Growing evidence indicates that N6-methyladenosine (m6A) is the most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells in vitro and in vivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream m6A targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between m6A modification and plasticity of the tumor microenvironment.

Left ventricular remodeling after acute myocardial infarction (AMI) is associated with adverse prognosis. It is becoming increasingly clear that circulating miRNAs could be promising biomarkers for various pathological processes in the heart, including myocardial infarction, myocardial remodeling and progression to heart failure. In the present study, a total of 359 consecutive patients were recruited. Plasma samples were collected on admission. Echocardiographic studies were performed during the admission and at six months follow-up after AMI. Remodeling was defined as an at least 10% increase from baseline in the left ventricular end-diastolic volume. Plasma miRNA levels were assessed for association with six months mortality or development of heart failure. Results showed that levels of plasma miR-208b and miR-34a were significantly higher in patients with remodeling than those without. Increased miRNA levels were strongly associated with increased risk of mortality or heart failure within six months for miR-208b (OR 17.91, 95% confidence interval = 2.07–98.81, p = 0.003), miR-34a (OR 4.18, 95% confidence interval = 1.36–12.83, p = 0.012) and combination of the two miRNAs (OR 18.73, 95% confidence interval = 1.96–101.23, p = 0.000). The two miRNA panels reclassified a significant proportion of patients with a net reclassification improvement of 11.7% (p = 0.025) and an integrated discrimination improvement of 7.7% (p = 0.002). These results demonstrated that circulating miR-208b and miR-34a could be useful biomarkers for predicting left ventricular remodeling after AMI, and the miRNA levels are associated with increased risk of mortality or heart failure.

Background/Aims: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo–Yap pathway in human rectal cancer tumorigenesis and metastasis. Methods: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. Results: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. Conclusion: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy.

Long non-coding RNAs (lncRNAs) are powerful factors influencing the tumorigenesis and metastasis of multiple carcinomas. LncRNA MNX1-AS1 plays critical roles in the progression of tumor formation according to recent research, while its roles in esophageal squamous cell carcinoma (ESCC) remains unknown. The expression levels of lncRNA MNX1-AS1 were examined in ESCC tissues by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The role of lncRNA MNX1-AS1 was performed by WST-1 proliferation assays, migration and invasion assays. Besides, the molecular mechanism of lncRNA MNX1-AS1 was verified by online bioinformatics, qRT-PCR and rescue assays. MNX1-AS1 was signifcantly upregulated in ESCC tissues. It was conformed that high MNX1-AS1 expression was associated with ESCC lymph node metastasis. Moreover, we found that knockdown of MNX1-AS1 apparently suppressed the cell proliferation, migration, and invasion capacity. Flow cytometry analysis showed MNX1-AS1 regulated ESCC cell cycle and apoptosis progression. Mechanism analysis revealed that miR-34a inhibitor could rescue the influence of inhibiting MNX1-AS1 on ESCC cells migration by serving as competing endogenous RNA (ceRNAs). Furthermore, we found that miR-34a specifically targeted SIRTI. Taken together, we demonstrated that lncRNA MNX1-AS1/miR-34a/SIRT1 regulatory axis could play an important role in ESCC progression, and MNX1-AS1 may act as a novel potential biomarker for esophageal squamous cell carcinoma.

A total knee arthroplasty (TKA) has always been associated with moderate-to-severe pain. A systematic review of randomized controlled trials (RCTs) and non-RCTs was performed to evaluate the efficacy and safety of pain control of adductor canal block (ACB) and femoral nerve block (FNB) after TKA.Relevant literatures about the ACB and FNB after TKA for reducing pain were searched from Medline (1996-January, 2015), Embase (1980-January, 2015), PubMed (1980-January, 2015), Web of Science (1980-January, 2015), and The Cochrane Central Register of Controlled Trials. High-quality RCTs and non-RCTs were picked to evaluate the visual analogue scale (VAS) and other outcome. This systematic review and meta-analysis were performed according to the PRISMA statement criteria. The software RevMan 5.30 was used for the meta-analysis.Eight literatures fitted into the inclusion criteria. There were no significant differences in VAS score with rest or mobilization at 4, 24, and 48 h between ACB group and FNB group. There were also no significant differences in the strength of quadriceps and adductor, the length of hospital stay, and complications of vomiting and nausea.Present meta-analysis indicated that ACB shows no superiority than FNB group. Both of them can reduce the pain score after TKA. As referred to which method to adopt, it is determined by the preference of the surgeons and anesthesiologists.