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Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer

  • Authors:
    • Akihito Kotani
    • Yota Tatara
    • Riki Sakamoto
    • Andrzej Wojcik
    • Yasushi Mariya
    • Satoru Monzen
  • View Affiliations / Copyright

    Affiliations: Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan, Department of Stress Response Science, Biomedical Research Center, Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori 036‑8562, Japan, Centre for Radiation Protection Research, Stockholm University, SE‑10691 Stockholm, Sweden, Center for Cancer Treatment and Examination, Aomori Rosai Hospital, Hachinohe, Aomori 031‑8551, Japan
    Copyright: © Kotani et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 160
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    Published online on: September 23, 2025
       https://doi.org/10.3892/or.2025.8993
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Abstract

Thyroid cancer is the most common malignant endocrine tumor. Differentiated thyroid cancer (DTC) accounts for 95% of thyroid cancer cases. The primary treatment for intermediate‑ and high‑risk DTC is total thyroidectomy. Postoperatively, serum thyroglobulin (Tg) and anti‑Tg antibody (Tg/Ab) levels are monitored to detect residual, recurrent or metastatic disease. Radioactive iodine (131I) therapy is administered orally when Tg and Tg/Ab levels exceed standard levels. Recombinant human thyroid‑stimulating hormone (rhTSH) administration methods that do not require thyroid hormone withdrawal treatment and hospitalization have been recommended. However, serum Tg levels, a biomarker of thyroid tissue ablation, are often disturbed by Tg/Ab interference, which is observed in one‑quarter of patients with DTC. The present study aimed to elucidate the molecular mechanisms underlying metabolic changes in patients with DTC treated with 131I, and to identify Tg/Ab‑independent biomarker candidates using the TPC‑1 cell model. Blood serum samples were collected from patients with DTC before and after administration of 131I, which was performed following stimulation with rhTSH. Intra‑individual variations in Tg and Tg/Ab levels were observed in the same patients before and after 131I administration. Serum metabolomic analysis showed elevated levels of branched‑chain amino acid (BCAA), including valine, leucine and isoleucine, in all 3 patients, who exhibited favorable clinical outcomes. Although the number of cases was limited, this may suggest a possible association between BCAA levels and treatment response. Additionally, while overall boronophenylalanine uptake decreased in the total cell population after ionizing radiation exposure, the surviving viable TPC‑1 cells exhibited relatively increased amino acid uptake, assessed using boronophenylalanine as a leucine analog, which corresponded to the findings presented in the cell‑based experiments. Higher expression levels of the CD98 cell surface antigen were observed in irradiated TPC‑1 cells compared with non‑irradiated controls, which may contribute to increased uptake of BCAAs. However, the mRNA expression levels of L‑type amino acid transporter type 1 (LAT1), L‑type amino acid transporter type 2 and CD98hc did not change upon exposure to IR. These results indicated that the increased BCAA uptake in IR‑exposed DTC cells was a transient response likely mediated by LAT1/CD98hc at the cell surface, as suggested by flow cytometry analysis, despite no corresponding increase in LAT1 mRNA expression.
View Figures

Figure 1

Blood biomarkers measured before
131I administration (baseline), on the day of
131I administration (day 0) and 30 days after treatment
(day 30) in 3 patients with differentiated thyroid cancer after
thyroidectomy. (A) RBC, (B) WBC, (C) PLT, (D) TSH, (E) FT3, (F)
FT4, (G) Tg and (H) Tg/Ab. Statistical analysis was performed using
the Wilcoxon signed-rank test for paired comparisons involving two
timepoints. For TSH, comparisons across three timepoints were
performed using the Friedman test. No significant differences were
observed in any of the biomarkers. Normal reference ranges: RBC,
4.0–5.5×106/µl; WBC, 4.0–9.0×103/µl; PLT,
15–35×104/µl; TSH, 0.4–4.0 µIU/ml; FT3, 2.3–4.1 pg/ml;
FT4, 0.9–1.7×10−2 ng/ml; Tg, <30 ng/ml; Tg/Ab, <40
IU/ml. FT3, free triiodothyronine; FT4, free thyroxine; PLT,
platelets; RBC, red blood cells; Tg, thyroglobulin; Tg/Ab,
thyroglobulin antibody; TSH, thyroid-stimulating hormone; WBC,
white blood cells.

Figure 2

Quantification of serum metabolites
using mass spectrometry. Analysis of the serum samples collected
from patients with differentiated thyroid cancer before (day 0) and
after 131I administration (day 30). The levels of 12
metabolites, namely (A) methionine, (B) ornitine, (C) threonine,
(D) valine, (E) leucine, (F) isoleucine, (G) α-AAA, (H) kynurenine,
(I) t4-OH-Pro, (J) PC aa C32:0, (K) PC ae C38:0 and (L) SM C24:0,
are shown. *P<0.05 and **P<0.01 (Wilcoxon signed-rank test).
α-AAA, α-aminoadipic acid; PC aa C32:0, phosphatidylcholine type aa
C32:0; PC ae C38:0, phosphatidylcholine type ae C38:0; SM C24:0,
sphingomyelin type C24:0; t4-OH-Pro, trans-4-hydroxyprolin.

Figure 3

Analysis of radiation responses in
TPC-1 cells. (A) Representative images of colony formation after IR
exposure in 35-mm dishes. Cells were stained with Giemsa. The
corresponding plating efficiency is shown. (B) Clonogenic survival
curve showing the surviving fraction of cells exposed to IR ≤8 Gy.
(C) Representative histograms of cell cycle distribution. (D)
Quantitation of cells in the G2/M phase. (E)
Representative images of trypan blue exclusion assay. The grid
shown corresponds to 0.2-mm squares. (F) Percentage of viable cells
after 12 h of 8 Gy-IR exposure Data are presented as the mean ± SD
of four or five independent experiments. *P<0.05 (Welch
two-sample t-test). **P<0.01 (one-way ANOVA with Tukey-Kramer
post hoc test). IR, ionizing radiation; PE, plating efficiency.

Figure 4

Analysis of BPA uptake. (A) BPA
uptake in plated cells exposed to 8 Gy IR was analyzed using a
microplate reader. Data are presented as the mean ± SD of the ratio
of the IR group (n=6) relative to the control group (n=10). (B)
Representative histogram of BPA uptake in single cells analyzed by
flow cytometry. (C) Quantification of BPA uptake in single cells
(n=3). *P<0.01 (unpaired Student's t-test). BPA,
boronophenylalanine; IR, ionizing radiation.

Figure 5

CD98 cell surface antigen expression
in TPC-1 cells. (A) Representative flow cytometry histogram. (B)
Mean fluorescence intensity of CD98 in cells exposed to IR. Data
are presented as the mean ± SD of independent experiments (control,
n=3; IR, n=4). *P<0.01 (unpaired Student's t-test). IR, ionizing
radiation.

Figure 6

Quantitative mRNA expression analysis
via reverse transcription-quantitative PCR. Analysis of (A)
LAT1, (B) LAT2 and (C) CD98hc mRNA expression
in TPC-1 cells after exposure to radiation (2–8 Gy). Data are
presented as the mean ± SD of three independent experiments.
Statistical analysis was performed using one-way ANOVA followed by
the Tukey-Kramer post hoc test; no statistically significant
differences were observed among the groups. IR, ionizing radiation;
LAT1, L-type amino acid transporter type 1; LAT2,
L-type amino acid transporter type 2.

Figure 7

Schematic of the interactions among
BCAA, LAT1 and CD98 in the present study. BCAA, branched-chain
amino acid; DTC, differentiated thyroid cancer; IR, ionizing
radiation; LAT1, L-type amino acid transporter type 1; LAT2, L-type
amino acid transporter type 2.
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Copy and paste a formatted citation
Spandidos Publications style
Kotani A, Tatara Y, Sakamoto R, Wojcik A, Mariya Y and Monzen S: Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer. Oncol Rep 54: 160, 2025.
APA
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., & Monzen, S. (2025). Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer. Oncology Reports, 54, 160. https://doi.org/10.3892/or.2025.8993
MLA
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., Monzen, S."Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer". Oncology Reports 54.6 (2025): 160.
Chicago
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., Monzen, S."Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer". Oncology Reports 54, no. 6 (2025): 160. https://doi.org/10.3892/or.2025.8993
Copy and paste a formatted citation
x
Spandidos Publications style
Kotani A, Tatara Y, Sakamoto R, Wojcik A, Mariya Y and Monzen S: Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer. Oncol Rep 54: 160, 2025.
APA
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., & Monzen, S. (2025). Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer. Oncology Reports, 54, 160. https://doi.org/10.3892/or.2025.8993
MLA
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., Monzen, S."Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer". Oncology Reports 54.6 (2025): 160.
Chicago
Kotani, A., Tatara, Y., Sakamoto, R., Wojcik, A., Mariya, Y., Monzen, S."Relationship between amino acid transporter activity and radioactive iodine therapy efficacy in differentiated thyroid cancer". Oncology Reports 54, no. 6 (2025): 160. https://doi.org/10.3892/or.2025.8993
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