The role of AUF1 in thyroid carcinoma progression

Abstract

AUF1/heterogeneous nuclear ribonucleoprotein D is an adenylate-uridylate-rich elements (AREs) -binding protein, which regulates the mRNA stability of many genes related to growth regulation, such as proto-oncogenes, growth factors, cytokines, and cell cycle-regulatory genes. Several studies demonstrated AUF1 involvement in the processes of apoptosis, tumorigenesis, and development by its interactions with ARE-bearing mRNAs. We report here that AUF1 may be involved in thyroid carcinoma progression. Investigations on thyroid tissues revealed that cytoplasmic expression of AUF1 in malignant tissues was increased when compared with benign thyroid tissues. In thyroid carcinoma cell lines, AUF1 was mostly detectable in the nucleus; however, in dividing cells, its increased production was also observed in the cytoplasm. We found AUF1 in complexes with ARE-bearing mRNAs, previously described to be crucial for proliferation and cell cycle of thyroid carcinoma. Total or exon-selective knockdown of AUF1 led to growth inhibition accompanied by induction of cell cycle inhibitors and decreased levels of cell cycle promoters. Our data demonstrate the existence of a complex network between AUF1 and mRNAs encoding proteins related to cell proliferation. AUF1 may control the balance between stabilizing and destabilizing effects, both of which are exerted on cell cycle machinery in thyroid carcinoma. Although we cannot exclude participation of other factors, thyroid carcinoma may recruit cytoplasmic AUF1 to disturb the stability of mRNAs encoding cyclin-dependent kinase inhibitors, leading to uncontrolled growth and progression of tumor cells. Thus, AUF1 may be considered as a new, additional marker for thyroid carcinoma.

MicroRNA-141 and MicroRNA-146b-5p Inhibit the Prometastatic Mesenchymal Characteristics through the RNA-binding Protein AUF1 Targeting the Transcription Factor ZEB1 and the Protein Kinase AKT

“…Furthermore, overexpression of AUF1 enhanced tumorigenesis in murine models (15), and mice engineered to overexpress the p37 isoform of AUF1 developed undifferentiated sarcomas with high vascularization and cellularity (36). Moreover, cytoplasmic expression of AUF1 was higher in malignant thyroid tissues as compared with benign tissues, and total or exon-selective knockdown of AUF1 led to growth inhibition accompanied by the induction of cell cycle inhibitors (37). Additionally, in breast carcinoma cells, AUF1 showed increased binding to a number of mRNAs linked to the transformation of epithelial cells (38).…”

Expression of ARE-binding proteins AUF1 and HuR in follicular adenoma and carcinoma of thyroid gland

“…We found that the low levels of both proteins in benign and adenoma tissues are extremely high in thyroid carcinoma tissues. Furthermore, in addition to our previously published data [33,34], we were able to quantify the expression of both proteins on total protein lysates obtained from homogenized thyroid resectants. More importantly, by employment of AUF1 and/or HuR anti-sera on human samples often containing other and unwanted types of the cells (i.e.…”

“…Our previous studies demonstrated that ARE-binding protein AUF1 promotes thyroid carcinogenesis and may serve as a new additional marker for thyroid carcinoma progression [33]. Given that FNA biopsy samples may contain variable and limited number of thyroid epithelial cells and unwanted blood cells, we applied total tissue lysates obtained from surgical resection for investigation with specific AUF1 and HuR anti-sera.…”

Modulation of Gene Expression by RNA Binding Proteins: mRNA Stability and Translation

“…Unlike HuR, AUF1 promotes the degradation of the vast majority of its known targets through the recruitment of the mRNA to the exosome and the proteasome [23,24], for example: cell cycle related genes such as cyclin D1, p21, p27 and p16INK4a [59][60][61][62], apoptosis regulators such as B cell leukemia (BCL-2) and growth arrest and DNA-damageinducible protein alpha (GADD45α) [63,64]; inflammatory related genes such as granulocyte-macrophage colony-stimulating factor (GM-CSF): and interleukin 6 (IL6) and human inducible nitric oxide synthase (NOS) [65][66][67] and DNA replication and repair related genes such as thymidylate synthase (TYMS), jun D proto-oncogene (JUND and c-fos (FOS) [68][69][70]. However, AUF1 can promote the stability and translation of some target transcripts.…”