Abstract 3508: The RNA-binding protein CELF1 regulates the tumor suppressive protein IL-24/mda-7 expression in oral squamous cell carcinoma

The majority of oral squamous cell carcinoma (OSCC) patients are diagnosed at an advanced disease stage and the overall 5-year survival rate, surprisingly, has not changed dramatically over the past several decades. Therefore, identification and subsequent characterization of new molecular determinants of OSCC, may aid in the discovery of novel targets capable of predicting patient treatment response and disease prognosis. Co- and post-transcriptional gene expression plays a crucial role in disease development. RNA binding proteins (RBPs) are critical regulators of messenger RNA (mRNA) fate within mammalian cells. The RBP CELF1 associates with GU-rich element (GRE) containing mRNAs and post transcriptionally regulates mRNA stability, translation and pre-mRNA alternative splicing. Our previous studies demonstrated that the protein levels of CELF1, increased as HNSCC disease progressed from Stage I-IV. In addition, reduction of CELF1 in oral cancer cells promoted programmed cell death and decreased tumor burden in a xenograft mouse model. In an effort to understand the underlying mechanism employed by CELF1 to promote anti-tumor activity, we utilized genomic techniques to identify CELF1 mRNA targets in oral cancer cells. Interestingly, the gene IL-24/mda-7 was one of the top aberrantly expressed mRNAs identified as a function of CELF1 levels in oral cancer cells. Interleukin -24 also known as melanoma differentiation associated gene-7 (IL-24/mda-7) is a member of the IL-10 related family of cytokines. IL-24 protein expression is absent in most cancers and forced expression of IL-24 using an adenoviral vector enhances tumor cell-specific apoptosis. Although the mechanism of IL-24 induced cell death has been studied for several cancers, the role of IL-24 in HNSCC is not well known. In addition, the regulatory mechanisms controlling IL-24 expression in cancer are not well studied. Here, we show that IL-24 mRNA is overexpressed in HNSCC tissues compared to normal specimens. Furthermore, utilizing a mouse model of oral carcinogenesis we determined that IL-24 mRNA levels are enhanced in hyperplastic/dysplastic and oral squamous cell carcinoma tissues compared to normal, which is coincident with increased protein levels of CELF1. Surprisingly, loss of CELF1 expression in oral cancer cells dramatically increased IL-24 protein from undetectable levels to robust expression. We are currently exploring the mechanism of the CELF-1/IL-24 axis in mediating apoptosis in ora