Noncoding RNAs in tumorigenesis and tumor therapy

Tumorigenesis is a complicated process in which numerous modulators are involved in different ways.Previous studies have focused primarily on tumor-associated protein-coding genes such as oncogenes and tumor suppressor genes,as well as their associated oncogenic pathways.However,noncoding RNAs(ncRNAs),rising stars in diverse physiological and pathological processes,have recently emerged as additional modulators in tumorigenesis.In this review,we focus on two typical kinds of ncRNAs:long noncoding RNAs(lncRNAs)and circular RNAs(circRNAs).We describe the molecular patterns of ncRNAs and focus on the roles of ncRNAs in cancer stem cells(CSCs),tumor cells,and tumor environmental cells.CSCs are a small subset of tumor cells and are generally considered to be cells that initiate tumorigenesis,and dozens of ncRNAs have been defined as critical modulators in CSC maintenance and oncogenesis.Moreover,ncRNAs are widely involved in oncogenetic processes,including sustaining proliferation,resisting cell death,genome instability,metabolic disorders,immune escape and metastasis.We also discuss the potential applications of ncRNAs in tumor diagnosis and therapy.The progress in ncRNA research greatly improves our understanding of ncRNAs in oncogenesis and provides new potential targets for future tumor therapy.

Regulation of noncoding RNAs in innate lymphoid cells

Innate lymphoid cells(ILCs)have been defined in recent years and are important effector cells against pathogens and critical regulators in maintaining tissue homeostasis[1].Noncoding RNAs(ncRNAs),such as circular RNAs(circRNAs),long noncoding RNAs(lncRNAs),and microRNAs(miRNAs),in ILCs are emerging and have been described to function in ILC biology.These ncRNAs are distributed with unique patterns in ILCs and function in different molecular mechanisms.Accumulating research evidence demonstrates that ncRNA dysregulation links ILC-mediated immune responses and diseases.

E）NA sensor cGAS-mediated immune recognition

The host takes use of pattern recognition receptors （PRRs） to defend against pathogen invasion or cellular damage. Among microorganism-associated molecular patterns detected by host PRRs, nucleic acids derived from bacteria or viruses are tightly supervised, providing a fundamental mechanism of host defense. Pathogenic DNAs are supposed to be detected by DNA sensors that induce the activation of NFKB or TBKI-IRF3 pathway. DNA sensor cGAS is widely expressed in innate immune cells and is a key sensor of invading DNAs in several cell types, cGAS binds to DNA, followed by a conformational change that allows the synthesis of cyclic guanosine monophosphate-adenosine monophosphate （cGAMP） from adenosine triphosphate and guanosine triphos- phate, cGAMP is a strong activator of STING that can activate IRF3 and subsequent type I interferon produc- tion. Here we describe recent progresses in DNA sensors especially cGAS in the innate immune responses against pathogenic DNAs.

Structural insights into the regulatory mechanism of the Pseudomonas aeruginosa YfiBNR system

YfiBNR is a recently identified bis-（3＇-5＇）-cyclic dimeric GMP （c-di-GMP） signaling system in opportunistic pathogens. It is a key regulator of biofilm formation, which is correlated with prolonged persistence of infection and antibiotic drug resistance. In response to cell stress, YfiB in the outer membrane can sequester the pariplasmic protein YfiR, releasing its inhibition of YfiN on the inner membrane and thus provoking the diguanylate cyclase activity of YfiN to induce c-di-GMP production. However, the detailed regulatory mechanism remains elusive. Here, we report the crystal struc- tures of YfiB alone and of an active mutant YfiB^L43P complexed with YfiR with 2：2 stoichiometry. Structural analyses revealed that in contrast to the compact conformation of the dimeric YfiB alone, YfiB^L43P adopts a stretched conformation allowing activated YfiB to penebate the peptidoglycan （PG） layer and access YfiR. YfiBL43P shows a more compact PG-binding pocket and much higher PG binding affinity than wild-type YflB, suggesting a tight correlation between PG binding and YfiB activation. In addition, our crystallographic analyses revealed that YflR binds Vitamin B6 （VB6） or L-Trp at a YfiB-binding site and that both VB6 and L-Trp are able to reduce YfiBL43P-induced biofilm formation. Based on the structural and biochemical data, we propose an updated regulatory model of the YfiBNR system.

Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m6A demethylation of Nr4a1 mRNA

Group 3 innate lymphoid cells(ILC3s)play critical roles in innate immunity and gut homeostasis.However,how ILC3 homeostasis is regulated remains elusive.Here,we identified a novel circular RNA,circZbtb20,that is highly expressed in ILC3s and required for their maintenance and function.CircZbtb20 deletion causes reduced ILC3 numbers,increasing susceptibility to C.rodentium infection.Mechanistically,circZbtb20 enhances the interaction of Alkbh5 with Nr4a1 mRNA,leading to ablation of the m6A modification of Nr4a1 mRNA to promote its stability.Nr4a1 initiates Notch2 signaling activation,which contributes to the maintenance of ILC3 homeostasis.Deletion of Alkbh5 or Nr4a1 also impairs ILC3 homeostasis and increases susceptibilities to bacterial infection.Thus,our findings reveal an important role of circular RNA in the regulation of innate lymphoid cell homeostasis.

Induction of functional neutrophils from mouse fibroblasts by thymidine through enhancement of Tet3 activity

Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whether neutrophils can be generated by transdifferentiation strategies is unknown.Here,we show that thymidine induces the conversion of mouse fibroblasts to neutrophils.Induced neutrophils(iNeus)showed antibacterial effects and did not undergo malignant transformation in vivo.Importantly,iNeu transplantation cured neutropenia in mice in vivo.Mechanistically,thymidine mediates iNeu conversion by enhancing Tet3 activity.Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils.Therefore,the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.