Abstract
Pancreatic cancer is characterized by early metastasis and high mortality. In this study, the role of miR-143 in invasion and metastasis was investigated in pancreatic cancer cells. miR-143 expression was established by an adenovirus-carried miR-143 expression cassette. mRNA and protein levels of gene expression were examined by RT-PCR and Western blot assay, respectively. Rho GTPases activity was measured by the pull down assay. The role of miR-143 in migration and invasion of Panc-1 cells was tested in vitro. The antimetastatic effect of miR-143 was tested in a liver metastasis model, while its antitumor growth effect was tested in a xenograft Panc-1 tumor model. Results demonstrated that ARHGEF1 (GEF1), ARHGEF2 (GEF2), and K-RAS genes are the targets of miR-143. miR-143 expression significantly decreased mRNA and protein levels of GEF1, GEF2, and K-RAS genes; lowered the constitutive activities of RhoA, Rac1, and Cdc42 GTPases; decreased the protein levels of MMP-2 and MMP-9; but significantly increased the protein level of E-cadherin. miR-143 expression also significantly inhibited the migration and invasion of Panc-1 cells in vitro, liver metastasis, and xenograft tumor growth in vivo. Our study suggested that miR-143 plays a central role in the invasion and metastasis of pancreatic cancer and miR-143 is a potential target for pancreatic cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Blotting, Northern
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Blotting, Western
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Cell Movement*
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Cell Proliferation
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Female
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / prevention & control*
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Liver Neoplasms / secondary
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / pathology
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Pancreatic Neoplasms / prevention & control*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins p21(ras)
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Rho Guanine Nucleotide Exchange Factors
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Signal Transduction / drug effects
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Tumor Cells, Cultured
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cdc42 GTP-Binding Protein / genetics
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cdc42 GTP-Binding Protein / metabolism
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
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ras Proteins / genetics
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ras Proteins / metabolism
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rhoB GTP-Binding Protein / genetics
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rhoB GTP-Binding Protein / metabolism
Substances
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ARHGEF2 protein, human
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Guanine Nucleotide Exchange Factors
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KRAS protein, human
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MIRN143 microRNA, human
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MicroRNAs
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Proto-Oncogene Proteins
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RAC1 protein, human
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RNA, Messenger
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Rho Guanine Nucleotide Exchange Factors
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Proto-Oncogene Proteins p21(ras)
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cdc42 GTP-Binding Protein
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rac1 GTP-Binding Protein
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ras Proteins
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rhoB GTP-Binding Protein