The four major RNA adenosine modifications, i.e., m
A, m
A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical ...mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these "writers" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown.
We systematically characterized mRNA expression and genetic alterations of 26 RNA modification "writers" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification "writers". Subsequently, we constructed the RNA modification "writer" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy.
We demonstrated that multi-layer alterations of RNA modification "writer" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. In response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these "writers" to aid the clinical benefits of immunotherapy.
Our study is the first to provide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification "writers" in cancer therapy.
The aim of this study was to develop a noninvasive serological diagnostic approach in identifying and evaluating a panel of candidate autoantibodies to tumor‐associated antigens (TAAs) based on ...protein microarray technology for early detection of ovarian cancer (OC). Protein microarray based on 154 proteins encoded by 138 cancer driver genes was used to screen candidate anti‐TAA autoantibodies in a discovery cohort containing 17 OC and 27 normal controls (NC). Indirect enzyme‐linked immunosorbent assay (ELISA) was used to detect the content of candidate anti‐TAA autoantibodies in sera from 140 subjects in the training cohort. Differential anti‐TAA autoantibodies were further validated in the validation cohort with 328 subjects. Subsequently, 112 sera from the patients with ovarian benign diseases with 104 OC sera and 104 NC sera together were recruited to identify the specificity of representative autoantibodies to OC among ovarian diseases. Five TAAs (GNAS, NPM1, FUBP1, p53, and KRAS) were screened out in the discovery phase, in which four of them presented higher levels in OC than controls (P < .05) in the training cohort, which was consistent with the result in the subsequent validation cohort. An optimized panel of three anti‐TAA (GNAS, p53, and NPM1) autoantibodies was identified to have relatively high sensitivity (51.2%), specificity (86.0%), and accuracy (68.6%), respectively. This panel can identify 51% of OC patients with CA125 negative. This study supports our assumption that anti‐TAA autoantibodies can be considered as potential diagnostic biomarkers for detection of OC; especially a panel of three anti‐TAA autoantibodies could be a good tool in immunodiagnosis of OC.
We developed a noninvasive serological diagnostic approach of ovarian cancer (OC). Autoantibodies can be considered as potential biomarkers for the detection of OC. A panel of three anti‐TAA (GNAS, p53, and NPM1) autoantibodies was identified.
Regulatory T (Treg) cells are essential for maintaining immune homeostasis and tolerance, but the mechanisms regulating the stability and function of Treg cells have not been fully elucidated. Here ...we show SUMO-specific protease 3 (SENP3) is a pivotal regulator of Treg cells that functions by controlling the SUMOylation and nuclear localization of BACH2. Treg cell-specific deletion of Senp3 results in T cell activation, autoimmune symptoms and enhanced antitumor T cell responses. SENP3-mediated BACH2 deSUMOylation prevents the nuclear export of BACH2, thereby repressing the genes associated with CD4
T effector cell differentiation and stabilizing Treg cell-specific gene signatures. Notably, SENP3 accumulation triggered by reactive oxygen species (ROS) is involved in Treg cell-mediated tumor immunosuppression. Our results not only establish the role of SENP3 in the maintenance of Treg cell stability and function via BACH2 deSUMOylation but also clarify the function of SENP3 in the regulation of ROS-induced immune tolerance.
Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, ...the cellular and molecular mechanisms underlying this pathology remain controversial. Here, we show that mice deficient in the double-stranded DNA sensor AIM2 are protected from both subtotal body irradiation-induced gastrointestinal syndrome and total body irradiation-induced hematopoietic failure. AIM2 mediates the caspase-1-dependent death of intestinal epithelial cells and bone marrow cells in response to double-strand DNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Our results suggest that AIM2 may be a new therapeutic target for ionizing radiation exposure.
The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. It has been known that these tumor associated immune cells may possess tumor-antagonizing or ...tumor-promoting functions. Although the tumor-antagonizing immune cells within TME tend to target and kill the cancer cells in the early stage of tumorigenesis, the cancer cells seems to eventually escape from immune surveillance and even inhibit the cytotoxic function of tumor-antagonizing immune cells through a variety of mechanisms. The immune evasion capability, as a new hallmark of cancer, accidently provides opportunities for new strategies of cancer therapy, namely harnessing the immune cells to battle the cancer cells. Recently, the administrations of immune checkpoint modulators (represented by anti-CTLA4 and anti-PD antibodies) and adoptive immune cells (represented by CAR-T) have exhibited unexpected antitumor effect in multiple types of cancer, bringing a new era for cancer therapy. Here, we review the biological functions of immune cells within TME and their roles in cancer immunotherapy, and discuss the perspectives of the basic studies for improving the effectiveness of the clinical use.
•The biological functions of the immune cells within the tumor microenvironment.•The roles of the immune cells in cancer immunotherapy.•The perspectives of the basic studies for improving the effectiveness of the clinical use.
This work elaborated the underlying mechanism for the non-passivation of CoCrFeMnNi HEA in chloride solution based on the dissolution-diffusion-deposition model. A novel N-alloying strategy was ...proposed to significantly improve the corrosion resistance of CoCrFeMnNi HEA. Modelling results indicated that N could consume H+ and relieve the acidification on the surface of HEA, thus accelerating deposition of Cr and Fe oxides and hydroxides. Thereby, the nucleation rate and growth rate of passive film were apparently enhanced after N-alloying, which agreed well with the less defective and thinner passive film. Finally, the element selection for designing corrosion resistant HEAs was recommended.
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•The model describing passive film formation on CoCrFeMnNi HEA was established.•The non-passivation of CoCrFeMnNi HEA in chloride solution was interpreted.•N accelerated passive film deposition and dramatically enhanced corrosion resistance.•The model gave recommendation for designing corrosion resistant HEAs.
RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are ...involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8
T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.
MicroRNAs (miRNAs) are endogenous, small noncoding RNAs that play important roles in various cellular functions and tumor development. Recent studies have indicated that miR-21 is one of the ...important miRNAs associated with tumor growth and metastasis, but the role and molecular mechanism of miR-21 in regulating tumor angiogenesis remain to be elucidated. In this study, miR-21 was overexpressed by transfecting pre-miR-21 into human prostate cancer cells and tumor angiogenesis was assayed using chicken chorioallantoic membrane (CAM). We found that overexpression of miR-21 in DU145 cells increased the expression of HIF-1α and VEGF, and induced tumor angiogenesis. AKT and extracellular regulated kinases (ERK) 1/2 are activated by miR-21. Inhibition of miR-21 by the antigomir blocked this process. Overexpression of the miR-21 target, PTEN, also inhibited tumor angiogenesis by partially inactivating AKT and ERK and decreasing the expression of HIF-1 and VEGF. The AKT and ERK inhibitors, LY294002 and U0126, suppressed HIF-1α and VEGF expression and angiogenesis. Moreover, inhibition of HIF-1α expression alone abolished miR-21-inducing tumor angiogenesis, indicating that HIF-1α is required for miR-21-upregulated angiogenesis. Therefore, we demonstrate that miR-21 induces tumor angiogenesis through targeting PTEN, leading to activate AKT and ERK1/2 signaling pathways, and thereby enhancing HIF-1α and VEGF expression; HIF-1α is a key downstream target of miR-21 in regulating tumor angiogenesis.
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•Effect of N on corrosion of steel in S2O32−-Cl- solution was firstly reported.•N significantly enhanced corrosion resistance of 316 L in S2O32−-Cl- solution.•N restrained reduction ...of S2O32− by consuming H+ and alleviated its harmful effect.•N reduced defects and raised fraction of Cr2O3 and Fe2O3 in passive film.
Thiosulfate is a threat to corrosion resistance of steels in chloride solution. This work revealed the inhibitory effect of nitrogen (N) on thiosulfate-accelerated corrosion of stainless steel by electrochemical measurements, microscopy observation and X-ray photoelectron spectroscopy analyses. Results manifested that N-alloying significantly enhanced pitting corrosion resistance and repassivation ability of 316 L steel in thiosulfate-chloride solution. On the one hand, N consumed H+, then restrained reduction of S2O32− and subsequent formation of S and MS2. On the other hand, N reduced defect density and strengthened passive film by increasing fraction of Cr2O3 and Fe2O3, thus improving protective ability of passive film.
T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly ...divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have demonstrated that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development.
γδ T cells undergo a series of well‐characterized and complicated developmental processes. m6A, one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Here, we mainly speculate on the potential role of m6A modification in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development.
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