ObjectiveThe aim of the study was to investigate the role and regulatory mechanisms of fibroblast-like synoviocytes (FLSs) and their senescence in the progression of osteoarthritis (OA).MethodsSynovial tissues from normal patients and patients with OA were collected. Synovium FLS senescence was analysed by immunofluorescence and western blotting. The role of methyltransferase-like 3 (METTL3) in autophagy regulation was explored using N6-methyladenosine (m6A)-methylated RNA and RNA immunoprecipitation assays. Mice subjected to destabilisation of the medial meniscus (DMM) surgery were intra-articularly injected with or without pAAV9 loaded with small interfering RNA (siRNA) targeting METTL3. Histological analysis was performed to determine cartilage damage.ResultsSenescent FLSs were markedly increased with the progression of OA in patients and mouse models. We determined that impaired autophagy occurred in OA-FLS, resulting in the upregulation of senescence-associated secretory phenotype (SASP). Re-establishment of autophagy reversed the senescent phenotype by suppressing GATA4. Further, we observed for the first time that excessive m6A modification negatively regulated autophagy in OA-FLS. Mechanistically, METTL3-mediated m6A modification decreased the expression of autophagy-related 7, an E-1 enzyme crucial for the formation of autophagosomes, by attenuating its RNA stability. Silencing METTL3 enhanced autophagic flux and inhibited SASP expression in OA-FLS. Intra-articular injection of synovium-targeted METTL3 siRNA suppressed cellular senescence propagation in joints and ameliorated DMM-induced cartilage destruction.ConclusionsOur study revealed the important role of FLS senescence in OA progression. Targeted METTL3 inhibition could alleviate the senescence of FLS and limit OA development in experimental animal models, providing a potential strategy for OA therapy.

Introduction: Human epidermal growth factor receptor 2 (HER2) is regarded as a poor prognostic factor in many tumors. Conflicting data in many literatures were reported about the association between HER2 and poor prognosis in lung cancer. Methods: We conducted a meta-analysis of published studies from 1966 to the 12th week of 2010. In absence of significant quality difference between positive and negative studies, combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated in terms of overall survival. Results: Forty studies(6135 patients) were included in the analysis. The pooled data showed that HER2 overexpression was a marker of poor prognosis in lung cancer. HR was 1.48 (95% CI: 1.22-1.80) and 3.11 (95% CI: 2.26 -4.28) for non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) by immunohistochemistry (IHC) assay, respectively. In the NSCLC subgroup analysis of early stage and ethnicities using IHC and in SCLC subgroup of extensive stage using IHC, it also showed that HER2 overexpression determined by IHC was a marker of poor prognosis in NSCLC and SCLC. In other subgroup of squamous cell carcinoma tested by IHC, the combined HR was 0.87 (95% CI: 0.61-1.25), indicating that HER2 overexpression was not a prognostic factor for squamous cell carcinoma. Finally, in the subgroup analysis of HER2 amplification status of NSCLC using fluorescence in situ hybridization, we also found that HER2 amplification determined by fluorescence in situ hybridization was not significantly related to prognosis. Conclusions: Although bias could be inevitable, this meta-analysis suggests that HER2 overexpression is a poor prognostic factor in lung cancer, especially for SCLC, adenocarcinoma, and early-stage NSCLC.

Both the deregulation of microRNAs and epidermal growth factor receptor (EGFR) are emerging as important factors in non‐small‐cell lung cancer (NSCLC). Here, miR‐133b was found to be associated with tumor stage, the extent of regional lymph node involvement, stage, visceral pleura or vessel invasion and EGFR mRNA expression in Chinese patients with NSCLC. Bioinformatic analysis and luciferase reporter assay revealed that miR‐133b can interact specifically with the 3′‐UTR of EGFR mRNA. Functionally, miR‐133b transfection showed regulatory activity in translationally repressing EGFR mRNA. Moreover, miR‐133b transfection may modulate apoptosis, invasion and sensitivity to EGFR‐TKI through the EGFR signaling pathways, especially in EGFR‐addicted NSCLC cells. Taken together, our findings show that miR‐133b can inhibit cell growth of NSCLC through targeting EGFR and regulating its downstream signaling pathway. This finding has important implications for the development of targeted therapeutics for a number of EGFR‐addicted cancers.

No abstract