Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2): Novel markers of neuroendocrine tumors

Susi Barollo, Loris Bertazza, Sara Watutantrige-Fernando, Simona Censi, Elisabetta Cavedon, Francesca Galuppini, Gianmaria Pennelli, Ambrogio Fassina, Marilisa Citton, Beatrice Rubin, Raffaele Pezzani, Clara Benna, Giuseppe Opocher, Maurizio Iacobone, Caterina Mian

Research output: Contribution to journalArticle

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Abstract

Background 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18 F-FDOPA) PET is a useful tool in the clinical management of pheochromocytoma (PHEO) and medullary thyroid carcinoma (MTC). 18F-FDOPA is a large neutral amino acid biochemically resembling endogenous L-DOPA and taken up by the L-type amino acid transporters (LAT1 and LAT2). This study was conducted to examine the expression of the LAT system in PHEO and MTC. Methods Real-time PCR and Western blot analyses were used to assess LAT1 and LAT2 gene and protein expression in 32 PHEO, 38 MTC, 16 normal adrenal medulla and 15 normal thyroid tissue samples. Immunohistochemistry method was applied to identify the proteins' subcellular localization. Results LAT1 and LAT2 were overexpressed in both PHEO and MTC by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO (15.1- and 4.1-fold increases, respectively) than in MTC (9.9- and 4.1-fold increases, respectively). Furthermore we found a good correlation between LAT1/2 and GLUT1 expression levels. A positive correlation was also found between urinary noradrenaline and adrenaline levels and LAT1 gene expression in PHEO. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. Conclusions The present study is the first to provide experimental evidence of the overexpression in some NET cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT1 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells.

Original languageEnglish
Article numbere0156044
JournalPLoS One
Volume11
Issue number5
DOIs
Publication statusPublished - May 1 2016

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amino acid transporters
Amino Acid Transport Systems
Neuroendocrine Tumors
Tumors
Pheochromocytoma
carcinoma
neoplasms
Tissue
adrenal medulla
L-dopa
Neutral Amino Acids
Gene Expression
gene expression
Proteins
Adrenal Medulla
epinephrine
norepinephrine
Medullary Thyroid cancer
Gene expression
Epinephrine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Barollo, S., Bertazza, L., Watutantrige-Fernando, S., Censi, S., Cavedon, E., Galuppini, F., ... Mian, C. (2016). Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2): Novel markers of neuroendocrine tumors. PLoS One, 11(5), [e0156044]. https://doi.org/10.1371/journal.pone.0156044

Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2) : Novel markers of neuroendocrine tumors. / Barollo, Susi; Bertazza, Loris; Watutantrige-Fernando, Sara; Censi, Simona; Cavedon, Elisabetta; Galuppini, Francesca; Pennelli, Gianmaria; Fassina, Ambrogio; Citton, Marilisa; Rubin, Beatrice; Pezzani, Raffaele; Benna, Clara; Opocher, Giuseppe; Iacobone, Maurizio; Mian, Caterina.

In: PLoS One, Vol. 11, No. 5, e0156044, 01.05.2016.

Research output: Contribution to journalArticle

Barollo, S, Bertazza, L, Watutantrige-Fernando, S, Censi, S, Cavedon, E, Galuppini, F, Pennelli, G, Fassina, A, Citton, M, Rubin, B, Pezzani, R, Benna, C, Opocher, G, Iacobone, M & Mian, C 2016, 'Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2): Novel markers of neuroendocrine tumors', PLoS One, vol. 11, no. 5, e0156044. https://doi.org/10.1371/journal.pone.0156044
Barollo S, Bertazza L, Watutantrige-Fernando S, Censi S, Cavedon E, Galuppini F et al. Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2): Novel markers of neuroendocrine tumors. PLoS One. 2016 May 1;11(5). e0156044. https://doi.org/10.1371/journal.pone.0156044
Barollo, Susi ; Bertazza, Loris ; Watutantrige-Fernando, Sara ; Censi, Simona ; Cavedon, Elisabetta ; Galuppini, Francesca ; Pennelli, Gianmaria ; Fassina, Ambrogio ; Citton, Marilisa ; Rubin, Beatrice ; Pezzani, Raffaele ; Benna, Clara ; Opocher, Giuseppe ; Iacobone, Maurizio ; Mian, Caterina. / Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2) : Novel markers of neuroendocrine tumors. In: PLoS One. 2016 ; Vol. 11, No. 5.
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T1 - Overexpression of L-Type amino acid transporter 1 (LAT1) and 2 (LAT2)

T2 - Novel markers of neuroendocrine tumors

AU - Barollo, Susi

AU - Bertazza, Loris

AU - Watutantrige-Fernando, Sara

AU - Censi, Simona

AU - Cavedon, Elisabetta

AU - Galuppini, Francesca

AU - Pennelli, Gianmaria

AU - Fassina, Ambrogio

AU - Citton, Marilisa

AU - Rubin, Beatrice

AU - Pezzani, Raffaele

AU - Benna, Clara

AU - Opocher, Giuseppe

AU - Iacobone, Maurizio

AU - Mian, Caterina

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Background 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18 F-FDOPA) PET is a useful tool in the clinical management of pheochromocytoma (PHEO) and medullary thyroid carcinoma (MTC). 18F-FDOPA is a large neutral amino acid biochemically resembling endogenous L-DOPA and taken up by the L-type amino acid transporters (LAT1 and LAT2). This study was conducted to examine the expression of the LAT system in PHEO and MTC. Methods Real-time PCR and Western blot analyses were used to assess LAT1 and LAT2 gene and protein expression in 32 PHEO, 38 MTC, 16 normal adrenal medulla and 15 normal thyroid tissue samples. Immunohistochemistry method was applied to identify the proteins' subcellular localization. Results LAT1 and LAT2 were overexpressed in both PHEO and MTC by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO (15.1- and 4.1-fold increases, respectively) than in MTC (9.9- and 4.1-fold increases, respectively). Furthermore we found a good correlation between LAT1/2 and GLUT1 expression levels. A positive correlation was also found between urinary noradrenaline and adrenaline levels and LAT1 gene expression in PHEO. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. Conclusions The present study is the first to provide experimental evidence of the overexpression in some NET cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT1 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells.

AB - Background 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (18 F-FDOPA) PET is a useful tool in the clinical management of pheochromocytoma (PHEO) and medullary thyroid carcinoma (MTC). 18F-FDOPA is a large neutral amino acid biochemically resembling endogenous L-DOPA and taken up by the L-type amino acid transporters (LAT1 and LAT2). This study was conducted to examine the expression of the LAT system in PHEO and MTC. Methods Real-time PCR and Western blot analyses were used to assess LAT1 and LAT2 gene and protein expression in 32 PHEO, 38 MTC, 16 normal adrenal medulla and 15 normal thyroid tissue samples. Immunohistochemistry method was applied to identify the proteins' subcellular localization. Results LAT1 and LAT2 were overexpressed in both PHEO and MTC by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO (15.1- and 4.1-fold increases, respectively) than in MTC (9.9- and 4.1-fold increases, respectively). Furthermore we found a good correlation between LAT1/2 and GLUT1 expression levels. A positive correlation was also found between urinary noradrenaline and adrenaline levels and LAT1 gene expression in PHEO. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. Conclusions The present study is the first to provide experimental evidence of the overexpression in some NET cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT1 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells.

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