| Osteopontin regulates epithelial mesenchymal transition-associated growth of hepatocellular cancer in a mouse xenograft model. | |
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MedLine Citation:
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PMID: 22241292 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: To determine the efficacy of osteopontin (OPN) targeting in hepatocellular cancer (HCC). SUMMARY/BACKGROUND: OPN is associated with HCC growth and metastasis and represents a unique therapeutic target. METHODS: OPN and epithelial-mesenchymal transition (EMT) markers, α-smooth muscle actin (SMA), vimentin, and tenascin-c, were measured in archived human HCC tissues from metastatic (n = 4) and nonmetastatic (n = 4) settings. Additional studies utilized human Sk-Hep-1 (high OPN expression) and Hep3b (low OPN expression) HCC cells. An RNA aptamer (APT) that avidly binds (Kd = 18 nM; t1/2 = 7 hours) and ablates OPN binding was developed. Adhesion, migration/invasion, and EMT markers were determined with APT or a mutant control aptamer (Mu-APT). RFP-Luc-Sk-Hep-1 were implanted into NOD-scid mice livers and followed by using bioluminescence imaging. After verification of tumor growth, at week 3, APT (0.5 mg/kg; n = 4) or Mu-APT (0.5 mg/kg; n = 4) was injected q48h. When mice were killed at week 8, tumor cells were reisolated and assayed for EMT markers. RESULTS: OPN and EMT markers were significantly increased in the metastatic cohort. APT inhibited Sk-Hep-1 adhesion and migration/invasion by 5- and 4-fold, respectively. APT significantly decreased EMT protein markers, SMA, vimentin, and tenascin-c. In contrast, APT did not alter Hep3B adhesion, or migration/invasion. EMT markers were slightly decreased. In the in vivo model, at weeks 6 to 8, APT inhibited HCC growth by more than 10-fold. SMA, vimentin, and tenascin-c mRNAs were decreased by 60%, 40%, and 49%, respectively, in RFP-positive Sk-Hep-1 recovered by fluorescence-activated cell sorting (P < 0.04 vs Mu-APT for all). CONCLUSIONS: APT targeting of OPN significantly decreases EMT and tumor growth of HCC. |
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Authors:
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Syamal D Bhattacharya; Zhiyong Mi; Victoria M Kim; Hongtao Guo; Lindsay J Talbot; Paul C Kuo |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Annals of surgery Volume: 255 ISSN: 1528-1140 ISO Abbreviation: Ann. Surg. Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-01-13 Completed Date: 2012-03-20 Revised Date: 2012-05-30 |
Medline Journal Info:
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Nlm Unique ID: 0372354 Medline TA: Ann Surg Country: United States |
Other Details:
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Languages: eng Pagination: 319-25 Citation Subset: AIM; IM |
Affiliation:
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Department of Surgery, Duke University Medical Center, Durham, NC, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adult Animals Aptamers, Nucleotide Blotting, Western Carcinoma, Hepatocellular / metabolism*, pathology Cell Line, Tumor Epithelial-Mesenchymal Transition / physiology* Humans Liver Neoplasms / metabolism*, pathology Liver Neoplasms, Experimental / metabolism, pathology Mice Middle Aged Neoplasm Metastasis Neoplasm Transplantation Osteopontin / metabolism* Real-Time Polymerase Chain Reaction SELEX Aptamer Technique Tumor Markers, Biological / metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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R01 GM065113/GM/NIGMS NIH HHS; R01 GM065113/GM/NIGMS NIH HHS; R01 GM065113-05A2/GM/NIGMS NIH HHS; T32 CA093245/CA/NCI NIH HHS; T32 GM069331/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Aptamers, Nucleotide; 0/Tumor Markers, Biological; 106441-73-0/Osteopontin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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