Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application.

The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, and immunosuppression. One of the most common RNA modifications, N6-methyladenosine (m6A) methylation, is widely involved in the regulation of physiological and pathological processes, including tumor development. Compelling evidence indicates that m6A methylation regulates transcription and protein expression through shearing, export, translation, and processing, thereby participating in the dynamic evolution of TME. Specifically, m6A methylation-mediated adaptation to hypoxia, metabolic dysregulation, and phenotypic shift of immune cells synergistically promote the formation of an immunosuppressive TME that supports tumor proliferation and metastasis. In this review, we have focused on the involvement of m6A methylation in the dynamic evolution of tumor-adaptive TME and described the detailed mechanisms linking m6A methylation to change in tumor cell biological functions. In view of the collective data, we advocate treating TME as a complete ecosystem in which components crosstalk with each other to synergistically achieve tumor adaptive changes. Finally, we describe the potential utility of m6A methylation-targeted therapies and tumor immunotherapy in clinical applications and the challenges faced, with the aim of advancing m6A methylation research.

TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment.

As an important component of the immunosuppressive tumor microenvironment (TME), it has been established that mesenchymal stem cells (MSCs) promote the progression of tumor cells. MSCs can directly promote the proliferation, migration, and invasion of tumor cells via cytokines and chemokines, as well as promote tumor progression by regulating the functions of anti-tumor immune and immunosuppressive cells. MSCs-derived extracellular vesicles (MSCs-EVs) contain part of the plasma membrane and signaling factors from MSCs; therefore, they display similar effects on tumors in the immunosuppressive TME. The tumor-promoting role of macrophage migration inhibitory factor (MIF) in the immunosuppressive TME has also been revealed. Interestingly, MIF exerts similar effects to those of MSCs in the immunosuppressive TME. In this review, we summarized the main effects and related mechanisms of tumor-associated MSCs (TA-MSCs), TA-MSCs-EVs, and MIF on tumors, and described their relationships. On this basis, we hypothesized that TA-MSCs-EVs, the MIF axis, and TA-MSCs form a positive feedback loop with tumor cells, influencing the occurrence and development of tumors. The functions of these three factors in the TME may undergo dynamic changes with tumor growth and continuously affect tumor development. This provides a new idea for the targeted treatment of tumors with EVs carrying MIF inhibitors.

High-speed rail model reveals the gene tandem amplification mediated by short repeated sequence in eukaryote.

The occurrence of gene duplication/amplification (GDA) provide potential material for adaptive evolution with environmental stress. Several molecular models have been proposed to explain GDA, recombination via short stretches of sequence similarity plays a crucial role. By screening genomes for such events, we propose a "SRS (short repeated sequence) *N + unit + SRS*N" amplified unit under USCE (unequal sister-chromatid exchange) for tandem amplification mediated by SRS with different repeat numbers in eukaryotes. The amplified units identified from 2131 well-organized amplification events that generate multi gene/element copy amplified with subsequent adaptive evolution in the respective species. Genomic data we analyzed showed dynamic changes among related species or subspecies or plants from different ecotypes/strains. This study clarifies the characteristics of variable copy number SRS on both sides of amplified unit under USCE mechanism, to explain well-organized gene tandem amplification under environmental stress mediated by SRS in all eukaryotes.

Application of engineered extracellular vesicles for targeted tumor therapy.

All cells, including prokaryotes and eukaryotes, could release extracellular vesicles (EVs). EVs contain many cellular components, including RNA, and surface proteins, and are essential for maintaining normal intercellular communication and homeostasis of the internal environment. EVs released from different tissues and cells exhibit excellent properties and functions (e.g., targeting specificity, regulatory ability, physical durability, and immunogenicity), rendering them a potential new option for drug delivery and precision therapy. EVs have been demonstrated to transport antitumor drugs for tumor therapy; additionally, EVs' contents and surface substance can be altered to improve their therapeutic efficacy in the clinic by boosting targeting potential and drug delivery effectiveness. EVs can regulate immune system function by affecting the tumor microenvironment, thereby inhibiting tumor progression. Co-delivery systems for EVs can be utilized to further improve the drug delivery efficiency of EVs, including hydrogels and liposomes. In this review, we discuss the isolation technologies of EVs, as well as engineering approaches to their modification. Moreover, we evaluate the therapeutic potential of EVs in tumors, including engineered extracellular vesicles and EVs' co-delivery systems.

Mesenchymal stem cell-derived exosome: A tumor regulator and carrier for targeted tumor therapy.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that have the ability to differentiate into multiple cell types. Several studies have shown that exosomes secreted by MSCs (MSCs-Exo) play an important role in tumor growth, angiogenesis, invasion, and drug resistance. However, contradictory results have suggested that MSCs-Exo can also suppress tumors through specific mechanisms, such as regulating immune responses and intercellular signaling. Consequently, the relationship between MSCs-Exo and tumors remains controversial. However, it is undeniable that exosomes, as natural vesicles, can be excellent drug carriers and show promise for application in targeted tumor therapy. Here, we review the current knowledge regarding the involvement of MSCs-Exo in tumor progression and their potential as drug delivery systems in targeted therapy. We argue that MSCs-Exo can be used as safe carriers of antitumor drugs.

HDAC3-dependent transcriptional repression of FOXA2 regulates FTO/m6A/MYC signaling to contribute to the development of gastric cancer.

As one of the deadliest malignancies, gastric cancer (GC) is often accompanied by a low 5-year survival following initial diagnosis, which accounts for a substantial proportion of cancer-related deaths each year worldwide. Altered epigenetic modifications of cancer oncogenes and tumor suppressor genes emerge as novel mechanisms have been implicated the pathogenesis of GC. In the current study, we aim to elucidate whether histone deacetylase 3 (HDAC3) exerts oncogenic role in GC, and investigate the possible mechanism. Initially, we collected 64 paired cancerous and noncancerous tissues surgically resected from GC patients. Positive expression of HDAC3, FTO, and MYC in the tissues was measured using Immunohistochemistry. Meanwhile, GC cell line BGC-823/AGS was selected and treated with lentivirus vectors for alteration of HDAC3, FTO, or FOXA2 expressions, followed by detection on mRNA and protein levels of HDAC3, FOXA2, FTO, and MYC using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot assays. The results demonstrated that the expressions of HDAC3, FTO and MYC were upregulated, while FOXA2 expression was downregulated in GC tissues and cells. After that, the cell viability, migration, and invasion of GC cells were assessed by CCK-8 and Transwell assays, revealing that HDAC3 accelerated GC cell viability, migration and invasion by degrading FOXA2. Subsequently, the binding relationship among HDAC3, FOXA2, FTO, and MYC was assessed by assays of immunoprecipitation, dual-luciferase reporter gene, and chromatin immunoprecipitation assay. Methylation of m6A mRNA in GC cells was detected via gene-specific m6A qPCR and dot-blot assays. The transcription factor FOXA2 was found to bind to the FTO gene promoter and decreased its expression, while FTO stabilized MYC mRNA by reducing m6A methylation of MYC in GC cells. In addition, HDAC3 was observed to maintain the FTO/m6A/MYC signaling and regulated GC progression, which was also supported by in vivo animal study data of GC cell tumorigenesis in nude mice. These key observations uncover the tumor-initiating activities of HDAC3 in GC through its regulation on FOXA2-mediated FTO/m6A/MYC axis, highlighting the potential of therapeutically targeting epigenetic modifications to combat GC.

Glycyrrhetinic Acid Functionalized Nanoparticles for Drug Delivery to Liver Cancer.

Liver cancer is one of the most common human malignancies worldwide. Currently, chemotherapy remains the cornerstone for liver cancer treatment. However, chemotherapy often causes many side effects, such as leukopenia, digestive reaction, hepatic and renal dysfunction and hair loss. Recently, great advances in nanoparticles-based liver-targeting drug delivery systems have been developed to overcome these problems. Glycyrrhetinic acid (GA), a pentacyclic triterpenoid extracted from the root of licorice, and has been widely used in liver cancer therapy. GA is capable of binding to hepatocytes via the specific site of GA-R on the surface of hepatic parenchymatous cells. From this prospective, this review highlights GA-mediated nanoparticles liver-targeting drug delivery systems from different polymer materials.

Pattern of myopia progression in Chinese medical students: a two-year follow-up study.

OBJECTIVE: To estimate myopia progression during a 2-year period in a cohort of medical students in mainland China. METHODS: A 2-year longitudinal study was performed among 2,053 Chinese medical students (mean age 18.27 years, 1,057 females and 996 males) with their refraction measured at the start and the end of this study by autorefraction in cycloplegia. Information about the students' age, gender, home origin (urban or rural), and eye history was obtained through a questionnaire. RESULTS: The overall prevalence of myopia increased significantly from 78.5 % to 84.1 % (P < 0.001, right eye) and the mean refractive error increased significantly from -2.52 ± 2.13 D to -2.84 ± 2.16 D (P < 0.001, right eye) over the 2 years. The rural students had a significantly greater increase in prevalence of myopia and the refractive error towards myopia than the urban ones (P < 0.01 and 0.001 respectively). Females had a significantly faster myopic shift than males (P < 0.001). Participants with myopia initially showed the fastest myopic shift among the initial refractive groups. The relationship between the initial refractive error and the myopic shift remained significant after adjusting for sex and home origin (P < 0.05). CONCLUSIONS: Myopia progressed as increase in prevalence of myopia and change in refraction towards myopia in this study population. Participants who were more myopic at baseline were more likely to have myopia progression. Female and rural participants had a faster myopic shift compared to male and urban ones, respectively.

Wnt signaling pathway is involved in the pathogenesis of amyotrophic lateral sclerosis in adult transgenic mice.

OBJECTIVE: Our aim was to examine the change in expression of molecules involved in Wnt signaling in the pathogenesis of amyotrophic lateral sclerosis (ALS) in adult transgenic mice, and to reveal the relationship between the Wnt signaling pathway and the pathogenesis of ALS. METHODS: We determined the expression of Wnt2, Wnt7a, and GSK-3beta in the spinal cord of SOD1(G93A) ALS transgenic mice at different ages using reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemistry. Using double labeling, we determined whether Wnt2, Wnt7a, and GSK-3beta were colocalized with beta-tubulin III, for neurons, or glial fibrillary acidic protein, for mature astrocytes. RESULTS: Wnt2, Wnt7a mRNA and protein in the spinal cord of ALS mice were upregulated and compared with wild-type mice. Phospho-GSK-3beta (Ser 9) protein levels in the spinal cord of ALS mice were upregulated. Moreover, the immunoreactivity of Wnt2, Wnt7a, and phospho-GSK-3beta (Ser 9) was strong in ALS mice but weak in wild-type mice at the same time points. Double immunofluorescence labeling showed that Wnt2 and Wnt7a were expressed in both neurons and astrocytes, whereas GSK-3beta was expressed only in neurons. Most of the double positive cells were located in the ventral horns of the gray matter, the locus of neurodegeneration. DISCUSSION: Neurodegeneration upregulated the expression of Wnt2 and Wnt7a in the spinal cord of ALS mice, which in turn activated Wnt signaling, and accordingly inhibited GSK-3beta activity in disease progression of ALS in adult transgenic mice; this could regulate the downstream gene of the Wnt signaling pathway and promote cell proliferation.