Gene therapy with RNAi targeting UHRF1 driven by tumor-specific promoter inhibits tumor growth and enhances the sensitivity of chemotherapeutic drug in breast cancer in vitro and in vivo.
UHRF1, also known as ICBP90 (inverted CCAAT box binding protein 90) in human, is a nuclear protein that acts as a fundamental regulator in cell proliferation and maintains DNA methylation. It is reported that UHRF1 is obviously upregulated in various human malignancies, but unchanged in differentiated tissues, suggesting that UHRF1 plays a crucial role in carcinogenesis and can be a useful anticancer drug target. In this study, we explored whether UHRF1 can be a therapeutic target for human breast carcinoma. We successfully constructed the tumor-specific shRNA expression vector driven by survivin promoter targeting UHRF1 gene. The tumor-specific RNA interference system efficiently and specifically knocked down UHRF1 expression, induced the apoptosis of tumor cells, and enhanced chemosensitivity of tumor cells to cisplatinum, but not in normal cells in vitro and in vivo. Therefore, the survivin promoter-driving shRNA expression system targeting UHRF1 may play a vital and potential role for the treatment of specificity and high efficacy in human breast carcinomas.
Department of Clinical Diagnosis, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, Xi'an, 710038 Shaanxi Province, China.
Lin
L
Fang
Li
L
Shanqu
Gao
G
Ping
He
H
Ting
Wang
W
Xi
Dong
D
Ke
Long
L
Min
Wei
W
Junxia
Zhang
Z
Huizhong
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D034741:RNA, Small Interfering; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases; D002945:Cisplatin