Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer
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...
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MDPI AG
2023-06-01
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| Online Access: | https://www.mdpi.com/2227-9059/11/6/1688 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hyeon Jeong Lee |
| collection | DOAJ |
| description | 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 C<sup>11</sup>-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 C<sup>11</sup>-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C<sup>11</sup>-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C<sup>11</sup>-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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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T02:44:52Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-85554391744a4f0896d0dd0a8b56e3252023-11-18T09:26:49ZengMDPI AGBiomedicines2227-90592023-06-01116168810.3390/biomedicines11061688Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid CancerHyeon Jeong Lee0Cheol Ryong Ku1Arthur Cho2TaeHo Cho3ChaeEun Lee4Chan Woo Kang5Daham Kim6Yoon Hee Cho7JaeHyung Koo8Eun Jig Lee9Endocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaEndocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of Nuclear Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of New Biology, DGIST, Daegu 42988, Republic of KoreaDepartment of New Biology, DGIST, Daegu 42988, Republic of KoreaEndocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaEndocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaEndocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaDepartment of New Biology, DGIST, Daegu 42988, Republic of KoreaEndocrinology, Institute of Endocrine Research, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of KoreaMedullary 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 C<sup>11</sup>-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 C<sup>11</sup>-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C<sup>11</sup>-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C<sup>11</sup>-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.https://www.mdpi.com/2227-9059/11/6/1688odorant receptorsacetatecalcitoninparafollicular C-cellsmedullary thyroid cancerpositron emission tomography |
| spellingShingle | 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 Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer Biomedicines odorant receptors acetate calcitonin parafollicular C-cells medullary thyroid cancer positron emission tomography |
| title | Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer |
| title_full | Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer |
| title_fullStr | Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer |
| title_full_unstemmed | Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer |
| title_short | Acetate-Mediated Odorant Receptor OR51E2 Activation Results in Calcitonin Secretion in Parafollicular C-Cells: A Novel Diagnostic Target of Human Medullary Thyroid Cancer |
| title_sort | acetate mediated odorant receptor or51e2 activation results in calcitonin secretion in parafollicular c cells a novel diagnostic target of human medullary thyroid cancer |
| topic | odorant receptors acetate calcitonin parafollicular C-cells medullary thyroid cancer positron emission tomography |
| url | https://www.mdpi.com/2227-9059/11/6/1688 |
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