BACKGROUND: Gene expression can be posttranscriptionally regulated by a complex network of proteins. N1-methyladenosine (m1A) is a newly validated RNA modification. However, little is known about both its influence and biogenesis in tumor development. METHODS: This study analyzed TCGA data of patients with five kinds of gastrointestinal (GI) cancers. Using data from cBioPortal, molecular features of the nine known m1A-related enzymes in GI cancers were investigated. Using a variety of bioinformatics approach, the impact of m1A regulators on its downstream signaling pathway was studied. To further confirm this regulation, the effect of m1A writer ALKBH3 knockdown was studied using RNA-seq data from published database. RESULTS: Dysregulation and multiple types of genetic alteration of putative m1A-related enzymes in tumor samples were observed. The ErbB and mTOR pathways with ErbB2, mTOR, and AKT1S1 hub genes were identified as being regulated by m1A-related enzymes. The expression of both ErbB2 and AKT1S1 was decreased after m1A writer ALKBH3 knockdown. Furthermore, Gene Ontology analysis revealed that m1A downstream genes were associated with cell proliferation, and the results showed that m1A genes are reliably linked to mTOR. CONCLUSION: This study demonstrated for the first time the dysregulation of m1A regulators in GI cancer and its signaling pathways and will contribute to the understanding of RNA modification in cancer.

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Tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally found to be produced by inflammatory cells and play important roles in the immune system and surveillance of tumour growth. By activating distinct signalling pathways of nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and JAK/STAT, TNFα and IFNγ were reported to effectively trigger cell death and perform powerful anti-cancer effects. In this review, we will discuss the new advancements of TNFα and IFNγ in anti-cancer therapy.

Rationale: Methylation at the N6 position of adenosine (m 6 A) is the most prevalent RNA modification within protein-coding mRNAs in mammals, and it is a reversible modification with various important biological functions. The formation and function of m 6 A are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of m 6 A in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known m 6 A writer, eraser, and reader proteins in GI cancer. Methods: Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used. Gene alteration and pathway analysis were done in cBioportal. The protein network of m 6 A regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. m 6 A modification sites were predicted by SRAMP. m 6 A related SNPs were analyzed by m 6 ASNP. The modulation of m 6 A on its related pathway members was validated by m 6 A-seq, real-time PCR and phosphor-MAPK array. Results: We found that m 6 A regulators were mostly upregulated in GI cancer and their differential expression significantly influenced the overall survival of patients with GI cancer. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways were found to be potentially affected by m 6 A modification in most human cancers, including GI cancer, which was further verified by m 6 A-Seq and phospho-MAPK array. Conclusions: Our findings suggest that m 6 A RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.