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Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer

 Hyeon Jeong Lee  ;  Cheol Ryong Ku  ;  Arthur Cho  ;  TaeHo Cho  ;  ChaeEun Lee  ;  Chan Woo Kang  ;  Daham Kim  ;  Yoon Hee Cho  ;  JaeHyung Koo  ;  Eun Jig Lee 
 BIOMEDICINES, Vol.11(6) : 1688, 2023-06 
Journal Title
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acetate ; calcitonin ; medullary thyroid cancer ; odorant receptors ; parafollicular C-cells ; positron emission tomography
Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Kang, Chan Woo(강찬우)
Ku, Cheol Ryong(구철룡) ORCID logo https://orcid.org/0000-0001-8693-9630
Kim, Daham(김다함) ORCID logo https://orcid.org/0000-0003-1871-686X
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Cho, Yoon Hee(조윤희)
Cho, Arthur Eung Hyuck(조응혁) ORCID logo https://orcid.org/0000-0001-8670-2473
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