title: EpCAM Aptamer-mediated Survivin Silencing Sensitized Cancer Stem Cells to Doxorubicin in a Breast Cancer Model.
abstract: Understanding the molecular basis of drug resistance and utilising this information to overcome chemoresistance remains a key challenge in oncology. Here we report that survivin, a key protein implicated in drug resistance, is overexpressed in cancer stem cell pool of doxorubicin-resistant breast cancer cells. Moreover, by utilising an active targeting system consisting of an RNA aptamer targeted against the epithelial cell adhesion molecule and a Dicer substrate survivin siRNA, we could deliver a high dose of the siRNA to cancer stem cells in xenograft tumours. Importantly, silencing of survivin with this aptamer-siRNA chimera in cancer stem cell population led to the reversal of chemoresistance, such that combined treatment with low dose of doxorubicin inhibited stemness, eliminated cancer stem cells via apoptosis, suppressed tumour growth, and prolonged survival in mice bearing chemoresistant tumours. This strategy for in vivo cancer stem cell targeting has wide application for future effective silencing of anti-death genes and in fact any dysregulated genes involved in chemoresistance and tumour relapse.
authors.affiliation: 1. School of Nursing, Zhengzhou University, Zhengzhou, P. R. China, 450001. ; 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: 3. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia ; 4. Department of Molecular and Translational Science, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gantier
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Dongxi
authors.initials: D
authors.lastname: Xiang
authors.affiliation: 5. CSIRO Australian Animal Health Laboratory, Private Bag 24, Geelong, Victoria 3220, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bean
authors.affiliation: 5. CSIRO Australian Animal Health Laboratory, Private Bag 24, Geelong, Victoria 3220, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bruce
authors.affiliation: 6. Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Alister
authors.initials: A
authors.lastname: Ward
authors.affiliation: 7. Department of Gynecologic Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: 8. School of Medical Science & Griffith Health Institute, Gold Coast Campus, Griffith University, Southport, QLD 4222, Australia.
authors.forename: Ming Q
authors.initials: MQ
authors.lastname: Wei
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Hadi
authors.initials: H
authors.lastname: AlShamaileh
authors.affiliation: 9. Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
authors.forename: Lijue
authors.initials: L
authors.lastname: Chen
authors.affiliation: 9. Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: She
authors.affiliation: 10. Department of Biochemistry and Molecular Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, P. R. China, 610041.
authors.forename: Jia
authors.initials: J
authors.lastname: Lin
authors.affiliation: 9. Institute for Frontier Materials, Deakin University, Waurn Ponds, Victoria, 3216, Australia.
authors.forename: Lingxue
authors.initials: L
authors.lastname: Kong
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Shigdar
authors.affiliation: 2. School of Medicine, Deakin University, 75 Pigdons Road, Waurn Ponds, Victoria, 3217, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077022:Survivin; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; C107489:BIRC5 protein, human; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D004317:Doxorubicin
keywords: Aptamer; Breast cancer; Cancer stem cell; RNA interference; Survivin