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.
Highlights
Oral cancer is the eighth most common malignancies in the head and neck with over 145,500 deaths annually worldwide [International Agency for Research on Cancer (IARC; 2011)][1] and oral squamous cell carcinomas (OSCC) accounts approximately for 90% of all oral cancers
To evaluate the potential clinical significance of Insulin-like growth factor (IGF)-1R and insulin receptor substrate-2 (IRS-2) expression, we examined the levels of IGF-1 receptor (IGF-1R) and IRS-2 expression by IHC staining in 64 OSCC samples and 20 normal tissues
C~E, LV-let-7b- and LV-CN- infected tumors were excised from mice, the expression levels of IGF-1R and IRS-2 mRNA were measured by qRT–PCR and the protein expression levels of IGF-1R and IRS-2 were analyzed by Western blot and immunohistochemistry staining (40×)(lower), respectively
Summary
Oral cancer is the eighth most common malignancies in the head and neck with over 145,500 deaths annually worldwide [International Agency for Research on Cancer (IARC; 2011)][1] and oral squamous cell carcinomas (OSCC) accounts approximately for 90% of all oral cancers. Despite of the numerous advances in cancer treatment, the 5-year survival rate of OSCC patients is 50%, which remains unchanged over the last decade[2]. Several environmental factors, including tobacco smoking, betel nut chewing and human papillomavirus (HPV) infection, are the main causes of OSCC[3, 4]. Not everyone exposed to these predisposing factors develops oral cancer. A better understanding of regulatory networks among molecular interactions and signalling pathways is essential for identification of novel prognostic markers or therapeutic targets for OSCC
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