Tianxiao Wang

// Jianwei Xu 1,* , Tianxiao Wang 2,* , Zhe Cao 1 , Hua Huang 1 , Jian Li 1 , Wenjing Liu 1 , Shanglong Liu 1 , Lei You 1 , Li Zhou 1 , Taiping Zhang 1 , Yupei Zhao 1 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of head and neck Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China * These authors contributed equally to this work Correspondence: Taiping Zhang , email: // Yupei Zhao , email: // Keywords : pancreatic cancer, miRNA, chemoresistance, prognosis Received : May 06, 2014 Accepted : July 06, 2014 Published : July 08, 2014 Abstract Chemoresistance is one of the causes of poor prognosis in pancreatic cancer patients. However, the mechanisms of resistance remain unclear. Here we screened miRNAs associated with drug resistance in pancreatic cancer, and identified a panel of miRNAs dysregulated in gemcitabine-resistance pancreatic cancer cells, including 13 downregulated miRNAs and 20 upregulated miRNAs. Further studies focusing on miR-497 demonstrated that miR-497 suppressed cells proliferation, decreased the percentage of S phase cells, re-sensitized cells to gemcitabine and erlotinib, and attenuated migration and invasion capacities. Furthermore, fibroblast growth factor 2 and fibroblast growth factor receptor 1 were confirmed as miR-497 targets. Overexpression of miR-497 inhibited tumor growth in vivo . Additionally, miR-497 expression was significantly downregulated in pancreatic cancer tissues compared with tumor-adjacent samples (P=0.000). Low expression of miR-497 was an independent adverse prognostic factor of pancreatic cancer (P=0.01, hazard ratio=2.762, 95% confidence interval: 1.159–6.579). Together these results indicate that miR-497 could be a new therapeutic target and prognostic marker of pancreatic cancer.

// Tianxiao Wang 1 , Jingxuan Yang 2 , Jianwei Xu 1 , Jian Li 1 , Zhe Cao 1 , Li Zhou 1 , Lei You 1 , Hong Shu 1 , Zhaohui Lu 3 , Huihua Li 4 , Min Li 2 , Taiping Zhang 1 , and Yupei Zhao 1 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 The Vivian L. Smith Department of Neurosurgery, the University of Texas Medical School at Houston, Houston, Texas, USA 3 Department of Pathology and Pathophysiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 4 Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China Correspondence: Min Li, email: // Taiping Zhang, email: // Yupei Zhao, email: // Keywords : CHIP, EGFR, pancreatic cancer, ubiquitination Received : February 25, 2014 Accepted : April 06, 2014 Published : April 08, 2014 Abstract Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathways. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo . The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.

Irradiation has been reported to increase radioresistance and epithelial-mesenchymal transition (EMT) in gastric cancer (GC) cells. The Notch pathway is critically implicated in cancer EMT and radioresistance. In the present study, we investigated the use of a Notch-1 inhibiting compound as a novel therapeutic candidate to regulate radiation-induced EMT in GC cells. According to previous screening, tangeretin, a polymethoxylated flavonoid from citrus fruits was selected as a Notch-1 inhibitor. Tangeretin enhanced the radiosensitivity of GC cells as demonstrated by MTT and colony formation assays. Tangeretin also attenuated radiation-induced EMT, invasion and migration in GC cells, accompanied by a decrease in Notch-1, Jagged1/2, Hey-1 and Hes-1 expressions. Tangeretin triggered the upregulation of miR-410, a tumor-suppressive microRNA. Furthermore, re-expression of miR-410 prevented radiation-induced EMT and cell invasion. An in vivo tumor xenograft model confirmed the antimetastasis effect of tangeretin as we observed in vitro. In nude mice, tumor size was considerably diminished by radiation plus tangeretin co-treatment. Tangeretin almost completely inhibited lung metastasis induced by irradiation. Tangeretin may be a novel antimetastatic agent for radiotherapy.