Hypoxia induces TWIST-activated epithelial-mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice.
The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data. Expression of TWIST and HIF-1α proteins was significantly upregulated, whereas expression of E-cadherin and p16 was down-regulated in PDAC tissues compared to that of non-tumor tissues and in tumor tissues obtained from patients with tumor involving splenic artery than those without splenic artery involvement. Up-regulated TWIST in tumor tissues were associated with worse prognosis in PDAC patients. The in vitro data showed that HIF-1α-induced TWIST overexpression promoted tumor cell growth and EMT under a hypoxic condition via TWIST interaction with Ring1B and EZH2. In vivo data showed that TWIST overexpression or a hypoxic condition induce xenograft growth, abdominal metastasis and low mouse survival, whereas knockdown of either Ring1B or EZH2 expression suppressed tumor xenograft growth and metastasis and prolonged survival of nude mice. TWIST was the key player in promotion of pancreatic cancer development and metastasis under a hypoxic condition through interaction with Ring1B and EZH2 to regulate expression of E-cadherin and p16 proteins in pancreatic cancer cells.
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China; Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China; Department of General Surgery, Research Institute of Pancreatic Disease, Ruijin Hospital Affiliated to Shanghai Jiaotong, University School of Medicine, Shanghai, China.
Shi
S
Chen
Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
Jiang-Zhi
JZ
Chen
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China; Department of General Surgery, Research Institute of Pancreatic Disease, Ruijin Hospital Affiliated to Shanghai Jiaotong, University School of Medicine, Shanghai, China.
Jia-Qiang
JQ
Zhang
Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
Hui-Xin
HX
Chen
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
Mao-Lin
ML
Yan
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
Long
L
Huang
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China.
Yi-Feng
YF
Tian
Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China. Electronic address: drchenyl@126.com.
Yan-Lin
YL
Chen
Department of Hepatobiliary Surgery, Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China. Electronic address: wangyaodongch@163.com.
Yao-Dong
YD
Wang
D000008:Abdominal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D000072258:Tumor Hypoxia; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D015703:Antigens, CD; C513384:CDH1 protein, human; C000614131:CDKN2A protein, human; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human
EMT; Hypoxia; Pancreatic cancer; Prognosis; TWIST