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.

Circular RNA Circ_0000119 promotes gastric cancer progression via circ_0000119/miR-502-5p/MTBP axis.

Dysregulated circular RNAs (circRNAs) are significantly related with tumor initiation and progression. However, biological activity and potential molecular mechanism of circRNAs in gastric cancer (GC) deserve further exploration. We carried out total RNA sequencing and acquired the expression profiles of circRNAs. Quantitative real-time PCR as well as RNA in situ hybridization helped to validate circ_0000119 dysregulation. Various in vitro experiments were utilized to investigate the biological activities of circ_0000119 in GC, and the clinical relation of circ_0000119 in vivo was identified through nude mouse xenograft models. Finally, the molecular mechanism of circ_0000119 was clarified via luciferase assays, western blot, and rescue experiments. Compared with adjacent normal tissues, the study found an increase in the expression of circ_0000119 as well as its host linear gene MAN1A2 in GC tissues. Circ_0000119 overexpression promoted proliferation and migration of GC cells in vitro and in vivo, whereas circ_0000119 suppression had the opposite effect. Mechanistically, circ_0000119 sponged miR-502-5p which played an inhibitory role in tumors. Furthermore, we found that miR-502-5p alleviated GC progression through targeting MTBP and downregulating its expression at mRNA and protein levels. In conclusion, our findings reveal a new regulatory mechanism for circ_0000119, which sponges the miR-502-5p, suppresses MTBP expression, and finally promotes GC 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.

LINC00659 cooperated with ALKBH5 to accelerate gastric cancer progression by stabilising JAK1 mRNA in an m6 A-YTHDF2-dependent manner.

BACKGROUND: N6-methyladenosine (m6 A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m6 A in noncoding RNAs makes a difference, and the aberrant expression of m6 A-associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known. METHODS: The quantitative real-time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP-seq), RIP and RNA pull-down assays were performed to examine the influence of LINC00659 on the ALKBH5-JAK1 interaction. RESULTS: ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m6 A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m6 A-YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC. CONCLUSION: ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m6 A-YTHDF2-dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

Savolitinib monotherapy exerted significant benefit in a non-small cell lung cancer patient with osimertinib resistance harboring primary EGFR L858R mutation and MET amplification: a case report.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved response in all stages of patients with EGFR positive mutations in nonsmall cell lung cancer. However, the primary resistance mechanism of EGFR-TKIs has not been thoroughly revealed. Here, we described a case of a 64-year-old male with lung adenocarcinoma presented primary resistance on osimertinib combined with bevacizumab and platinum-based chemotherapy, next-generation sequencing revealed EGFR exon 21 L858R mutation and MET gene amplification. Afterward, savolitinib monotherapy was started until now, and the treatment was temporarily successful, the last follow-up clinical evaluation was near complete response, the progression-free survival has over 7 months. Our case highlights that EGFR-TKIs may be not the optimal choice for lung adenocarcinoma with primary EGFR -sensitive mutation with MET amplification simultaneously, whereas MET inhibitor alone may be an effective treatment option. In clinical practice, we should fully consider the possibility of primary resistance in EGFR-TKIs administration.

Hsa_circ_0007967 promotes gastric cancer proliferation through the miR-411-5p/MAML3 axis.

Circular RNAs are an important kind of noncoding RNAs and involved in cancerogenesis, but the specific mechanism between gastric cancer and circRNAs needs further study. Hsa_circ_0007967 was selected by RNA sequencing. Here, hsa_circ_0007967 was highly expressed in gastric cancer tissues than adjacent normal tissues. Overexpressing hsa_circ_0007967 promoted gastric cancer cell proliferation in vitro and in vivo, while suppression of hsa_circ_0007967 inhibited gastric cancer cell proliferation in vitro and in vivo. Mechanistically, hsa_circ_0007967 sponged miR-411-5p to increase MAML3 expression. Overall, hsa_circ_0007967 is a promising biomarker for gastric cancer diagnosis and a potential molecule for gastric cancer treatment.

The evolving landscape of N6-methyladenosine modification in the tumor microenvironment.

The tumor microenvironment (TME), controlled by intrinsic mechanisms of carcinogenesis and epigenetic modifications, has, in recent years, become a heavily researched topic. The TME can be described in terms of hypoxia, metabolic dysregulation, immune escape, and chronic inflammation. RNA methylation, an epigenetic modification, has recently been found to have a pivotal role in shaping the TME. The N6-methylation of adenosine (m6A) modification is the most common type of RNA methylation that occurs in the N6-position of adenosine, which is the primary internal modification of eukaryotic mRNA. Compelling evidence has demonstrated that m6A regulates transcriptional and protein expression through splicing, translation, degradation, and export, thereby mediating the biological processes of cancer cells and/or stromal cells and characterizing the TME. The TME also has a crucial role in the complicated regulatory network of m6A modifications and, subsequently, influences tumor initiation, progression, and therapy responses. In this review, we describe the features of the TME and how the m6A modification modulates and interacts with it. We also focus on various factors and pathways involved in m6A methylation. Finally, we discuss potential therapeutic strategies and prognostic biomarkers with respect to the TME and m6A modification.