N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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Functions of N6-methyladenosine and its role in cancer.

The epigenetic regulation of immune response has been demonstrated in recent studies. Nonetheless, potential roles of RNA N6-methyladenosine (m6A) modification in tumor microenvironment (TME) cell infiltration remain unknown. We comprehensively evaluated the m6A modification patterns of 1938 gastric cancer samples based on 21 m6A regulators, and systematically correlated these modification patterns with TME cell-infiltrating characteristics. The m6Ascore was constructed to quantify m6A modification patterns of individual tumors using principal component analysis algorithms. Three distinct m6A modification patterns were determined. The TME cell-infiltrating characteristics under these three patterns were highly consistent with the three immune phenotypes of tumors including immune-excluded, immune-inflamed and immune-desert phenotypes. We demonstrated the evaluation of m6A modification patterns within individual tumors could predict stages of tumor inflammation, subtypes, TME stromal activity, genetic variation, and patient prognosis. Low m6Ascore, characterized by increased mutation burden and activation of immunity, indicated an inflamed TME phenotype, with 69.4% 5-year survival. Activation of stroma and lack of effective immune infiltration were observed in the high m6Ascore subtype, indicating a non-inflamed and immune-exclusion TME phenotype, with poorer survival. Low m6Ascore was also linked to increased neoantigen load and enhanced response to anti-PD-1/L1 immunotherapy. Two immunotherapy cohorts confirmed patients with lower m6Ascore demonstrated significant therapeutic advantages and clinical benefits. This work revealed the m6A modification played a nonnegligible role in formation of TME diversity and complexity. Evaluating the m6A modification pattern of individual tumor will contribute to enhancing our cognition of TME infiltration characterization and guiding more effective immunotherapy strategies.

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m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in gastric cancer.

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is installed by m6A methyltransferases (METTL3/14, WTAP, RBM15/15B, VIRMA and ZC3H13, termed “writers”), removed by demethylases (FTO, ALKBH5, and ALKBH3, termed “erasers”), and recognized by m6A-binding proteins (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNP, and eIF3, termed “readers”). Accumulating evidence suggests that m6A RNA methylation greatly impacts RNA metabolism and is involved in the pathogenesis of many kinds of diseases, including cancers. In this review, we focus on the physiological functions of m6A modification and its related regulators, as well as on the potential biological roles of these elements in human tumors.

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The potential role of RNA N6-methyladenosine in Cancer progression

Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N6-methyladenosine (m6A) modifications of RNAs are emerging as a new layer of epigenetic regulation. As the most abundant chemical modification of eukaryotic mRNA, m6A is essential for the regulation of mRNA stability, splicing, and translation. Alterations of m6A regulatory genes play important roles in the pathogenesis of a variety of human diseases. However, whether this mRNA modification participates in the glucose metabolism of colorectal cancer (CRC) remains uncharacterized. Transcriptome-sequencing and liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate the correlation between m6A modifications and glucose metabolism in CRC. Mass spectrometric metabolomics analysis, in vitro and in vivo experiments were conducted to investigate the effects of METTL3 on CRC glycolysis and tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation and RNA stability assay were used to explore the molecular mechanism of METTL3 in CRC. A strong correlation between METTL3 and 18F-FDG uptake was observed in CRC patients from Xuzhou Central Hospital. METTL3 induced-CRC tumorigenesis depends on cell glycolysis in multiple CRC models. Mechanistically, METTL3 directly interacted with the 5′/3’UTR regions of HK2, and the 3’UTR region of SLC2A1 (GLUT1), then further stabilized these two genes and activated the glycolysis pathway. M6A-mediated HK2 and SLC2A1 (GLUT1) stabilization relied on the m6A reader IGF2BP2 or IGF2BP2/3, respectively. METTL3 is a functional and clinical oncogene in CRC. METTL3 stabilizes HK2 and SLC2A1 (GLUT1) expression in CRC through an m6A-IGF2BP2/3- dependent mechanism. Targeting METTL3 and its pathway offer alternative rational therapeutic targets in CRC patients with high glucose metabolism.

https://link.springer.com/content/pdf/10.1186/s12943-020-01190-w.pdf

m6A-dependent glycolysis enhances colorectal cancer progression.

Objective N6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation and progression via the regulation of RNA function. This study explored the biological function and clinical significance of METTL3 in gastric cancer (GC). Design The prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human GC cohort. The biological role and mechanism of METTL3 in GC tumour growth and liver metastasis were determined in vitro and in vivo. Results The level of m6A RNA was significantly increased in GC, and METTL3 was the main regulator involved in the abundant m6A RNA modification. METTL3 expression was significantly elevated in GC tissues and associated with poor prognosis. Multivariate Cox regression analysis revealed that METTL3 expression was an independent prognostic factor and effective predictor in human patients with GC. Moreover, METTL3 overexpression promoted GC proliferation and liver metastasis in vitro and in vivo. Mechanistically, P300-mediated H3K27 acetylation activation in the promoter of METTL3 induced METTL3 transcription, which stimulated m6A modification of HDGF mRNA, and the m6A reader IGF2BP3 then directly recognised and bound to the m6A site on HDGF mRNA and enhanced HDGF mRNA stability. Secreted HDGF promoted tumour angiogenesis, while nuclear HDGF activated GLUT4 and ENO2 expression, followed by an increase in glycolysis in GC cells, which was correlated with subsequent tumour growth and liver metastasis. Conclusions Elevated METTL3 expression promotes tumour angiogenesis and glycolysis in GC, indicating that METTL3 expression is a potential prognostic biomarker and therapeutic target for human GC.

METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

Solid tumors consist of various types of stromal cells in addition to cancer cells. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and play an essential role in tumor progression and metastasis in a variety of malignancies, including gastric cancer. However, the effects of CAFs on gastric cancer cells' progression and metastasis are not well studied. Here we show that matrix metalloproteinase 11 (MMP11) in exosomes secreted from CAFs can be delivered into gastric cancer cells. Gastric CAFs promote gastric cancer cell migration partially through exosomal MMP11. Moreover, MMP11 is overexpressed in exosomes purified from plasma of gastric cancer patients and tumor tissues and associated with overall survival of gastric patients. We also find that MMP11 is negatively regulated by exosomal miR-139 in the CAFs of gastric cancer. Exosomal miR-139 inhibits tumor growth and metastasis of gastric cancer cells by decreasing the expression of MMP11 in vitro and in vivo. Thus, we propose that exosomal miR-139 derived from gastric CAFs could inhibit the progression and metastasis of gastric cancer by decreasing MMP11 in tumor microenvironment.

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Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression.

Background and aims: Endoscopic resection is increasingly performed for gastric gastrointestinal stromal tumors (GIST). However, the safety and outcomes remain elusive. We aimed in this retrospective study to compare operative complications and prognosis between endoscopically and surgically resected small (≤ 5 cm) GIST tumor groups.

Methods: In this single-center retrospective study, we compared demographics, clinical outcomes, and the R0 resection rate between the endoscopy (n =268) and surgery (n =141) groups. Only GIST tumors in size of ≤ 5.0 cm were recruited for this comparison study.

Results: Overall, the mean age of patients was 59.0 years (range: 31.0-83.0). The male-female ratio was 0.68. The most common site of GIST was, in the descending order, the gastric fundus (55%), corpus (27.6%), cardia (10.8%), and antrum (6.6%). Compared with the surgery group, GIST tumors in the endoscopy group were significantly smaller (1.69±0.9 cm, vs. 3.20±1.2 cm in the surgery group; P <0.001) in size; postoperative hospital stay was significantly shorter (4.66±1.5 days, vs. 8.11±5.0; P <0.001); post-resection time to first liquid diet was significantly shorter (1.94±1.1 days, vs. 4.63±2.6; P < 0.001); the incidence of operative and post-operative complications was significantly fewer (p < 0.05), and hospital costs were significantly lower (20115.4±5113.5¥, vs. 43378.4±16795.7¥; P < 0.001). The R0 resection rate was significantly lower in the endoscopy (93.3%) than in the surgery (99.3%) groups (P< 0.01). In the endoscopy group, 176 (65.7%) and 69 (25.7%) patients were found to be at very low and low risk of aggressiveness, respectively, in comparison to 27(19.2%) and 86 (61.0%) patients in the surgery group, respectively (P <0.001). Among 409 cases, 50 (12.2%) were found to be at intermediate or high risk of aggressiveness, 20 of which were treated with adjuvant imatinib therapy and but only 8/20 taking imatinib for 1 to 3 months because of side effects and high costs. No local or distant tumor recurrence was observed over an average of 33.5-month follow-ups. Two patients died of other disease in the surgery group.

Conclusions: Endoscopic resection of selected small gastric GISTs (≤ 5cm) was feasible, safe, and associated with better intraoperative results and an equal postoperative course, compared to surgical resection.

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Comparison of Safety and Outcomes between Endoscopic and Surgical Resections of Small (≤ 5 cm) Primary Gastric Gastrointestinal Stromal Tumors.

Retrospective Comparison of Endoscopic Full-Thickness Versus Laparoscopic or Surgical Resection of Small (≤ 5 cm) Gastric Gastrointestinal Stromal Tumors

Yan Zhao

Papers

METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression.

Comparison of Safety and Outcomes between Endoscopic and Surgical Resections of Small (≤ 5 cm) Primary Gastric Gastrointestinal Stromal Tumors.

Retrospective Comparison of Endoscopic Full-Thickness Versus Laparoscopic or Surgical Resection of Small (≤ 5 cm) Gastric Gastrointestinal Stromal Tumors