Mechanism and its regulation of tumor-induced angiogenesis

Background: Pancreatic cancer is one of the most lethal human cancers.N⁶-methyladenosine (m⁶A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive.Methods: LC/MS was used to profile m⁶A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m⁶A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.Results: We found that the m⁶A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m⁶A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo,via direct targeting of the downstreamPERPmRNA (p53 effector related to PMP-22) in an m⁶A-dependent manner. Methylation of the target adenosine lead to increasedPERPmRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.Conclusions: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m⁶A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

Established closure techniques for the pancreatic remnant after distal pancreatectomy include stapler, suture and anastomotic closure. However, controversy remains regarding the ideal technique; therefore, the aim of this study was to compare closure techniques and risk of postoperative pancreatic fistula (POPF). A systematic review was carried out according to PRISMA guidelines for studies published before January 2014 that compared at least two closure techniques for the pancreatic remnant in distal pancreatectomy. A random-effects model was constructed using weighted odds ratios (ORs). Thirty-seven eligible studies matched the inclusion criteria and 5252 patients who underwent distal pancreatectomy were included. The primary outcome measure, the POPF rate, ranged 0 from to 70 per cent. Meta-analysis of the 31 studies comparing stapler versus suture closure showed that the stapler technique had a significantly lower rate of POPF, with a combined OR of 0·77 (95 per cent c.i. 0·61 to 0·98; P = 0·031). Anastomotic closure was associated with a significantly lower POPF rate than suture closure (OR 0·55, 0·31 to 0·98; P = 0·042). Combined stapler and suture closure had significantly lower POPF rates than suture closure alone, but no significant difference compared with stapler closure alone. The use of stapler closure or anastomotic closure for the pancreatic remnant after distal pancreatectomy significantly reduces POPF rates compared with suture closure. The combination of stapler and suture closure shows superiority over suture closure alone.

Pancreatic cancer (PC) is one of the most lethal diseases, and effective treatment of PC patients remains an enormous challenge. Rocaglamide A (Roc-A), a bioactive molecule extracted from the plant Aglaia elliptifolia, has aroused considerable attention as a therapeutic choice for numerous cancer treatments. Nevertheless, the effects and underlying mechanism of Roc-A in PC are still poorly understood. Here, we found that Roc-A inhibited growth and stimulated apoptosis by induction of mitochondria dysfunction in PC. Moreover, Roc-A accelerated autophagosome synthesis and triggered mitophagy involving the PTEN-induced putative kinase 1 (PINK1)/Parkin signal pathway. We also demonstrated that inhibition of autophagy/mitophagy can sensitize PC cells to Roc-A. Finally, Roc-A treatment results in an obvious accumulation of reactive oxygen species (ROS), and pretreatment of cells with the reactive oxygen species scavenger N-acetylcysteine reversed the apoptosis and autophagy/mitophagy induced by Roc-A. Together, our results elucidate the potential mechanisms of action of Roc-A. Our findings indicate Roc-A as a potential therapeutic agent against PC and suggest that combination inhibition of autophagy/mitophagy may be a promising therapeutic strategy in PC.