Abstract
Insulin-like growth factor (IGF) signaling is involved in oral squamous cell carcinoma (OSCC), but IGF-1 receptor (IGF-1R)-mediated intricate regulatory networks among molecular interactions and signalling path ways in OSCC remain unclear. Here, we found that overexpression of IGF-1R and insulin receptor substrate-2 (IRS-2) was negatively associated with histological differentiation. IGF signaling stimulated OSCC cell growth. Conversely, overexpression of let-7b inhibited proliferation and colony formation and triggered S/G2 cell cycle arrest by targeting IGF-1R and IRS-2 through the Akt pathway. Also, the inverse relationship between expression of let-7b and IGF-1R/IRS-2 was confirmed in OSCC tumor xenografts and clinical specimens. Furthermore, by activating ERK1/2, IGF-1R transcriptionally upregulated IRS-2. Our results indicate that let-7b/IGF-1R-mediated crosstalk between IRS-2/Akt and MAPK is involved in OSCC and is a potential therapeutic target for therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Apoptosis
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Blotting, Western
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism
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Carcinoma, Squamous Cell / pathology*
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Cell Cycle
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Cell Differentiation
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Cell Proliferation*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Immunoenzyme Techniques
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Insulin Receptor Substrate Proteins / antagonists & inhibitors
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism*
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Male
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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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Middle Aged
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mouth Neoplasms / genetics
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Mouth Neoplasms / metabolism
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Mouth Neoplasms / pathology*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Insulin Receptor Substrate Proteins
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MicroRNAs
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RNA, Messenger
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mirnlet7 microRNA, human
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Phosphatidylinositol 3-Kinases
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Receptor, IGF Type 1
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases