Slug inhibition upregulates radiation-induced PUMA activity leading to apoptosis in cholangiocarcinomas.
Resistance of cholangiocarcinoma to irradiation therapy is a major problem in cancer treatment. Slug, a snail family transcription factor, is a suppressor of PUMA (p53 upregulated modulator of apoptosis), which has been shown to be involved in the control of apoptosis. In this study, we investigated whether the modulation of Slug expression, using adeno-associated-virus-mediated transfer of siRNA targeting Slug gene (rAAV2-Slug siRNA), affects cholangiocarcinoma sensitivity to radiation. In the present study, we used rAAV2-Slug siRNA to downregulate the expression of Slug in QBC939 cholangiocarcinoma cell lines in vitro before γ-irradiation. In vivo studies were done with orthotopic cholangiocarcinoma, and radiosensitivity was evaluated both in vitro and in vivo. rAAV2-Slug siRNA transfection resulted in downregulation of the levels of Slug in QBC939 cells. In addition, rAAV2-Slug siRNA, in combination with radiation, increased levels of the PUMA, which contributes to the radiosensitivity of cholangiocarcinomas. Finally, treatment with rAAV2-Slug siRNA plus γ-irradiation completely regressed tumor growth in orthotopic cholangiocarcinomas model. In summary, integrating gene therapy with radiotherapy could have a synergistic effect, thereby improving the survival of patients with cholangiocarcinomas.
Department of General Surgery, The Affiliated Hospital of Medical College, QingDao University, 266003 QingDao, Shan Dong Province, People's Republic of China. wlsdermyy@163.com
Kejun
K
Zhang
Bingyuan
B
Zhang
Yun
Y
Lu
Chuandong
C
Sun
Wei
W
Zhao
Xuelong
X
Jiao
Jilin
J
Hu
Peng
P
Mu
Hai
H
Lu
Changyong
C
Zhou
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D015854:Up-Regulation / Q000528:radiation effects
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors