Adoptive T cell therapy has achieved dramatic success in a clinic, and the Food and Drug Administration approved two chimeric antigen receptor-engineered T cell (CAR-T) therapies that target ...hematological cancers in 2018. A significant issue faced by CAR-T therapies is the lack of tumor-specific biomarkers on the surfaces of solid tumor cells, which hampers the application of CAR-T therapies to solid tumors. Intracellular tumor-related antigens can be presented as peptides in the major histocompatibility complex (MHC) on the cell surface, which interact with the T cell receptors (TCR) on antigen-specific T cells to stimulate an anti-tumor response. Multiple immunotherapy strategies have been developed to eradicate tumor cells through targeting the TCR-peptide/MHC interactions. Here, we summarize the current status of TCR-based immunotherapy strategies, with particular focus on the TCR structure, activated signaling pathways, the effects and toxicity associated with TCR-based therapies in clinical trials, preclinical studies examining immune-mobilizing monoclonal TCRs against cancer (ImmTACs), and TCR-fusion molecules. We propose several TCR-based therapeutic strategies to achieve optimal clinical responses without the induction of autoimmune diseases.
Increasing studies have found that circular RNAs (circRNAs) are aberrantly expressed and play important roles in the occurrence and development of human cancers. However, the function of circRNAs on ...environmental carcinogen-induced gastric cancer (GC) progression remains poorly elucidated. In the present study, hsa_circ_0110389 was identified as a novel upregulated circRNA in malignant-transformed GC cells through RNA-seq, and subsequent quantitative real-time PCR verified that hsa_circ_0110389 was significantly increased in GC tissues and cells. High hsa_circ_0110389 expression associates with advanced stages of GC and predicts poor prognosis. Knockdown and overexpression assays demonstrated that hsa_circ_0110389 regulates proliferation, migration, and invasion of GC cells in vitro. In addition, hsa_circ_0110389 was identified to sponge both miR-127-5p and miR-136-5p and SORT1 was validated as a direct target of miR-127-5p and miR-136-5p through multiple mechanism assays; moreover, hsa_circ_0110389 sponged miR-127-5p/miR-136-5p to upregulate SORT1 expression and hsa_circ_0110389 promoted GC progression through the miR-127-5p/miR-136-5p-SORT1 pathway. Finally, hsa_circ_0110389 knockdown suppressed GC growth in vivo. Taken together, our findings firstly identify the role of hsa_circ_0110389 in GC progression, which is through miR-127-5p/miR-136-5p-SORT1 pathway, and our study provides novel insight for the identification of diagnostic/prognostic biomarkers and therapeutic targets for GC.
The recycling and reutilization of cotton waste are in line with the sustainable development of society. Therefore, in this work, an environmentally friendly cellulose phosphate ammonium salt was ...synthesized by phosphorylation of cotton waste. Then the cotton fabrics were modified with cellulose phosphate ammonium salt by using the dip–dry–cure technique to obtain flame-retardant cotton fabric. The surface morphology, characteristic functional groups, and elemental components were characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The results indicated that the cellulose phosphate ammonium salt was immobilized onto the cotton fabric through a P–O–C chemical bond. Vertical combustion tests before and after washing showed that the treated cotton fabric had durable flame-retardant properties. Thermogravimetry demonstrated that the treated cotton fabric retained a large amount of residual char and the pyrolysis temperature was significantly earlier than that of the control sample. Compared with the blank sample, the peak of heat release rate and total heat release of the modified fabric was reduced by 90.8% and 84.1%, respectively. Thermogravimetric infrared of flame-retardant cotton fabric proved that cellulose phosphate ammonium salt acted both in the gas and condensed phase during the decomposition of the treated fabric.
Mutants in the gene encoding mitochondrion-associated protein LRPPRC were found to be associated with French Canadian Type Leigh syndrome, a human disorder characterized with neurodegeneration and ...cytochrome c oxidase deficiency. LRPPRC interacts with one of microtubule-associated protein family MAP1S that promotes autophagy initiation and maturation to suppress genomic instability and tumorigenesis. Previously, although various studies have attributed LRPPRC nuclear acid-associated functions, we characterized that LRPPRC acted as an inhibitor of autophagy in human cancer cells. Here we show that liver-specific deletion of LRPPRC causes liver-specific increases of YAP and P27 and decreases of P62, leading to an increase of cell polyploidy and an impairment of autophagy maturation. The blockade of autophagy maturation and promotion of polyploidy caused by LRPPRC depletion synergistically enhances diethylnitrosamine-induced DNA damage, genome instability, and further tumorigenesis so that LRPPRC knockout mice develop more and larger hepatocellular carcinomas and survive a shorter lifespan. Therefore, LRPPRC suppresses genome instability and hepatocellular carcinomas and promotes survivals in mice by sustaining Yap-P27-mediated cell ploidy and P62-HDAC6-controlled autophagy maturation.
Increasing studies confirmed that abnormal lncRNAs expression play a critical role in cervical cancer (CC) development and progression. LncRNA TPT1-AS1, a novel lncRNA, its role and underlying ...mechanisms involved in CC remain largely unknown.
Colony formation, EdU and Transwell assays were used to determine colony formation, proliferation, migration and invasion in vitro. The subcutaneous tumor model and tail vein injection lung metastasis model were performed to check tumor growth and metastasis in vivo. Luciferase activity and RIP experiment were carried out to determine the interaction between miR-324-5p and TPT1-AS1.
We demonstrated for the first time that TPT1-AS1 expression was up-regulated in CC tissues and cell lines. High TPT1-AS1 was significantly correlated with adverse prognostic characteristics and poor survival. TPT1-AS1 overexpression and knockdown experiments revealed that TPT1-AS1 promoted cell colony formation, proliferation, migration, invasion and EMT progression of CC cells in vitro and in vivo. The underlying mechanism indicated that TPT1-AS1 functioned as an endogenous sponge for miR-324-5p in CC cells. Gain- and loss- experiment confirmed that miR-324-5p inhibited cell colony formation, proliferation, migration, invasion and EMT progression of CC cells, and mediated the biological effects of TPT1-AS1. Further investigations confirmed that SP1 was a direct target of miR-324-5p and mediated the effects of TPT1-AS1 and miR-324-5p in CC.
We demonstrated for the first time that TPT1-AS1 as an oncogenic lncRNA in CC progression and as a potential target for CC cure.
Abstract
Background
Circular RNAs (circRNAs) are a new class of noncoding RNAs that have gained increased attention in human tumor research. However, the identification and function of circRNAs are ...largely unknown in the context of gastric cancer (GC). This study aims to identify novel circRNAs and determine their action networks in GC.
Methods
A comprehensive strategy of data mining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and computational biology were conducted to discover novel circRNAs and to explore their potential mechanisms in GC. Promising therapeutic drugs for GC were determined by connectivity map (CMap) analysis.
Results
Six overlapped differentially expressed circRNAs (DECs) were screened from selected microarray and RNA-Seq datasets of GC, and the six DECs were then validated by sanger sequencing and RNase R treatment. Subsequent RT-qPCR analysis of GC samples confirmed decreased expressions of the six DECs (hsa_circ_0000390, hsa_circ_0000615, hsa_circ_0001438, hsa_circ_0002190, hsa_circ_0002449 and hsa_circ_0003120), all of which accumulated preferentially in the cytoplasm. MiRNA binding sites and AGO2 occupation of the six circRNAs were predicted using online databases, and circRNA–miRNA interactions including the six circRNAs and 33 miRNAs were determined. Then, 5320 target genes of the above 33 miRNAs and 1492 differently expressed genes (DEGs) from The Cancer Genome Atlas (TCGA) database were identified. After intersecting the miRNA target genes and the 889 downregulated DEGs, 320 overlapped target genes were acquired. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that these target genes were related to two critical tumor-associated signaling pathways. A protein–protein interaction network with the 320 target genes was constructed using STRING, and fifteen hubgenes (ATF3, BTG2, DUSP1, EGR1, FGF2, FOSB, GNAO1, GNAI1, GNAZ, GNG7, ITPR1, ITPKB, JUND, NR4A3, PRKCB) in the network were identified. Finally, bioactive chemicals (including vorinostat, trichostatin A and astemizole) based on the fifteen hubgenes were identifed as therapeutic agents for GC through the CMap analysis.
Conclusions
This study provides a novel insight for further exploration of the pathogenesis and therapy of GC from the circRNA-miRNA-mRNA network perspective.
Cancer immunotherapy has been regarded as the most significant scientific breakthrough of 2013, and antibody therapy is at the core of this breakthrough. Despite significant success achieved in ...recent years, it is still difficult to target intracellular antigens of tumor cells with traditional antibodies, and novel therapeutic strategies are needed. T cell receptor (TCR)-like antibodies comprise a novel family of antibodies that can recognize peptide/MHC complexes on tumor cell surfaces. TCR-like antibodies can execute specific and significant anti-tumor immunity through several distinct molecular mechanisms, and the success of this type of antibody therapy in melanoma, leukemia, and breast, colon, and prostate tumor models has excited researchers in the immunotherapy field. Here, we summarize the generation strategy, function, and molecular mechanisms of TCR-like antibodies described in publications, focusing on the most significant discoveries.
Endometriosis (EMS) is a "tumour-like" gynaecological disease with distant metastasis, and studies have shown that EMS can induce distant metastasis through vascular vessels, but the driving factors ...and their mechanism are not clear.
We used an EMS animal model and gene knockout technique to explore the role of EMS-induced angiogenesis in EMS metastasis in vivo and in vitro and clarify the role and molecular mechanism of oxLDL in promoting EMS-induced angiogenesis.
We found that microvascular density (MVD) in metastasized ectopic endometrium and eutopic endometrial tissue was higher than that in normal endometrial tissue, and plasma oxLDL was positively correlated with the distant metastasis of EMS. Furthermore, we clarified that oxLDL enhanced the MVD of endometrial tissue by increasing VEGF-A expression and secretion in endometrial cells. Finally, we illustrated the mechanism by which oxLDL promotes VEGF-A expression through the AKT-HIF-1α signalling pathway.
OxLDL is a risk factor promoting distant EMS metastasis by increasing VEGF-A expression and secretion through AKT-HIF-1α signalling. This finding may provide theoretical support and therapeutic targets for the clinical prevention and treatment of EMS.
RASSF1A (Ras association domain family 1 isoform A) is a tumor suppressor and frequently inactivated by promoter hypermethylation in hepatocellular carcinoma (HCC). Autophagy is to degrade misfolded ...or aggregated proteins and dysfunctional organelles. Autophagy defects enhance oxidative stress and genome instability to promote tumorigenesis. Activating autophagy flux by increasing levels of the RASSF1A-interacting microtubule-associated protein 1 S (MAP1S) leads to suppression of HCC in addition to extending lifespans. Here we tested whether RASSF1A itself functions as a HCC suppressor and activates autophagy similarly as MAP1S does. We show that RASSF1A deletion leads to an acceleration of diethylnitrosamine-induced HCC and a 31% reduction of median survival times in mice. RASSF1A enhances autophagy initiation by suppressing PI3K-AKT-mTOR through the Hippo pathway-regulatory component MST1 and promotes autophagy maturation by recruiting autophagosomes on RASSF1A-stabilized acetylated microtubules through MAP1S. RASSF1A deletion causes a blockade of autophagy flux. Therefore, RASSF1A may suppress HCC and improve survival by activating autophagy flux.
Abstract The epigenetic regulation of N6-methyladenosine (m 6 A) has attracted considerable interest in tumor research, but the potential roles of m 6 A regulator-related genes, remain largely ...unknown within the context of gastric cancer (GC) and tumor microenvironment (TME). Here, a comprehensive strategy of data mining and computational biology utilizing multiple datasets based on 28 m 6 A regulators (including novel anti-readers) was employed to identify m 6 A regulator-related genes and patterns and elucidate their underlying mechanisms in GC. Subsequently, a scoring system was constructed to evaluate individual prognosis and immunotherapy response. Three distinct m 6 A regulator-related patterns were identified through the unsupervised clustering of 56 m 6 A regulator-related genes (all significantly associated with GC prognosis). TME characterization revealed that these patterns highly corresponded to immune-inflamed, immune-excluded, and immune-desert phenotypes, and their TME characteristics were highly consistent with different clinical outcomes and biological processes. Additionally, an m 6 A-related scoring system was developed to quantify the m 6 A modification pattern of individual samples. Low scores indicated high survival rates and high levels of immune activation, whereas high scores indicated stromal activation and tumor malignancy. Furthermore, the m 6 A-related scores were correlated with tumor mutation loads and various clinical traits, including molecular or histological subtypes and clinical stage or grade, and the score had predictive values across all digestive system tumors and even in all tumor types. Notably, a low score was linked to improved responses to anti-PD-1/L1 and anti-CTLA4 immunotherapy in three independent cohorts. This study has expanded the important role of m 6 A regulator-related genes in shaping TME diversity and clinical/biological traits of GC. The developed scoring system could help develop more effective immunotherapy strategies and personalized treatment guidance.
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