Autophagy activity is associated with membranous sodium iodide symporter expression and clinical response to radioiodine therapy in non-medullary thyroid cancer

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Title:	Autophagy activity is associated with membranous sodium iodide symporter expression and clinical response to radioiodine therapy in non-medullary thyroid cancer
Author(s):	Plantinga, T.S. ; Tesselaar, M.H.; Morreau, H.; Corssmit, E.P.; Willemsen, B.K.T.; Kusters, B. ; Grunsven, A.C.H. van ; Smit, J.W.A. ; Netea-Maier, R.T.
Publication year:	2016
Source:	Autophagy, vol. 12, iss. 7, (2016), pp. 1195-1205
ISSN:	1554-8627
DOI:	https://doi.org/10.1080/15548627.2016.1174802
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/165918
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Subject:	Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 18: Healthcare improvement science RIHS: Radboud Institute for Health Sciences Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences
Organization:	Pathology Internal Medicine
Journal title:	Autophagy
Volume:	vol. 12
Issue:	iss. 7
Page start:	p. 1195
Page end:	p. 1205
Abstract:	Although non-medullary thyroid cancer (NMTC) generally has a good prognosis, 30-40% of patients with distant metastases develop resistance to radioactive iodine (RAI) therapy due to tumor dedifferentiation. For these patients, treatment options are limited and prognosis is poor. In the present study, expression and activity of autophagy was assessed in large sets of normal, benign and malignant tissues and was correlated with pathology, SLC5A5/hNIS (solute carrier family 5 member 5) protein expression, and with clinical response to RAI ablation therapy in NMTC patients. Fluorescent immunostaining for the autophagy marker LC3 was performed on 100 benign and 80 malignant thyroid tissues. Semiquantitative scoring was generated for both diffuse LC3-I intensity and number of LC3-II-positive puncta and was correlated with SLC5A5 protein expression and clinical parameters. Degree of diffuse LC3-I intensity and number of LC3-II-positive puncta scoring were not discriminative for benign vs. malignant thyroid lesions. Interestingly, however, in NMTC patients significant associations were observed between diffuse LC3-I intensity and LC3-II-positive puncta scoring on the one hand and clinical response to RAI therapy on the other hand (odds ratio [OR] = 3.13, 95% confidence interval [CI] =1.91-5.12, P = 0.01; OR = 5.68, 95%CI = 3.02-10.05, P = 0.002, respectively). Mechanistically, the number of LC3-II-positive puncta correlated with membranous SLC5A5 expression (OR = 7.71, 95%CI = 4.15-11.75, P<0.001), number of RAI treatments required to reach remission (P = 0.014), cumulative RAI dose (P = 0.026) and with overall remission and recurrence rates (P = 0.031). In conclusion, autophagy activity strongly correlates with clinical response of NMTC patients to RAI therapy, potentially by its capacity to maintain tumor cell differentiation and to preserve functional iodide uptake.