m6A demethylation of FOSL1 mRNA protects hepatoma cells against necrosis under glucose deprivation.

Stress-adaptive mechanisms enabling cancer cells to survive under glucose deprivation remain elusive. N6-methyladenosine (m6A) modification plays important roles in determining cancer cell fate and cellular stress response to nutrient deficiency. However, whether m6A modification functions in the regulation of cancer cell survival under glucose deprivation is unknown. Here, we found that glucose deprivation reduced m6A modification levels. Increasing m6A modification resulted in increased hepatoma cell necrosis under glucose deprivation, whereas decreasing m6A modification had an opposite effect. Integrated m6A-seq and RNA-seq revealed potential targets of m6A modification under glucose deprivation, including the transcription factor FOSL1; further, glucose deprivation upregulated FOSL1 by inhibiting FOSL1 mRNA decay in an m6A-YTHDF2-dependent manner through reducing m6A modification in its exon1 and 5'-UTR regions. Functionally, FOSL1 protected hepatoma cells against glucose deprivation-induced necrosis in vitro and in vivo. Mechanistically, FOSL1 transcriptionally repressed ATF3 by binding to its promoter. Meanwhile, ATF3 and MAFF interacted via their leucine zipper domains to form a heterodimer, which competed with NRF2 for binding to antioxidant response elements in the promoters of NRF2 target genes, thereby inhibiting their transcription. Consequently, FOSL1 reduced the formation of the ATF3-MAFF heterodimer, thereby enhancing NRF2 transcriptional activity and the antioxidant capacity of glucose-deprived-hepatoma cells. Thus, FOSL1 alleviated the necrosis-inducing effect of glucose deprivation-induced reactive oxygen species accumulation. Collectively, our study uncovers the protective role of m6A-FOSL1-ATF3 axis in hepatoma cell necrosis under glucose deprivation, and may provide new targets for cancer therapy.

Percutaneous transhepatic variceal embolization with cyanoacrylate versus endoscopic ligation in management of esophageal variceal bleeding / 中华消化内镜杂志

Objective To compare the therapeutic effect of percutaneous transhepatic variceal em-bolization (PTVE) with Cyanoacrylate(TH glue) with that of endoscopic variceal ligatien (EVL) in the treatment of esophageal varlceal bleeding. Methods In this prospective randomized controlled trial, cirrhot-ic patients with acute or recent esophageal variceal bleeding were assigned randomly to PTVE (n = 52) or EVL (n=50) groups. Variants including upper gastrointestinal (UGI) re-bleeding, esophageal variceal re-bleeding, relapse of esophageal variees and survival were evaluated. Results During the follow-up (median 24 and 25 months in the PTVE and EVL groups, respectively), UGI re-bleeding developed in 8 patients (15. 4%) in PTVE group and in 21 (42%) in EVL group (X2 =8. 87, P=0. 005). Recurrent esophageal varices bleeding occurred in 3 patients (5. 8%) in FIVE group and 12 (24%) in EVL group (X2 =5.38, P =0. 012, relative risk 0. 24, 95% confidence interval 0. 05 -0. 74). Reccurent rates of esophageal vari-ces in two groups were 17.3% (9/52) and 52% (26/50), respectively (X2 =13.61, P<0.001). There was no significant difference in survival rate between two groups (X2 = 3.30, P = 0. 054). Conclusion With sufficient embolization of lower esophageal and pefi-esophngeal varices and/or the cardial submucosal and perforating vessels, PTVE was more effective than EVL in the management of esophageal varices recur-rence and re-bleeding.