AXL is a novel predictive factor and therapeutic target for radioactive iodine refractory thyroid cancer

Francesca Collina, Lucia La Sala, Federica Liotti, Nella Prevete, Elvira La Mantia, Maria Grazia Chiofalo, Gabriella Aquino, Laura Arenare, Monica Cantile, Giuseppina Liguori, Francesca Di Gennaro, Luciano Pezzullo, Nunzia Simona Losito, Giancarlo Vecchio, Gerardo Botti, Rosa Marina Melillo, Renato Franco

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number785
JournalCancers
Volume11
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

Fingerprint

Thyroid Neoplasms
Iodine
NF-kappa B
Oncogenes
Therapeutics
Thyroid Gland
Cell Line
Thymoma
Survival
Receptor Protein-Tyrosine Kinases
Papillary Thyroid cancer
Sarcoma
B-Lymphocytes
Immunohistochemistry
Phosphorylation
Ligands
Light
Recurrence
Mutation
Growth

Keywords

  • AXL
  • Disease persistence/recurrence
  • P65 NF-kB activation
  • Radioactive iodine (RAI)-refractoriness
  • Thyroid cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

AXL is a novel predictive factor and therapeutic target for radioactive iodine refractory thyroid cancer. / 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.

In: Cancers, Vol. 11, No. 6, 785, 01.06.2019.

Research output: Contribution to journalArticle

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AU - Collina, Francesca

AU - La Sala, Lucia

AU - Liotti, Federica

AU - Prevete, Nella

AU - La Mantia, Elvira

AU - Chiofalo, Maria Grazia

AU - Aquino, Gabriella

AU - Arenare, Laura

AU - Cantile, Monica

AU - Liguori, Giuseppina

AU - Di Gennaro, Francesca

AU - Pezzullo, Luciano

AU - Losito, Nunzia Simona

AU - Vecchio, Giancarlo

AU - Botti, Gerardo

AU - Melillo, Rosa Marina

AU - Franco, Renato

PY - 2019/6/1

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AB - 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.

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