Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future. 

/pdf/m6a-modification-recent-advances-anticancer-targeted-drug-2og6181j.pdf

m6A modification: recent advances, anticancer targeted drug discovery and beyond

Profiles of immune cell infiltration and immune-related genes in the tumor microenvironment of colorectal cancer.

N6-methyladenosine (m6A) has emerged as an abundant modification throughout the transcriptome with widespread functions in protein-coding and noncoding RNAs. It affects the fates of modified RNAs, including their stability, splicing, and/or translation, and thus plays important roles in posttranscriptional regulation. To date, m6A methyltransferases have been reported to execute m6A deposition on distinct RNAs by their own or forming different complexes with additional partner proteins. In this review, we summarize the function of these m6A methyltransferases or complexes in regulating the key genes and pathways of cancer biology. We also highlight the progress in the use of m6A methyltransferases in mediating therapy resistance, including chemotherapy, targeted therapy, immunotherapy and radiotherapy. Finally, we discuss the current approaches and clinical potential of m6A methyltransferase-targeting strategies.

/pdf/n6-methyladenosine-methyltransferases-functions-regulation-2c18it0sig.pdf

N6-methyladenosine methyltransferases: functions, regulation, and clinical potential

The N(6)-methyladenosine (m6A) modification is the most pervasive modification of human RNAs. In recent years, an increasing number of studies have suggested that m6A likely plays important roles in cancers. Many studies have demonstrated that m6A is involved in the biological functions of cancer cells, such as proliferation, invasion, metastasis, and drug resistance. In addition, m6A is closely related to the prognosis of cancer patients. In this review, we highlight recent advances in understanding the function of m6A in various cancers. We emphasize the importance of m6A to cancer progression and look forward to describe future research directions. 

/pdf/role-of-m6a-writers-erasers-and-readers-in-cancer-1iiup12i.pdf

Role of m6A writers, erasers and readers in cancer

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut.

N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role in colon cancer remains unclear. The expression of m6A associated enzymes and total m6A level were measured by Western Blotting analysis and m6A RNA Methylation Quantification Kit respectively. Cell cycle was analyzed by flowcytometry. The interaction of IGF2BP3 and related targets was analyzed by RNA immunoprecipitation (RIP) and m6A RNA immunoprecipitation (MeRIP) assays. We investigated all m6A regulated enzymes in colon cancer and found only the overexpression of IGF2BP3 was associated with cancer progression and survival based on The Cancer Genome Atlas (TCGA) databases. Additionally, we also demonstrated IGF2BP3 was associated with DNA replication in the cell cycle. Knockdown of IGF2BP3 significantly repressed percentage of S phase of cell cycle as well as cell proliferation. Further research demonstrated IGF2BP3 bound to the mRNA of Cyclin D1 (CCND1, checkpoint of G1/S phase of cell cycle) and reduced its mRNA stability via reading m6A modification in the CDS region. Overexpression of Cyclin D1 in IGF2BP3 down-regulated cells completely rescued the inhibited percentage of S phase in cell cycle as well as cell proliferation. Additionally, we also demonstrated a similar role of IGF2BP3 at VEGF. IGF2BP3 bound to the mRNA of VEGF and reads m6A modification, thus regulated both expression and stability of VEGF mRNA. Knockdown of IGF2BP3 repressed angiogenesis in colon cancer via regulating VEGF. Knockdown of IGF2BP3 repressed DNA replication in the S phase of cell cycle and angiogenesis via reading m6A modification of CCND1 and VEGF respectively. IGF2BP3 was a possible prognosis marker and potential therapeutic target of colon cancer.

/pdf/rna-n6-methyladenosine-reader-igf2bp3-regulates-cell-cycle-3jj57ibtty.pdf

RNA N6-Methyladenosine Reader IGF2BP3 Regulates Cell Cycle and Angiogenesis in Colon Cancer

/pdf/knockdown-of-rna-n6-methyladenosine-methyltransferase-mettl3-3xh15lbkiw.pdf

Knockdown of RNA N6-methyladenosine methyltransferase METTL3 represses Warburg effect in colorectal cancer via regulating HIF-1α.

Fluorescent sensors for discriminative detection of multiple targets in pathological processes

Autophagy plays a key role in colorectal cancer (CRC) development and reduces the sensitivity of CRC cells to treatment. The present study reported a novel tumor‑suppressive role for autophagy, which was demonstrated to be regulated through the novel oncogene neurotrophin‑4 (NTF4). NTF4 was significantly overexpressed in tumor tissue compared with non‑tumor mucosa, and the upregulation of NTF4 in CRC was associated with poor overall survival and advanced TNM stage. The genetic knockdown of NTF4 using short hairpin RNA in CRC cells prevented epithelial‑to‑mesenchymal transition and activated autophagy; this was regulated through the interaction between autophagy‑associated gene 5 (Atg5) and the mitogen‑activated protein kinase pathway. In addition, the knockdown of NTF4 inhibited cell invasion, migration, proliferation and colony formation, and promoted cell cycle arrest. Treatment of the cells with the autophagy inhibitor chloroquine (CQ) rescued these functions and promoted cell invasion, migration, proliferation and colony formation. Finally, the knockdown of NTF4 inhibited the growth of subcutaneous xenografts in Balb/c‑nu mice. In conclusion, these findings suggested that NTF4 may be a diagnostic marker associated with the overall survival and progression of patients with CRC. NTF4 was found to promote tumorigenesis and CRC development through autophagy regulation.

/pdf/upregulated-ntf4-in-colorectal-cancer-promotes-tumor-30niy3zs4e.pdf

Upregulated NTF4 in colorectal cancer promotes tumor development via regulating autophagy.

Interleukin (IL)-1β is a member of the IL-1 family of proteins. IL-1 receptor antagonist (IL-1RA) is an agent that binds to the IL-1 receptor, preventing IL-1 from transmitting signals to cells. The present study aimed to identify the role of the IL-1β/1RA axis in epithelial-mesenchymal transition (EMT), cell invasion, migration, proliferation and clone formation in colorectal cancer (CRC) and to determine its underlying mechanisms of action. Significantly increased expression of both IL-1β and IL-1RA was identified in CRC patient data uploaded in The Cancer Genome Atlas database, and in tumor tissues when compared with matched control tissue. High expression of IL-1β was associated with an increased rate of overall survival and recurrence-free survival. Further research revealed that the IL-1β gene was co-expressed with the IL-1RA gene in tumors of CRC patients. It was additionally determined that recombinant human (rh)IL-1β suppressed autophagy as well as EMT in HCT-116 cells compared with control-treated cells, whereas rhIL-1RA exhibited the opposite effect. In addition, autophagy activator rapamycin (RAPA) rescued the inhibition of EMT in rhIL-1β-treated HCT-116 cells. Moreover, rhIL-1β inhibited cell invasion, migration, proliferation and colony-formation ability, when compared with a control treatment. Compared with a control treatment rhIL-1RA promoted cell invasion, migration, proliferation, but had no effect on clone formation ability. Furthermore, both rhIL-1RA and RAPA rescued inhibition of cell invasion, migration and clone formation ability in rhIL-1β-treated HCT-116 cells. RAPA, but not rhIL-1RA, rescue inhibited proliferation in rhIL-1β-treated HCT-116 cells compared with controls. In addition, it was confirmed that rhIL-1β inhibited the growth of subcutaneous xenografts in nude mice, when compared with control treatments. These results indicated that upregulation of the IL-1β/1RA axis in CRC regulated EMT, cell invasion and migration, proliferation and clone formation via autophagy.

/pdf/interleukin-1b-1ra-axis-in-colorectal-cancer-regulates-tumor-2zth40of0v.pdf

Interleukin 1β/1RA axis in colorectal cancer regulates tumor invasion, proliferation and apoptosis via autophagy.

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