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Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5 + ISCs showed high expression of the immune cell–associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5 + ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 ( Il13ra1 ) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13‒IL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with β-catenin in rendering its nuclear translocation, which caused activation of the β-catenin pathway and the maintenance of Lgr5 + ISCs. Fan and colleagues show that circular RNA circPan3 controls expression of the cytokine receptor IL-13Rα1 on intestinal stem cells and, thus, the renewal of those cells in response to IL-13 derived from group 2 innate lymphoid cells.

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2 , as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3 −/− Rag1 −/− and circKcnt2 −/− Rag1 −/− mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis. Type 3 innate lymphoid cells (ILC3) are involved in maintaining gut immune homeostasis. Here the authors identify a circular RNA, circKcnt2 , to be induced in ILC3s from inflamed gut, yet circKcnt2 deletion aggravates mouse experimental colitis, thereby implicating circKcnt2 as a potential feedback regulator of ILC3 activation and gut immunity.

Liver tumour-initiating cells (TICs) contribute to tumour initiation, metastasis, progression and drug resistance. Metabolic reprogramming is a cancer hallmark and plays vital roles in liver tumorigenesis. However, the role of metabolic reprogramming in TICs remains poorly explored. Here, we identify a mitochondria-encoded circular RNA, termed mcPGK1 (mitochondrial circRNA for translocating phosphoglycerate kinase 1), which is highly expressed in liver TICs. mcPGK1 knockdown impairs liver TIC self-renewal, whereas its overexpression drives liver TIC self-renewal. Mechanistically, mcPGK1 regulates metabolic reprogramming by inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and promoting glycolysis. This alters the intracellular levels of α-ketoglutarate and lactate, which are modulators in Wnt/β-catenin activation and liver TIC self-renewal. In addition, mcPGK1 promotes PGK1 mitochondrial import via TOM40 interactions, reprogramming metabolism from oxidative phosphorylation to glycolysis through PGK1-PDK1-PDH axis. Our work suggests that mitochondria-encoded circRNAs represent an additional regulatory layer controlling mitochondrial function, metabolic reprogramming and liver TIC self-renewal. Metabolic reprogramming plays vital roles in tumorigenesis. Here, Chen et al. reveal that mitochondria-encoded mcPGK1 drives the mitochondrial translocation of PGK1, promoting liver tumorigenesis and TIC self-renewal by switching energy production from OXPHOS to glycolysis.

Background Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells also called cancer stem cells (CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. However, the role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive. Methods CircRNAs highly conserved in humans and mice were identified from 3 primary HCC samples by circRNA array. The expression and function of circIPO11 were further evaluated by Northern blot, limiting dilution xenograft analysis, chromatin isolation by RNA purification-PCR assay (ChIRP) and HCC patient-derived tumor cells (PDC) models. CircIpo11 knockout (KO) mice were generated by a CRISPR/Cas9 technology. Results CircIPO11 is highly expressed in HCC tumor tissues and liver CSCs. CircIPO11 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, circIPO11 recruits TOP1 to GLI1 promoter to trigger its transcription, leading to the activation of Hedgehog signaling. Moreover, GLI1 is also highly expressed in HCC tumor tissues and liver CSCs, and TOP1 expression levels positively correlate with the metastasis, recurrence and survival of HCC patients. Additionally, circIPO11 knockout in mice suppresses the progression of chemically induced liver cancer development. Conclusion Our findings reveal that circIPO11 drives the self-renewal of liver CSCs and promotes the propagation of HCC via activating Hedgehog signaling pathway. Antisense oligonucleotides (ASOs) against circIPO11 combined with TOP1 inhibitor camptothecin (CPT) exert synergistic antitumor effect. Therefore, circIPO11 and the Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients.

Colorectal cancer (CRC) is one of the most common tumors around the world. Circular RNA is widely involved in tumor progression via unclear mechanisms. Here, circREEP3 is found to be upregulated in CRC tissues. circREEP3 upregulation predicts poor patient survival. circREEP3 knockout suppresses CRC tumorigenesis and metastasis, and impairs stem cell‐like phenotype. Mechanistically, circREEP3 recruits the chromatin remodeling protein CHD7 to FKBP10 promoter and activates its transcription. Moreover, circREEP3 restricts RIG‐1‐dependent antitumor immunity. FKBP10 is highly expressed in CRC tissues and associated with poor prognosis. FKBP10 ectopic expression partially rescues the potential of proliferation and metastasis in circREEP3‐deficient CRC cells. Thus, the findings support circREEP3‐FKBP10 axis drives CRC progression and may be a critical prognostic marker. Circular RNA is widely involved in tumor progression via unclear mechanisms. This study shows circREEP3 upregulation predicts poor patient survival in colorectal cancer (CRC). circREEP3 promotes CRC tumorigenesis, metastasis, and stem cell‐like phenotype via activating FKBP10 transcription and restricting RIG‐1‐dependent antitumor immunity. Thus, circREEP3‐FKBP10 axis drives CRC progression and may be a critical prognostic marker.

BackgroundDue to the high recurrence and low 5-year survival rates of esophageal squamous cell carcinoma (ESCC) after treatment, the discovery of novel drugs for recurrence chemoprevention is of particular importance.MethodsWe screened the FDA-approved drug library and found that Nuplazid, an atypical antipsychotic that acts as an effective 5-HT 2 A receptor inverse agonist, could potentially exert anticancer effects in vitro and in vivo on ESCC.ResultsPull-down results indicated that Nuplazid binds with p21-activated kinase 4 (PAK4), and a kinase assay showed that Nuplazid strongly suppressed PAK4 kinase activity. Moreover, Nuplazid exhibited inhibitory effects on ESCC in vivo.ConclusionsOur findings indicate that Nuplazid can suppress ESCC progression through targeting PAK4.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients’ survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients’ poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-β signaling pathway. TGF-β signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-β signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention.

Background It is estimated that over 85% of human transcripts are non-coding RNAs, which play an important role in the regulation of numerous biological processes and are closely associated with the development of human cancers. Nevertheless, the functions of the vast majority of non-coding RNAs are yet to be clearly elucidated. Methods Long non-coding RNA (lncRNA) LINC02320 was screened out by RNA-sequencing using paired CRC samples. The level of LINC02320 in colorectal cancer (CRC) tissues and cell lines was validated by qRT-PCR and in situ hybridization (ISH). CCK8, colony formation, transwell, wound healing and xenograft experiments were carried out to investigate the function of LINC02320. Antisense oligonucleotide (ASO) was used to target LINC02320. Mass spectrometry, pull-down, western blot and CUT&Tag assays were conducted to investigate the molecular mechanism of LINC02320, ILF2, GRB7, MAPK and FOS. Results LINC02320 was highly expressed in metastatic colorectal cancer (CRC) tissues based on RNA-sequencing. ISH staining using tissue microarray (TMA) indicated that LINC02320 is associated with the clinical stage and survival rate of patients with CRC. The results of loss-of-function and gain-of-function experiments demonstrated that LINC02320 facilitates cancer cell proliferation and metastasis in vitro and in vivo while simultaneously inhibiting apoptosis. LINC02320 is present in both the nucleus and cytoplasm, with a nuclear function. Mechanistically, LINC02320 recruits the transcriptional regulator ILF2 to the GRB7 promoter, thereby initiating its transcription. GRB7 then activates the mitogen-activated protein kinase (MAPK) signaling pathway, which contributes to CRC progression and leads to increased phosphorylation of the transcription factor FOS. Phosphorylated FOS directly promotes LINC02320 transcription, forming a positive feedback loop and amplifies this pro-cancer signal. Notably, LINC02320-targeted ASO therapy significantly blocked tumor growth in vivo. Conclusion In summary, our findings demonstrate the essential role of LINC02320 involved in CRC progression, which provides novel insights into the importance of lncRNA as a therapeutic target in cancer treatment.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, characterized by molecular heterogeneity and limited therapeutic options. Here, we identified EPS8L2 as a novel driver of colorectal tumorigenesis. EPS8L2 is significantly upregulated in CRC tissues and negatively correlated with patients’ prognosis. Functionally, upregulation of EPS8L2 promotes proliferation and metastasis of CRC cells in vitro and in vivo, and vice versa. Similarly, EPS8L2 overexpression promotes patient-derived organoids growth. Mechanistically, EPS8L2 increases YBX1 phosphorylation by enhancing its interaction with phosphokinase S6K1. Phosphorylated YBX1 translocates into nucleus and initiates G3BP2 transcription, leading to activation of the MAPK signaling pathway. Moreover, knockout of Eps8l2 impairs CRC tumorigenesis in the AOM/DSS induced mouse model. In summary, we revealed a novel EPS8L2-YBX1-G3BP2 regulatory axis involved in CRC progression, which provides a new theoretical basis for tumor therapy.

Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. Misregulation of glutamylation is implicated in severe physiological abnormalities. However, how glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Here we show that cytosolic carboxypeptidases 1 (CCP1) or CCP6 deficiency substantially promotes induced pluripotent cell (iPSC) induction and pluripotency of embryonic stem cells (ESCs). Klf4 polyglutamylation at Glu381 by tubulin tyrosine ligase-like 4 (TTLL4) and TTLL1 during cell reprogramming impedes its lysine 48-linked ubiquitination and sustains Klf4 stability. Klf4-E381A knockin mice display impaired blastocyst development and embryonic lethality. Deletion of TTLL4 or TTLL1 abrogates cell reprogramming and early embryogenesis. Thus, Klf4 polyglutamylation plays a critical role in the regulation of cell reprogramming and pluripotency maintenance. Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.