was presented by hepatocyte CD1d, and activated liver-resident γδ T cells and maintained the IL-17 production. Moreover, microbiota promoted NAFLD through IL-17+ γδ T cells. Thus, new aspect of IL-17+ γδ T cells in the liver was characterized.

Aluminum hydroxide colloid vaccine encapsulated in yeast shells with enhanced humoral and cellular immune responses.

Aluminum salt (Alum) is one of the most important immune adjuvants approved for use in humans, however it is not suitable for vaccination against various chronic infectious diseases and cancers for not being able to induce cell-mediated (Th1) immunity. Here, we encapsulated an Alum colloid inside ß-glucan particles (GPs), which are a type of natural particles derived from the yeast glucan shells, to prepare hybrid GP-Alum (GP-Al) adjuvant particles with a very uniform size of 2-4 µm. These hybrid particles can be used to load antigen proteins through a simple mixing procedure, and can be highly specifically targeted to antigen-presenting cells (APCs) and strongly activate dendritic cells (DCs) maturation and cytokine secretion. In an animal model, they elicit a strong Th1-biased immune response and extremely high antibody titer, and cause marked prophylactic and therapeutic effects against tumors. As Alum has been proven to be a safe adjuvant to induce strong humoral responses and ß-glucans are safe for human use, this very uniform hybrid Alum particulate system could have important application as a vaccine carrier to stimulate humoral and cellular immune responses at the same time.

A novel antigen delivery system induces strong humoral and CTL immune responses.

New strategies with the ability to enhance both the humoral and cellular immune responses remain a priority for the development of future therapeutic cancer vaccines. In this study, we took advantage of ß-glucan particles (GPs) derived from Saccharomyces cerevisiae baker's yeast and a novel reverse micro-emulsion method to prepare an antigen-loaded GP carrier system for dendritic cell (DC) specific antigen delivery, followed by careful evaluation of the immune functions of the prepared particles in initiating both the humoral and cellular immune responses through in vitro and in vivo experiments. The prepared particles greatly promoted DC activation and cytokine production and cross presented the antigen to CD8 cells, inducing very strong OVA specific humoral and cellular immune responses. Treatment with these particles significantly prevented the growth of implanted EG7-OVA tumors in a prophylactic and pre-established tumor model. These results suggest that our strategy may be able to be utilized as a promising platform for cancer immunotherapy.

Tumor-derived transforming growth factor-ß is critical for tumor progression and evasion from immune surveillance.

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-ß(TGF-ß) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-ß produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-ß in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-ß using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and CD4+Foxp3+ Treg cells, and consequently enhanced IFN-γ production by CTLs. Knockdown of tumor-derived TGF-ß also significantly reduced the conversion of naive CD4+ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-ß suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-ß is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-ß may serve as a potential therapeutic approach for cancer.

Interleukin-6 promotes systemic lupus erythematosus progression with Treg suppression approach in a murine systemic lupus erythematosus model.

Our aim is to reveal the role of interleukin 6 (IL-6) in the pathogenesis of systemic lupus erythematosus (SLE) in a murine model of SLE. Normal female C57BL/6 mice were immunized with syngeneic-activated lymphocyte-derived DNA (ALD-DNA) to induce SLE. Non-immunized mice were used as control. SLE-associated markers, including anti-double-stranded DNA (anti-dsDNA) Abs, urine protein, and kidney histopathology, were assayed to ensure the induction of the disease. Compared with control mice, ALD-DNA immunized mice exhibited high levels of anti-dsDNA Abs, IL-6 expression in vivo and in vitro. We also found that IL-6 knockout (IL-6KO) mice were resistant to ALD-DNA-induced SLE. The activation of CD4(+) T cells in immunized IL-6KO mice was lower than in immunized wild-type (Wt) mice. Intracellular cytokine staining showed that Foxp3 expression in immunized IL-6KO mice was higher than in immunized Wt mice, which might be associated with the disease severity. We further discovered that ALD-DNA-stimulated dendritic cells supernatants could result in higher IL-6 and TNF-α expression and could suppress Foxp3 expression. In addition, blocking IL-6 could up-regulate Foxp3 expression. Therefore, our findings show that IL-6 promotes the progression of SLE via suppressing Treg differentiation.

A novel tylophorine analog W-8 up-regulates forkhead boxP3 expression and ameliorates murine colitis.

Tylophorine and analogs are phenanthroindolizidine alkaloids, several of which have been reported to have anticancer, antiviral, and anti-inflammatory properties. However, their function in the immune system remains widely unknown. Transcription factor Foxp3 is critical for the development and function of Treg, which down-regulates the immune system and maintains tolerance to self-antigens. In the present study, we defined a novel tylophorine analog, W-8, enhanced TGF-ß-induced Foxp3 expression at the mRNA and the protein levels. Interestingly, W-8 synergistically increased the level of TGF-ß-induced p-Smad3 through inhibition of the AKT/mTOR pathway and enhanced the demethylation of the promoter region of the Foxp3 through inhibition of the ERK pathway and DNMT1 expression. Moreover, administration of W-8 suppressed TNBS-induced murine colitis and increased Tregs in lymphoid tissues. Finally, W-8 enhanced conversion of naïve T cells to Tregs in vivo. In summary, our results defined a novel compound that enhanced Foxp3 expression through transcriptional and epigenetic programs, and it might serve as a therapeutic agent for inflammatory diseases.