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"Ye, Liang"
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TRIM21 inhibits irradiation-induced mitochondrial DNA release and impairs antitumour immunity in nasopharyngeal carcinoma tumour models
Although radiotherapy can promote antitumour immunity, the mechanisms underlying this phenomenon remain unclear. Here, we demonstrate that the expression of the E3 ubiquitin ligase, tumour cell-intrinsic tripartite motif-containing 21 (TRIM21) in tumours, is inversely associated with the response to radiation and CD8
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T cell-mediated antitumour immunity in nasopharyngeal carcinoma (NPC). Knockout of TRIM21 modulates the cGAS/STING cytosolic DNA sensing pathway, potentiates the antigen-presenting capacity of NPC cells, and activates cytotoxic T cell-mediated antitumour immunity in response to radiation. Mechanistically, TRIM21 promotes the degradation of the mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2) via K48-linked ubiquitination, which inhibits pore formation by VDAC2 oligomers for mitochondrial DNA (mtDNA) release, thereby inhibiting type-I interferon responses following radiation exposure. In patients with NPC, high TRIM21 expression was associated with poor prognosis and early tumour relapse after radiotherapy. Our findings reveal a critical role of TRIM21 in radiation-induced antitumour immunity, providing potential targets for improving the efficacy of radiotherapy in patients with NPC.
The molecular mechanisms determining the response to radiotherapy remain incompletely understood. Here, the authors demonstrate that the E3 ubiquitin ligase and intracellular Fc receptor, TRIM21, impairs CD8
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T cell responses in nasopharyngeal carcinoma tumour models following ionizing radiation.
Journal Article
Strain Effects in Twisted Spiral Antimonene
Van der Waals (vdW) layered materials exhibit fruitful novel physical properties. The energy band of such materials depends strongly on their structures, and a tremendous variation in their physical properties can be deduced from a tiny change in inter‐layer spacing, twist angle, or in‐plane strain. In this work, a kind of vdW layered material of spiral antimonene is constructed, and the strain effects in the material are studied. The spiral antimonene is grown on a germanium (Ge) substrate and is induced by a helical dislocation penetrating through few atomic‐layers of antimonene (β‐phase). The as‐grown spiral is intrinsically strained, and the lattice distortion is found to be pinned around the dislocation. Both spontaneous inter‐layer twist and in‐plane anisotropic strain are observed in scanning tunneling microscope (STM) measurements. The strain in the spiral antimonene can be significantly modified by STM tip interaction, leading to a variation in the surface electronic density of states (DOS) and a large modification in the work function of up to a few hundreds of millielectron‐volts (meV). Those strain effects are expected to have potential applications in building up novel piezoelectric devices. Antimonene spirals are epitaxially grown on a germanium substrate. Owing to the presence of a helical dislocation, the as‐grown spiral is anisotropically strained. The strain in the spiral can be changed by scanning tunneling microscopy tip manipulation, resulting in modulations of the electronic density of states and the work function.
Journal Article
Universal mechanical exfoliation of large-area 2D crystals
Two-dimensional materials provide extraordinary opportunities for exploring phenomena arising in atomically thin crystals. Beginning with the first isolation of graphene, mechanical exfoliation has been a key to provide high-quality two-dimensional materials, but despite improvements it is still limited in yield, lateral size and contamination. Here we introduce a contamination-free, one-step and universal Au-assisted mechanical exfoliation method and demonstrate its effectiveness by isolating 40 types of single-crystalline monolayers, including elemental two-dimensional crystals, metal-dichalcogenides, magnets and superconductors. Most of them are of millimeter-size and high-quality, as shown by transfer-free measurements of electron microscopy, photo spectroscopies and electrical transport. Large suspended two-dimensional crystals and heterojunctions were also prepared with high-yield. Enhanced adhesion between the crystals and the substrates enables such efficient exfoliation, for which we identify a gold-assisted exfoliation method that underpins a universal route for producing large-area monolayers and thus supports studies of fundamental properties and potential application of two-dimensional materials.
Here, the authors develop a one-step, contamination-free, Au-assisted mechanical exfoliation method for 2D materials, and isolate 40 types of single-crystalline monolayers, including elemental 2D crystals, metal-dichalcogenides, magnets and superconductors with millimetre size.
Journal Article
LINC00173 facilitates tumor progression by stimulating RAB1B‐mediated PA2G4 and SDF4 secretion in nasopharyngeal carcinoma
An increasing number of studies have found that long non‐coding RNA (lncRNA) play important roles in driving the progression of nasopharyngeal carcinoma (NPC). Our microarray screening revealed that expression of the lncRNA long intergenic non‐protein coding RNA 173 (LINC00173) was upregulated in NPC. However, its role and mechanism in NPC have not yet been elucidated. In this study, we demonstrate that high LINC00173 expression indicated a poor prognosis in NPC patients. Knockdown of LINC00173 significantly inhibited NPC cell proliferation, migration and invasion in vitro. Mechanistically, LINC00173 interacted and colocalized with Ras‐related protein Rab‐1B (RAB1B) in the cytoplasm, but the modulation of LINC00173 expression did not affect the expression of RAB1B at either the mRNA or protein levels. Instead, relying on the stimulation of RAB1B, LINC00173 could facilitate the extracellular secretion of proliferation‐associated 2G4 (PA2G4) and stromal cell‐derived factor 4 (SDF4; also known as 45‐kDa calcium‐binding protein) proteins, and knockdown of these proteins could reverse the NPC aggressive phenotype induced by LINC00173 overexpression. Moreover, in vivo LINC00173‐knockdown models exhibited a marked slowdown in tumor growth and a significant reduction in lymph node and lung metastases. In summary, LINC00173 serves as a crucial driver for NPC progression, and the LINC00173–RAB1B–PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients. Our study shows that LINC00173 is upregulated in nasopharyngeal carcinoma (NPC) and is associated with poor prognosis of patients. LINC00173 directly binds and interacts with RAB1B, subsequently facilitates PA2G4 and SDF4 secretion through exocytosis pathway, finally, promotes NPC cell proliferation, migration, invasion and metastasis. The LINC00173–RAB1B–PA2G4/SDF4 axis might provide a potential therapeutic target for NPC patients.
Journal Article
PJA1-mediated suppression of pyroptosis as a driver of docetaxel resistance in nasopharyngeal carcinoma
Chemoresistance is a main reason for treatment failure in patients with nasopharyngeal carcinoma, but the exact regulatory mechanism underlying chemoresistance in nasopharyngeal carcinoma remains to be elucidated. Here, we identify PJA1 as a key E3 ubiquitin ligase involved in nasopharyngeal carcinoma chemoresistance that is highly expressed in nasopharyngeal carcinoma patients with nonresponse to docetaxel-cisplatin-5-fluorouracil induction chemotherapy. We find that PJA1 facilitates docetaxel resistance by inhibiting GSDME-mediated pyroptosis in nasopharyngeal carcinoma cells. Mechanistically, PJA1 promotes the degradation of the mitochondrial protein PGAM5 by increasing its K48-linked ubiquitination at K88, which further facilitates DRP1 phosphorylation at S637 and reduced mitochondrial reactive oxygen species production, resulting in suppression of GSDME-mediated pyroptosis and the antitumour immune response. PGAM5 knockdown fully restores the docetaxel sensitization effect of PJA1 knockdown. Moreover, pharmacological targeting of PJA1 with the small molecule inhibitor RTA402 enhances the docetaxel sensitivity of nasopharyngeal carcinoma in vitro and in vivo. Clinically, high PJA1 expression indicates inferior survival and poor clinical efficacy of TPF IC in nasopharyngeal carcinoma patients. Our study emphasizes the essential role of E3 ligases in regulating chemoresistance and provides therapeutic strategies for nasopharyngeal carcinoma based on targeting the ubiquitin-proteasome system.
While chemotherapy may initially be effective in patient with nasopharyngeal carcinoma (NPC), resistance often develops. Here, the authors identify PJA1 as a driver of resistance to docetaxel via inhibition of GSDME-mediated proptosis and target this using a PJA1 inhibitor to restore sensitivity in preclinical models of NPC.
Journal Article
Cancer-associated fibroblasts-derived CXCL12 enhances immune escape of bladder cancer through inhibiting P62-mediated autophagic degradation of PDL1
Background
Cancer-associated fibroblasts (CAFs), the predominant stromal cell of tumor microenvironment (TME), play an important role in tumor progression and immunoregulation by remodeling extracellular matrix (ECM) and secreting cytokines. However, little is known about the details of the underlying mechanism in bladder cancer.
Methods
Bioinformatics analysis was performed to analyze the prognostic value of CAFs and CXCL12 using GEO, TCGA and SRA databases. The effects of CXCL12 on bladder cancer progression were investigated through in vitro and in vivo assays. The biological mechanism of the effect of CXCL12 on PDL1 were investigated using western blotting, immunoprecipitation, RT-PCR, immunofluorescence, mass spectrometry, protein stability, and flow cytometry.
Results
The results demonstrated that CAFs-derived CXCL12 promoted cancer cell migration and invasion and upregulated PDL1. Mechanistically, upon binding to its specific receptor, CXCL12 activated the downstream JAK2/STAT3 pathway and rapidly up-regulated the expression of deubiquitinase CYLD. CYLD deubiquitinated P62 causing P62 accumulation, which in turn inhibited the autophagic degradation of PDL1. In vivo experiments demonstrated that blocking CXCL12 inhibited tumor growth, reduced tumor PDL1 expression and increased immune cell infiltration.
Conclusions
This study revealed a novel mechanism for the role of CXCL12 in P62-mediated PDL1 autophagic regulation. Combined application of CXCL12 receptor blocker and PD1/PDL1 blocker can more effectively inhibit PDL1 expression and enhance antitumor immune response. Targeting CAFs-derived CXCL12 may provide an effective strategy for immunotherapy in bladder cancer.
Journal Article
Phylogenomic analyses highlight innovation and introgression in the continental radiations of Fagaceae across the Northern Hemisphere
Northern Hemisphere forests changed drastically in the early Eocene with the diversification of the oak family (Fagaceae). Cooling climates over the next 20 million years fostered the spread of temperate biomes that became increasingly dominated by oaks and their chestnut relatives. Here we use phylogenomic analyses of nuclear and plastid genomes to investigate the timing and pattern of major macroevolutionary events and ancient genome-wide signatures of hybridization across Fagaceae. Innovation related to seed dispersal is implicated in triggering waves of continental radiations beginning with the rapid diversification of major lineages and resulting in unparalleled transformation of forest dynamics within 15 million years following the K-Pg extinction. We detect introgression at multiple time scales, including ancient events predating the origination of genus-level diversity. As oak lineages moved into newly available temperate habitats in the early Miocene, secondary contact between previously isolated species occurred. This resulted in adaptive introgression, which may have further amplified the diversification of white oaks across Eurasia.
Fagaceae are diverse family including trees of ecological and economic importance. This phylogenomic analysis of nuclear and plastid genomes reconstructs evolutionary history and finds evidence of multiple adaptive introgression events in this important plant family.
Journal Article
Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment
Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer.
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Journal Article
Collinearity in ecological niche modeling: Confusions and challenges
Ecological niche models are widely used in ecology and biogeography. Maxent is one of the most frequently used niche modeling tools, and many studies have aimed to optimize its performance. However, scholars have conflicting views on the treatment of predictor collinearity in Maxent modeling. Despite this lack of consensus, quantitative examinations of the effects of collinearity on Maxent modeling, especially in model transfer scenarios, are lacking. To address this knowledge gap, here we quantify the effects of collinearity under different scenarios of Maxent model training and projection. We separately examine the effects of predictor collinearity, collinearity shifts between training and testing data, and environmental novelty on model performance. We demonstrate that excluding highly correlated predictor variables does not significantly influence model performance. However, we find that collinearity shift and environmental novelty have significant negative effects on the performance of model transfer. We thus conclude that (a) Maxent is robust to predictor collinearity in model training; (b) the strategy of excluding highly correlated variables has little impact because Maxent accounts for redundant variables; and (c) collinearity shift and environmental novelty can negatively affect Maxent model transferability. We therefore recommend to quantify and report collinearity shift and environmental novelty to better infer model accuracy when models are spatially and/or temporally transferred. Excluding highly correlated variables does not affect Maxent model performance. Model transfer may lead to novel environment and collinearity shift, while both can negatively affect model performance.
Journal Article