IGF-1R, a target of let-7b, mediates crosstalk between IRS-2/Akt and MAPK pathways to promote proliferation of oral squamous cell carcinoma

// Ling Gao 1,2 , Xiaolong Wang 1 , Xiaofei Wang 2 , Linmei Zhang 1 , Cui Qiang 1 , Su’e Chang 2 , Wenhao Ren 1 , Shaoming Li 1 , Yang Yang 2 , Dongdong Tong 2 , Cheng Chen 1 , Zongfang Li 3 , Tusheng Song 2 , Keqian Zhi 1 , Chen Huang 2 1 Department of Oral Maxillofacial Surgery, Stomatology Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, Shaanxi, P. R. China 2 Key Laboratory of Environment and Genes Related to Diseases, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China 3 Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China Correspondence: Chen Huang, email: // Keqian Zhi, email: // Keywords : oral squamous cell carcinoma; IGF-1R; IRS-2; let-7b; proliferation Received : January 8, 2014 Accepted : March 19, 2014 Published : March 21, 2014 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.