Stability of mRNA and carcinogenesis: The role of AUF1 in thyroid carcinoma progression

AUF1/ heterogeneous nuclear ribonucleoprotein D (hnRNPD) is an adenylate uridylate-rich elements (ARE) binding protein. AUF1 regulates the mRNA stability of many genes related to growth regulation, including proto-oncogenes, growth factors, cytokines and cell cycle regulatory genes. AUF1 is expressed in kidney, liver, lymphoid tissues and melanocytes, and is involved in apoptosis, tumorigenesis and development by its interactions with ARE-bearing mRNAs. Here we provide evidence for a role of AUF1 during thyroid carcinogenesis. We show that in human thyroid carcinoma cell lines AUF1 affects cell cycle progression and provide evidence for an altered nuclear/ cytoplasmic ratio of AUF1 expression during cell division. Moreover, siRNA knock-down of AUF1 resulted in increased cellular levels of c-Myc oncoprotein, the down-regulation of wild type p53 and elevated expression of cyclin-dependent kinase inhibitors. These findings correlate with a decreased proliferation rate of thyroid carcinoma cells. Subcellular fractionation and immunohistochemistry of thyroid tissues revealed significantly increased cytoplasmic expression of AUF1 in benign and malignant tissues as compared to normal thyroid tissues. Furthermore, logarithmic nuclear/ cytoplasmic ratio of total AUF1 expression in normal, goiter, adenoma and follicular thyroid carcinoma decreased along with tissue malignancy. Thus, we hypothesize that cytoplasmic AUF1 promotes thyroid carcinogenesis by affecting the half-life of mRNA transcripts contributing to thyroid carcinoma progression. This is the first report of the expression analysis of AUF1 in normal, benign and malignant thyroid tissues implicating AUF1 as a potential novel marker for human thyroid carcinoma.