m6A-modified circFOXK2 targets GLUT1 to accelerate oral squamous cell carcinoma aerobic glycolysis.

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, and its emerging roles have been gradually identified. However, the potential function of m6A and m6A-modified circular RNA (circRNA) is still unclear. Here, m6A-circRNA epitranscriptomic microarray analysis revealed a high-expressed m6A-modified circFOXK2 (hsa_circ_0000816, from FOXK2 gene) in oral squamous cell carcinoma (OSCC). For the biofunctions of OSCC, results revealed that circFOXK2 promoted the malignant phenotypes of OSCC cells. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) demonstrated that a remarkable m6A modified site was installed on glucose transporter 1 (GLUT1) mRNA. Mechanistically, circFOXK2 promoted the GLUT1 mRNA stability through cooperating with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) in a m6A-dependent manner. In summary, the present study explored the oncogenic role of m6A-modified circFOXK2 in OSCC through the m6A-dependent IGF2BP3/GLUT1 axis, indicating a potential therapeutic target for OSCC.

High-throughput microarray reveals the epitranscriptome-wide landscape of m6A-modified circRNA in oral squamous cell carcinoma.

BACKGROUND: Emerging transcriptome-wide high-throughput screenings reveal the landscape and functions of RNAs, such as circular RNAs (circRNAs), in human cancer. In addition, the post-transcriptional RNA internal modifications, especially N6-methyladenosine (m6A), greatly enrich the variety of RNAs metabolism. However, the m6A modification on circRNAs has yet to be addressed. RESULTS: Here, we report an epitranscriptome-wide mapping of m6A-modified circRNAs (m6A-circRNA) in oral squamous cell carcinoma (OSCC). Utilizing the data of m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A-circRNAs microarray, we found that m6A-circRNAs exhibited particular modification styles in OSCC, which was independent of m6A-mRNA. Besides, m6A modification on circRNAs frequently occurred on the long exons in the front part of the coding sequence (CDS), which was distinct from m6A-mRNA that in 3'-UTR or stop codon. CONCLUSION: In conclusion, our work preliminarily demonstrates the traits of m6A-circRNAs, which may bring enlighten for the roles of m6A-circRNAs in OSCC.

Isoliquiritigenin inhibits non-small cell lung cancer progression via m6A/IGF2BP3-dependent TWIST1 mRNA stabilization.

BACKGROUND: N6-methyladenosine (m6A) has been identified to regulate the tumorigenesis and development of various tumors, including non-small cell lung cancer (NSCLC). Isoliquiritigenin (ISL), derived from the Chinese herb licorice, shows a significant anti-tumor activity on multiple human cancers. However, the role of ISL on NSCLC through m6A is still unclear. PURPOSE: Here, we investigated the anti-tumor effect of ISL on NSCLC, and explored whether ISL affected the NSCLC phenotype by modulating its m6A modification. METHODS: Cell proliferation, migration and invasion assays were performed to evaluate the inhibitory effects of ISL on NSCLC cells. M6A enrichment was determined by m6A quantitative analysis. The mechanism regarding IGF2BP3 was explored using RIP-PCR, MeRIP-qPCR and RNA decay analysis. RESULTS: ISL significantly repressed the proliferation, migration and invasion of NSCLC cells in vitro. In addition, m6A reader IGF2BP3 expression significantly increased in NSCLC tissues compared to adjacent tissues, and was positively correlated with NSCLC patients' poor survival. Mechanistically, ISL reduced m6A modification and down-regulated IGF2BP3 expression in NSCLC. Furthermore, IGF2BP3 enhanced the mRNA stability of twist family bHLH transcription factor 1 (TWIST1) in m6A-dependent manner. Moreover, ISL treatment combined with TWSIT1 knockdown effectively reversed IGF2BP3 overexpression-induced NSCLC cells' proliferation, migration and invasion. CONCLUSION: Our findings uncover that ISL might function as an anticarcinogen through targeting IGF2BP3/m6A/TWIST1 axis for NSCLC.

METTL3 Facilitates Oral Squamous Cell Carcinoma Tumorigenesis by Enhancing c-Myc Stability via YTHDF1-Mediated m6A Modification.

N6-Methyladenosine (m6A) is the most common internal modification of eukaryotic messenger RNA (mRNA) that occurred on the N6 nitrogen of adenosine. However, the roles of m6A in oral squamous cell carcinoma (OSCC) are still elusive. Here, we investigate the function and mechanism of methyltransferase-like 3 (METTL3) in OSCC tumorigenesis. Clinically, METTL3 was significantly upregulated in tissue samples and correlated with the poor prognosis of OSCC patients. Functionally, loss and gain studies illustrated that METTL3 promoted the proliferation, invasion, and migration of OSCC cells in vitro, and METTL3 knockdown inhibited tumor growth in vivo. Mechanistically, methylated RNA immunoprecipitation sequencing (MeRIP-seq) illustrated that METTL3 targeted the 3' UTR (near to stop codon) of the c-Myc transcript to install the m6A modification, thereby enhancing its stability. Furthermore, results revealed that YTH N6-methyladenosine RNA binding protein 1 (YTH domain family, member 1 [YTHDF1]) mediated the m6A-increased stability of c-Myc mRNA catalyzed by METTL3. In conclusion, our findings herein identify that METTL3 accelerates the c-Myc stability via YTHDF1-mediated m6A modification, thereby giving rise to OSCC tumorigenesis.

Correction to: Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop.

Emerging evidences have suggested the vital roles of circular RNA (circRNA) in the human cancers. However, the underlying biological functions and biogenesis of circRNA in the oral squamous cell carcinoma (OSCC) is still ambiguous. Here, we investigate the oncogenic roles and biogenesis of the novel identified circRNA, circUHRF1 (hsa_circ_0002185), in the OSCC tumorigenesis. Results showed that circUHRF1 was markedly upregulated in the OSCC cells and tissue, besides, the overexpression was closely correlated with the poor prognosis of OSCC patients. Functionally, circUHRF1 promoted the proliferation, migration, invasion, and epithelial mesenchymal transformation (EMT) in vitro and the tumor growth in vivo. Mechanically, circUHRF1 acted as the sponge of miR-526b-5p, thereby positively regulating c-Myc. Transcription factor c-Myc could accelerate the transcription of TGF-ß1 and ESRP1. Moreover, splicing factor ESRP1 promoted the circularization and biogenesis of circUHRF1 by targeting the flanking introns, forming the circUHRF1/miR-526b-5p/c-Myc/TGF-ß1/ESRP1 feedback loop. In conclusion, our research identified the oncogenic roles of circUHRF1 in the OSCC tumorigenesis and EMT via circUHRF1/miR-526b-5p/c-Myc/TGF-ß1/ESRP1 feedback loop, shedding light on the pathogenic mechanism of circUHRF1 for OSCC and providing the potential therapeutic target.

Differential and Predictive Value of Galectin-3 and Soluble Suppression of Tumorigenicity-2 (sST2) in Heart Failure with Preserved Ejection Fraction.

BACKGROUND Galectin-3 and soluble suppression of tumorigenicity-2 (sST2) are promising biomarkers of cardiac fibrosis and ventricular remodeling. The purpose of this study was to investigate the diagnostic and predictive value of galectin-3 and sST2 for use in patients who have heart failure with preserved ejection fraction (HFpEF). MATERIAL AND METHODS A total of 217 hospitalized patients with HF and 30 controls from a physical examination center were included. Venous blood was collected for the detection of circulating expression of galectin-3 and sST2. All the included patients were followed up regularly for 1 year (12±1 months). RESULTS The concentrations of galectin-3 and NT-proBNP were substantially higher following decreased ejection fraction (both P=0.000), except for sST2 (P=0.068 vs. control). In ROC analyses, galectin-3 and NT-proBNP distinguished HFpEF from controls with an area under the curve (AUC) of 0.819 (95% CI: 0.75-0.89, P=0.000) and 0.806 (95% CI: 0.66-0.82, P=0.000). In contrast, sST2 obtained a lower AUC of 0.584 (95% CI: 0.49-0.68, P=0.17) compared to galectni-3 and NT-proBNP. After adjustment for clinical factors and NT-proBNP, galectin-3 was strongly correlated with an increased risk of the endpoint events in HFpEF patients, and the hazard ratio per 1 SD increase of the galectin-3 level was 2.33 (95%CI: 1.72-2.94, P=0.009). CONCLUSIONS Galectin-3 is superior to sST2 in distinguishing HFpEF from controls and HFrEF.