학술논문
AXL Is a Novel Predictive Factor and Therapeutic Target for Radioactive Iodine Refractory Thyroid Cancer.
Document Type
Article
Author
Collina, Francesca; La Sala, Lucia; Liotti, Federica; Prevete, Nella; La Mantia, Elvira; Chiofalo, Maria Grazia; Aquino, Gabriella; Arenare, Laura; Cantile, Monica; Liguori, Giuseppina; Di Gennaro, Francesca; Pezzullo, Luciano; Losito, Nunzia Simona; Vecchio, Giancarlo; Botti, Gerardo; Melillo, Rosa Marina; Franco, Renato
Source
Subject
*ANIMAL experimentation
*CANCER relapse
*CELL culture
*CELLULAR signal transduction
*DRUG resistance in cancer cells
*CLINICAL drug trials
*GENE expression
*IMMUNOHISTOCHEMISTRY
*LONGITUDINAL method
*GENETIC mutation
*ONCOGENES
*PHOSPHORYLATION
*RATS
*SARCOMA
*SODIUM
*SURVIVAL
*THYROID gland tumors
*TUMOR markers
*DNA-binding proteins
*PAPILLARY carcinoma
*PROTEIN-tyrosine kinase inhibitors
*THYMOMA
*IN vitro studies
*IODINE radioisotopes
*THERAPEUTICS
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Language
ISSN
2072-6694
Abstract
Papillary thyroid carcinomas (PTCs) have an excellent prognosis, but a fraction of them show aggressive behavior, becoming radioiodine (RAI)-resistant and/or metastatic. AXL (Anexelekto) is a tyrosine kinase receptor regulating viability, invasiveness and chemoresistance in various human cancers, including PTCs. Here, we analyze the role of AXL in PTC prognosis and as a marker of RAI refractoriness. Immunohistochemistry was used to assess AXL positivity in a cohort of human PTC samples. Normal and cancerous thyroid cell lines were used in vitro for signaling, survival and RAI uptake evaluations. 38.2% of human PTCs displayed high expression of AXL that positively correlated with RAI-refractoriness and disease persistence or recurrence, especially when combined with v-raf murine sarcoma viral oncogene homolog B(BRAF) V600E mutation. In human PTC samples, AXL expression correlated with V-akt murine thymoma viral oncogene homolog 1 (AKT1) and p65 nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation levels. Consistently, AXL stimulation with its ligand growth arrest-specific gene 6 (GAS6) increased AKT1- and p65 NF-kB-phosphorylation and promoted survival of thyroid cancer cell lines in culture. Enforced expression or activation of AXL in normal rat thyroid cells significantly reduced the expression of the sodium/iodide symporter (NIS) and the radioiodine uptake. These data indicate that AXL expression levels could be used as predictor of RAI refractoriness and as a possible novel therapeutic target of RAI resistant PTCs. [ABSTRACT FROM AUTHOR]