Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay.

Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan-Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

Cancer-derived non-coding RNAs endow tumor microenvironment with immunosuppressive properties.

Non-coding RNAs (ncRNAs) have attracted extensive attention due to their vital roles in tumorigenesis and progression, especially in the immunotherapy resistance. Tumor immunotherapy resistance is a crucial factor hindering the efficacy of tumor treatments, which can be largely attributed to the immunosuppressive properties of tumor microenvironment. Current studies have revealed that cancer-derived ncRNAs are involved in the formation of tumor immunosuppressive microenvironment (TIME) through multiple ways. They not only promote the expression of immune checkpoint ligands (e.g., PD-L1, CD47, Gal-9, and CD276) on cancer cell surfaces, but also enhance the secretion of immunosuppressive cytokines (e.g., TGF-ß, IL-6, IL-10, VEGF, and chemokines). Cancer-derived ncRNAs could also be transferred into surrounding immune-related cells through extracellular vesicles, thereby inhibiting the cytotoxicity of CD8+ T cells and NK cells, restraining the DC-mediated antigen presentation, inducing the immunosuppressive phenotype transformation of TAMs and CAFs, and enhancing the immunosuppressive functions of Tregs and MDSCs. Herein, we summarize the roles of cancer-derived ncRNAs in regulating TIME formation and further explore their potential applications as prognostic biomarkers and immunotherapeutic targets, which will help us to address the TIME-mediated immunotherapy resistance in the future. This article is categorized under: RNA in Disease and Development > RNA in Disease Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs.

The emerging roles of SUMOylation in the tumor microenvironment and therapeutic implications.

Tumor initiation, progression, and response to therapies depend to a great extent on interactions between malignant cells and the tumor microenvironment (TME), which denotes the cancerous/non-cancerous cells, cytokines, chemokines, and various other factors around tumors. Cancer cells as well as stroma cells can not only obtain adaption to the TME but also sculpt their microenvironment through a series of signaling pathways. The post-translational modification (PTM) of eukaryotic cells by small ubiquitin-related modifier (SUMO) proteins is now recognized as a key flexible pathway. Proteins involved in tumorigenesis guiding several biological processes including chromatin organization, DNA repair, transcription, protein trafficking, and signal conduction rely on SUMOylation. The purpose of this review is to explore the role that SUMOylation plays in the TME formation and reprogramming, emphasize the importance of targeting SUMOylation to intervene in the TME and discuss the potential of SUMOylation inhibitors (SUMOi) in ameliorating tumor prognosis.

Correlative dual-alternating-color photoswitching fluorescence imaging and AFM enable ultrastructural analyses of complex structures with nanoscale resolution.

There is a practical motivation for correlating different types of microscopy for revealing complementary information of ultrastructures with resolution beyond the diffraction limit. The correlative microscopy strategy based on the combination of super-resolution fluorescence imaging with atomic force microscopy (AFM) is expected to provide both the specificity and three-dimensional structural information of nanomaterials. Herein we synthesized a dual-alternating-color photoswitchable fluorescent probe based on a naphthalimide-spiropyran dyad (NI-SP) and explored the capability of such correlative microscopy for visualizing nanostructures with complex structural hierarchy. NI-SP underwent reversible photoswitching between green and red fluorescence based on a reversible photochemical reaction and such reaction-linked correlation between two distinct types of fluorescence signals intrinsically enabled mutual authentication in super-resolution fluorescence imaging. Additionally, such correlative microscopy also demonstrated mutual complementation between different pieces of structural information of the target acquired via fluorescence imaging and AFM, respectively, in which the former reveals spatial distribution of fluorescent dyes in the nanoscale polymer fibroid micelles while the latter maps the topographical structure of the target with complex structural hierarchy. The results obtained in this work proclaimed that the combination of such correlative microscopy with our NI-SP probe is an effective modality for ultrastructural analysis and has future applications in various complex systems such as tissue/organ imaging.