Spatial epigenome-transcriptome comapping technology.

Spatial omics facilitate an in-depth understanding of cell states and cell interactions. Recent work by Zhang et al. simultaneously seizes spatial epigenetic priming, differentiation, and gene regulation at nearly single-cell resolution by developing an epigenome-transcriptome comapping technology. This work displays how epigenetic features influence cell dynamics and transcriptional phenotypes at spatial and genome-wide levels.

Reclassification of Hepatocellular Cancer With Neural-Related Genes.

Neural infiltration is a critical component of the tumor microenvironment; however, owing to technological limitations, its role in hepatocellular cancer remains obscure. Herein, we obtained the RNA-sequencing data of liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas database and performed a series of bioinformatic analyses, including prognosis analysis, pathway enrichment, and immune analysis, using the R software packages, Consensus Cluster Plus and Limma. LIHC could be divided into two subtypes according to the expression of neural-related genes (NRGs); moreover, there are statistic differences in the prognosis, stage, and immune regulation between the two subtypes. The prognostic model showed that high expression of NRGs correlated with a poor survival prognosis (P<0.05). Further, CHRNE, GFRA2, GFRA3, and GRIN2D was significantly correlated with LIHC clinical prognosis, clinical stage, immune infiltration, immune response, and vital signaling pathways. There was nerve-cancer crosstalk in LIHC. A reclassification of LIHC based on NRG expression may prove beneficial to clinical practice. CHRNE, GFRA2, GFRA3, and GRIN2D may serve as potential biomarker for liver cancer prognosis or immune response.

A Pan-Cancer Analysis of the Oncogenic and Immunogenic Role of m6Am Methyltransferase PCIF1.

BACKGROUND: Phosphorylated CTD-interacting factor 1 (PCIF1) is identified as the only known methyltransferase of N6,2'-O-dimethyladenosine (m6Am) in mRNA. However, its oncogenic and immunogenic role in cancer research is at an initial stage. METHODS: Herein, we carried out a pan-cancer analysis of PCIF1, with a series of datasets (e.g., TIMER2.0, GEPIA2, cBioPortal). RESULTS: PCIF1 expression was higher in most cancers than normal tissues and was discrepant across pathological stages. Highly expressed PCIF1 was positively correlated with overall survival (OS) or disease-free survival (DFS) of some tumors. PCIF1 expression had a positive correlation with CD4+ T-cell infiltration in kidney renal clear cell carcinoma (KIRC), CD8+ T cells, macrophages, and B cells in thyroid carcinoma (THCA), and immune checkpoint genes (ICGs) in LIHC but a negative correlation with CD4+ T cells, neutrophils, myeloid dendritic cells, and ICGs in THCA. It also affected tumor mutational burden (TMB) and microsatellite instability (MSI) of most tumors. CONCLUSION: PCIF1 expression was correlated with cancer prognosis and immune infiltration, suggesting it to be a potential target for cancer therapy.

Immunogenic Cell Death-Based Cancer Vaccines.

Cancer immunotherapy has achieved great advancement in the past decades. Whereas, its response is largely limited in immunologically cold tumors, in an urgent need to be solve. In recent years, an increasing number of studies have shown that inducing immunogenic cell deaths (ICDs) is an attractive approach to activate antitumor immunity. Upon specific stress, cancer cells undergo ICDs and dying cancer cells release danger associated molecular patterns (DAMPs), produce neoantigens and trigger adaptive immunity. ICDs exert a cancer vaccine-like effect and Inducement of ICDs mimics process of cancer vaccination. In this review, we propose a concept of ICD-based cancer vaccines and summarize sources of ICD-based cancer vaccines and their challenges, which may broaden the understandings of ICD and cancer vaccines in cancer immunotherapy.

Exosomes: Powerful weapon for cancer nano-immunoengineering.

Cancer immunotherapy (CIT) that targets the tumor immune microenvironment is regarded as a revolutionary advancement in the fight against cancer. The success and failure of CIT are due to the complexity of the immunosuppressive microenvironment. Cancer nanomedicine is a potential adjuvant therapeutic strategy for immune-based combination therapy. Exosomes are natural nanomaterials that play a pivotal role in mediating intercellular communications and package delivery in the tumor microenvironment. They affect the immune response or the effectiveness of immunotherapy. In particular, exosomal PD-L1 promotes cancer progression and resistance to immunotherapy. Exosomes possess high bioavailability, biological stability, targeting specificity, low toxicity, and immune characteristics, which indicate their potential for cancer therapy. They can be engineered to act as effective cancer therapeutic tools that activate anti-tumor immune response and start immune surveillance. In the current review, we introduce the role of exosomes in a tumor immune microenvironment, highlight the application of engineered exosomes to CIT, and discuss the challenges and prospects for clinical application.

Microglia in neurodegenerative diseases.

A major feature of neurodegeneration is disruption of central nervous system homeostasis, during which microglia play diverse roles. In the central nervous system, microglia serve as the first line of immune defense and function in synapse pruning, injury repair, homeostasis maintenance, and regulation of brain development through scavenging and phagocytosis. Under pathological conditions or various stimulations, microglia proliferate, aggregate, and undergo a variety of changes in cell morphology, immunophenotype, and function. This review presents the features of microglia, especially their diversity and ability to change dynamically, and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration. This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.

The updated landscape of tumor microenvironment and drug repurposing.

Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Nonetheless, the clinical efficacy of therapeutic strategies targeting TME, especially the specific cells or pathways of TME, remains unsatisfactory. Classifying the chemopathological characteristics of TME and crosstalk among one another can greatly benefit further studies exploring effective treating methods. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. We then summarize conventional drugs including aspirin, celecoxib, ß-adrenergic antagonist, metformin, and statin in new antitumor application. These drugs are considered as viable candidates for combination therapy due to their antitumor activity and extensive use in clinical practice. We also provide our outlook on directions and potential applications of TME theory. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.

Organoids: A Platform Ready for Glioblastoma Precision Medicine?

Patient-derived organoids can recapitulate parental tumor heterogeneity. In a recent study in Cell, Jacob et al. cultivated glioblastoma organoids (GBOs) to mimic tumor heterogeneity and chimeric antigen receptor (CAR)-T cell immunotherapy, applied it for xenograft establishment and drug testing, and generated a biobank for the timely start of post-operation therapy.

Osthole induces cell cycle arrest and apoptosis in head and neck squamous cell carcinoma by suppressing the PI3K/AKT signaling pathway.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common lethal tumors with a high recurrence rate and low survival rate. Therefore, an urgent need exists for novel and effective treatment strategies for HNSCC patients. METHODS: Osthole, a natural ingredient extracted from Cnidium monnieri (L.) 'Cusson', has multiple pharmacological effects including antineoplastic activity. Regrettably, the antineoplastic effect of osthole in HNSCC cells remains undefined. We utilize in vitro assays to assess the anti-proliferative effects of osthole in HNSCC cells and tumorigenesis assays using FaDu cells in murine HNSCC models to assess in vivo function. Moreover, the possible molecular mechanisms of Osthole on HNSCC cells was also investigated. RESULTS: Our findings show that the anti-proliferation effect of osthole might function through induction of cell cycle arrest (G2/M phase) and apoptosis in HNSCC. Osthole could also down-regulating the protein level of cell cycle and apoptosis related proteins, such as Bcl-2, PARP1, Survivin, CyclinB1 and Cdc2, while up-regulating expression of Cleaved Caspase3/9, Cleaved PARP1 and Bax. Similarly, osthole suppressed the in vivo growth of FaDu cells in a subcutaneous tumor model. In terms of mechanism, our data show that osthole can suppress the PI3K/AKT pathway. CONCLUSIONS: In the current study, our in vitro and in vivo assay showed the suppressive effect of Osthole on HNSCC cells through induce cell cycle arrest (G2/M phase) and apoptosis. Moreover, the action mechanisms of Osthole on proliferation related signaling pathways was disclosed. Our present study suggests that osthole might be used as an effective therapeutic agent for patients with HNSCC.

Long Non-coding RNA DANCR as an Emerging Therapeutic Target in Human Cancers.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of numerous biological processes, especially in cancer development. Aberrantly expressed and specifically located in tumor cells, they exert distinct functions in different cancers via regulating multiple downstream targets such as chromatins, RNAs, and proteins. Differentiation antagonizing non-protein coding RNA (DANCR) is a cytoplasmic lncRNA that generally works as a tumor promoter. Mechanically, DANCR promotes the functions of vital components in the oncogene network by sponging their corresponding microRNAs or by interacting with various regulating proteins. DANCR's distinct expression in tumor cells and collective involvement in pro-tumor pathways make it a promising therapeutic target for broad cancer treatment. Herein, we summarize the functions and molecular mechanism of DANCR in human cancers. Furthermore, we introduce the use of CRISPR/Cas9, antisense oligonucleotides and small interfering RNAs as well as viral, lipid, or exosomal vectors for onco-lncRNA targeted treatment. Conclusively, DANCR is a considerable promoter of cancers with a bright prospect in targeted therapy.

Curaxin CBL0137 Exerts Anticancer Activity via Diverse Mechanisms.

Chemotherapy with or without radiation remains the first choice for most cancers. However, intolerant side effects and conventional drug resistance restrict actual clinical efficacy. Curaxin CBL0137 is designed to regulate p53 and nuclear factor-κB simultaneously and to prevent the resistance caused by a single target. Functionally, CBL0137 exhibits an antitumor activity in multiple cancers, including glioblastoma, renal cell carcinoma, melanoma, neuroblastoma, and small cell lung cancer (SCLC). Mechanistically, CBL0137 is originally identified to act by facilitates chromatin transcription (FACT) complex. Further investigations reveal that several pathways, such as NOTCH1 and heat shock factor 1 (HSF1), are involved in the process. CBL0137 has been reported to target cancer stem cells (CSCs) and enhance chemotherapy/monotherapy efficacy. The translational advance of CBL0137 into clinical practice is expected to provide a promising future for cancer treatment.

Ubiquitin-specific protease 22 acts as an oncoprotein to maintain glioma malignancy through deubiquitinating B cell-specific Moloney murine leukemia virus integration site 1 for stabilization.

Ubiquitin-specific protease 22 (USP22) is a member of the "death-from-cancer" signature, which plays a key role in cancer progression. Previous evidence has shown that USP22 is overexpressed and correlates with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy, especially cancer stemness, remain elusive. Herein, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlate with BMI1 at the post-translational level only rather than at the transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis shows that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of the USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially in those with elevated BMI1 expression.

Organoids: An intermediate modeling platform in precision oncology.

Cancer harbors variable heterogeneity and plasticity. Thus far, our comprehension is greatly based on cell lines, organoids, and patient-derived tumor xenografts (PDTXs). Organoids are a three-dimensional in vitro culture platform constructed from self-organizing stem cells. They can almost accurately recapitulate tumor heterogeneity and microenvironment "in a dish," which surpass established cell lines and are not as expensive and time-consuming as PDTXs. As an intermediate model, tumor organoids are also used to study the fundamental issues of tumorigenesis and metastasis. They are specifically applied for drug testing and stored as "living biobanks." In this review, we highlight the translational applications of organoid technologies in tumor research and precision medicine, discuss the advantages and limitations compared with other mentioned methods, and provide our outlook on its future.

Live or let die: Neuroprotective and anti-cancer effects of nutraceutical antioxidants.

Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric disorders and cancers, in addition to inherited factors. Currently, natural products or nutraceuticals (commonly called medical foods) are increasingly employed for adjunctive therapy of these patients. However, the potential molecular mechanisms of the nutrient efficacy remain elusive. In this review, we summarized the neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly through the differential modulations of redox homeostasis. In addition, the balance between reactive oxygen species (ROS) production and ROS elimination was manipulated by multiple molecular mechanisms, including cell signaling pathways, inflammation, transcriptional regulation and epigenetic modulation, which were involved in the therapeutic potential of nutraceutical antioxidants against neurological diseases and cancers. We specifically proposed that ROS scavenging was integral in the neuroprotective potential of nutraceuticals, while alternation of ROS level (either increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted the anti-cancer property of these compounds. We also hypothesized that ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death, was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting ferroptosis is advantageous to develop new nutraceuticals with more effective and lower adverse reactions for curing patients with neuropsychiatric diseases or carcinomas.

Reprogramming of the Tumor in the Hypoxic Niche: The Emerging Concept and Associated Therapeutic Strategies.

Hypoxia exerts a profound impact on diverse aspects of cancer biology. Increasing evidence has revealed novel functions of hypoxia in cancer cell epigenomics, epitranscriptomics, metabolism, and intercellular communication, all hotspots of cancer research. Several drugs have been developed to target intratumoral hypoxia and have entered clinical trials to treat refractory tumors. However, direct targeting of hypoxia signaling still has limitations in the clinic with regard to cancer progression and resistance to therapy. Comprehensive understanding of the molecular mechanisms by which hypoxia reshapes tumors and their microenvironment, as well as how tumor cells adapt to and thrive in hypoxic conditions, will therefore continue to be a focus of cancer research and will provide new directions for hypoxic tumor treatment.

The bad seed gardener: Deubiquitinases in the cancer stem-cell signaling network and therapeutic resistance.

Tumors are comprised of highly heterogeneous populations of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These rare cancer stem cells (CSCs) have been regarded as the "bad seeds" accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. CSC-targeted therapy seems to be a better avenue for radical cure of cancer. Deubiquitinases (DUBs), specifically disassembling ubiquitin chains, have been demonstrated to play an important role in rigidly maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis in normal circumstances. Dysfunction or deregulation of DUBs always leads to a series of disorders, even malignant transformation. Despite the accumulative evidence that DUB inhibitors in cancer remedy mainly target the tumor bulk, side effects like toxicity and resistance are still hard nuts to crack. In this article, we review the concept of ubiquitin proteasome system (UPS) and hallmarks of CSCs related to tumor obstinacy. We primarily summarize the CSC-related factors and signaling pathways and focus on the function of DUBs on biological traits of CSCs. We also illustrate the opportunities and challenges for the application of DUB inhibitors in the CSC-targeted therapy. Finally, we discuss the complexity of cancer stem cell hierarchy complexity and argue that a combination therapy for both CSCs and non-CSCs should be a desirable option.

Clinical significance of epigenetic silencing and re-expression of O6-methylguanine-DNA methyltransferase using epigenetic agents in laryngeal carcinoma.

The aim of the present study was to investigate the association between O6-methylguanine-DNA methyltransferase (MGMT) gene expression levels, and DNA methylation status and histone modifications in laryngeal squamous cell carcinoma (LSCC). Chromatin immunoprecipitation, methylation-specific polymerase chain reaction (PCR), and reverse transcription-quantitative PCR were performed to analyze histone modifications, DNA methylation status and mRNA expression levels in the promoter region of the MGMT gene in laryngeal carcinoma HEp-2 cells, as well as in 50 paired healthy and LSCC tissue samples. The present study demonstrated that treatment of HEp-2 cells with 5-aza-2'-deoxycytidine (Aza), a DNA methyltransferase inhibitor, significantly upregulated MGMT mRNA expression levels, reduced MGMT DNA methylation, reduced MGMT histone H3 lysine 9 (H3K9) di-methylation, and increased MGMT histone H3 lysine 4 di-methylation without a significant change in H3K9 acetylation. Trichostatin A (TSA), a histone deacetylase inhibitor, marginally upregulated MGMT mRNA expression levels without affecting the DNA methylation status, or H3K9 or H3K4 di-methylation, however, TSA treatment caused a significant increase in H3K9 acetylation. Furthermore, Aza and TSA combination treatment produced a synergistic effect. In the LSCC samples, the rate of DNA methylation in the MGMT gene was 54%, compared with 24% in the healthy control group (P<0.05). Therefore, data from the present study indicates that MGMT may serve as a novel therapeutic target in the treatment of LSCC.

[DNA methylation and histone modification relate to RASSF1A gene deletion in laryngeal carcinoma tissues].

OBJECTIVE: To investigate the relationship between RASSF1A gene expression and DNA methylation or histone modification in laryngeal carcinoma tissues. METHODS: Chromatin immunoprecipitation (ChIP), methylation specific polymerase chain reaction (MSP) and realtime quantitative reverse transcription polymerase chain reaction (realtime RT-PCR) were used to analyze RASSF1A gene promoter region histone H3 lysine 9 methylation, H3 lysine 4 methylation, H3 lysine 9 acetylation, DNA methylation, and RASSF1A gene expression in laryngeal carcinoma tissue of 50 cases. RESULTS: DNA methylation rate of gene RASSF1A was 62% in 50 cases of laryngeal carcinoma, but no DNA methylation was found in normal control group, with a significant difference (χ(2) = 15.381, P < 0.05). DNA methylation had no correlation with age, gender, differentiation degree, T stage, pathological type and lymph node metastasis (P > 0.05). The affection of DNA methylation group was more than unmethylation group to expression of gene RASSF1A (t = -3.108, P < 0.01). There was positive correlation between RASSF1A deletion and gene hypermethylation or between H3 lysine 9 methylation of RASSF1A gene promoter and DNA methylation in laryngeal carcinoma tissue(r = 0.816, P < 0.05), but there was negative correlation between H3 lysine 4 methylation of RASSF1A gene promoter and DNA methylation (r = -0.837, P < 0.05) and no correlation between H3 lysine 9 acetylation and DNA methylation (r = -0.383, P > 0.05). CONCLUSIONS: Laryngeal tumor suppressor gene RASSF1A promoter methylation is a key factor down-regulating the gene expression, and histone modifications also plays an important role in tumor development.