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Pancreas. 2009 Oct;38(7):e190-9. doi: 10.1097/MPA.0b013e3181ba82e1.

Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma.

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1
Ohio State University, Columbus, 43210, USA.

Abstract

OBJECTIVES:

The contribution of overexpressed microRNA-21 and -221 (miR-21 and miR-221) to the malignant phenotype was determined by inhibiting these miRNAs using antisense oligonucleotides.

METHODS:

The effects of antisense to miR-21 and miR-221 on cell proliferation, cell cycle arrest, induction of apoptosis, combinatorial effects with gemcitabine, and effects on target protein levels were studied.

RESULTS:

Low nanomolar concentrations of both antisense oligonucleotides reduced proliferation of pancreatic cancer cell lines. Reduced proliferation was less pronounced in the normal ductal epithelial cell line human pancreatic Nestin-expressing cell or in pancreatic cancer cell lines exposed to an irrelevant control oligonucleotide. Inhibition of miR-21 and miR-221 increased the amount of apoptosis in HS766T cells by 3- to 6-fold compared with the control oligonucleotide. HS766T cells exposed to miR-21 antisense resulted in cell cycle arrest (G1 phase). Protein levels of tumor suppressor targets of the miRNAs were increased by antisense to miR-21 (PTEN and RECK) and miR-221 (p27). Antisense to miR-21 and miR-221 sensitized the effects of gemcitabine, and the antisense-gemcitabine combinations were synergistic at high fraction affected.

CONCLUSIONS:

We demonstrate that antisense to miR-21 and miR-221 results in significant cell killing under various conditions and that antisense oligonucleotides targeted to miRNA represents a potential new therapy for pancreatic cancer.

PMID:
19730150
DOI:
10.1097/MPA.0b013e3181ba82e1
[Indexed for MEDLINE]

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