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EpCAM Aptamer-siRNA chimera targets and regress epithelial cancer

Subramanian, Nithya, Kanwar, Jagat R., Kanwar, Rupinder K., Sreemanthula, JagadeeshBabu, Biswas, Jyotirmay, Khetan, Vikas and Krishnakumar, Subramanian 2015, EpCAM Aptamer-siRNA chimera targets and regress epithelial cancer, PLoS one, vol. 10, no. 7, pp. 1-19, doi: 10.1371/journal.pone.0132407.

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Title EpCAM Aptamer-siRNA chimera targets and regress epithelial cancer
Author(s) Subramanian, Nithya
Kanwar, Jagat R.
Kanwar, Rupinder K.
Sreemanthula, JagadeeshBabu
Biswas, Jyotirmay
Khetan, Vikas
Krishnakumar, Subramanian
Journal name PLoS one
Volume number 10
Issue number 7
Start page 1
End page 19
Total pages 19
Publisher Public Library of Science (PLoS)
Place of publication San Francisco, Calif.
Publication date 2015
ISSN 1932-6203
Keyword(s) Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CELL ADHESION MOLECULE
DRUG-DELIVERY
BREAST-CANCER
RNA MOLECULES
STEM-CELLS
RETINOBLASTOMA
SELECTION
THERAPY
DNA
PHENOTYPE
Summary Epithelial cell adhesion molecule (EpCAM), a cancer stem cell (CSC) marker is over expressed in epithelial cancers and in retinoblastoma (RB). We fabricated an EpCAM targeting aptamer-siRNA chimera and investigated its anti-tumor property and EpCAM intracellular domain (EpICD) mediated signaling in epithelial cancer. The anti-tumor efficacy of EpCAM aptamer-siEpCAM chimera (EpApt-siEp) was evaluated by qPCR, northern and Western blotting in WERI-Rb1- RB cell line, primary RB tumor cells and in MCF7- breast cancer cell line. Anti-tumor activity of EpApt-siEp was studied in vivo using epithelial cancer (MCF7) mice xenograft model. The mechanism and pathways involved in the anti-tumor activity was further studied using protein arrays and qPCR. EpApt-siEp chimera was processed in vitro by dicer enzyme. Treatment of the WERI-Rb1 and MCF7 cells with EpApt-siEp revealed statistically significant down regulation of EpCAM expression (P<0.005) and concomitant reduction in cellular proliferation. In primary RB cells cultured from RB tumors, EpApt-siEp silenced EpCAM, significantly inhibited (P<0.01) cell proliferation and induced cytotoxicity. Knockdown of EpICD expressed in RB primary tumors led to repression of pluripotency markers, SOX2, OCT4, NANOG, and CD133. In vivo studies showed complete tumor growth regression without any toxicity in animals (P<0.001) and tumor tissues showed significant downregulation (P<0.05) of EpCAM, MRP1, ABCG2, stathmin, survivin and upregulation of ATM (P<0.05) leading to apoptosis by intrinsic pathway with minor alteration in cytokines. Our results revealed that EpApt-siEp potentially eradicated EpCAM positive cancer cells through CSC marker suppression and apoptosis, while sparing normal EpCAM negative adjacent cells.
Language eng
DOI 10.1371/journal.pone.0132407
Field of Research 111299 Oncology and Carcinogenesis not elsewhere classified
Socio Economic Objective 920102 Cancer and Related Disorders
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2015, Public Library of Science (PLoS)
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30078110

Document type: Journal Article
Collections: School of Medicine
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Created: Mon, 07 Sep 2015, 12:43:33 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.