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.