Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood. Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression. Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and β-catenin, and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer. Our systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.

Previous gastrectomy can lead to an increased incidence of cholecystocholedocholithiasis (CCL) and increased morbidity rate. However, the appropriate treatment strategy for patients with CCL and a history of gastrectomy remains unclear. We performed a retrospective cohort study of patients with CCL and a history of gastrectomy who underwent either one-stage laparoscopic common bile duct (CBD) exploration with stone clearance and laparoscopic cholecystectomy (LCBDE+LC) or two-stage endoscopic retrograde cholangiopancreatography followed by LC (ERCP+LC) from May 2010 to March 2018. The success rate of ERCP for CBD stone clearance was 81.2% in patients with a history of Billroth I gastrectomy and 23.7% in patients with a history of Billroth II or Roux-en-Y esophagojejunostomy [χ2 = 97.67, P < 0.001, risk ratio (RR) = 3.43]. The success rate of second-step LC after successful ERCP for removal of CBD stones and the success rate of LCBDE+LC after ERCP treatment failure were 96.8 and 87.7%, respectively, in patients with preoperative intra-abdominal adhesion evaluation scores of ≤3 points. These success rates were 28.6 and 27.6%, respectively, in patients with scores of > 3 points (χ2 = 59.70, P < 0.001, RR = 3.38 and χ2 = 53.41, P < 0.001, RR = 3.27, respectively). Based on the results of this study, ERCP+LC seems to be an attractive strategy for treatment of CCL in patients with a history of Billroth I gastrectomy, and LCBDE+LC appears to be suitable for patients with a history of Billroth II or Roux-en-Y esophagojejunostomy. Preoperative evaluation of intra-abdominal adhesions helps to reduce the conversion rate of laparoscopic surgery.