Yea Eun Kang1,2, Jin Man Kim3, Mi Ae Lim4, Seong Eun Lee2, Shinae Yi2, Jung Tae Kim2,5, Chan Oh5, Lihua Liu5, Yanli Jin5, Seung-Nam Jung4, Ho-Ryun Won4, Jae Won Chang4, Jeong Ho Lee6,7, Hyun Jung Kim6, Hyun Yong Koh6, Sangmi Jun8,9, Sun Wook Cho10, Minho Shong1,2, Bon Seok Koo4,5. 1. Department of Endocrinology and Metabolism, College of Medicine, Chungnam National University, Daejeon, South Korea. 2. Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, Republic of Korea. 3. Department of Pathology, College of Medicine, Chungnam National University, Daejeon, South Korea. 4. Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, South Korea. 5. Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea. 6. Graduate School of Medical Science and Engineering; Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. 7. Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. 8. Drug & Disease Target Group, Korea Basic Science Institute, Cheongju, South Korea. 9. Convergent Research Center for Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, South Korea. 10. Department of Endocrinology and Metabolism, College of Medicine, Seoul National University, Seoul, South Korea.
Abstract
Background: Mitochondrial stress is known to activate the mitochondrial unfolded protein response (UPRmt). The UPRmt results in the secretion of mitochondrial cytokines (mitokines), which can promote a hormetic response cell nonautonomously, and has been reported to be protumorigenic. Growth differentiation factor 15 (GDF15) is a well-characterized mitokine, which is reported to have a mitohormetic effect. Thus, we investigated whether GDF15 induction could prime a subpopulation of thyroid cancer cells to provide invasive advantages. Methods: The UPRmt, including mitokine expression, was assessed in the context of thyroid cancer in vitro and in vivo. GDF15 expression in 266 patients with papillary thyroid carcinoma (PTC) was determined by immunohistochemistry. The serum levels of GDF15 were measured in healthy subjects and PTC patients. In addition, our own and The Cancer Genome Atlas data were analyzed to determine the expression level of GDF15 in thyroid cancers. The role of GDF15 in tumor aggressiveness was investigated by observing the effects of GDF15 knockdown in BCPAP, TPC-1, 8505C, and FRO cells. Results: Pharmacological inhibition of mitochondrial oxidative phosphorylation function in thyroid cancer cells robustly increased GDF15 expression. The expression of GDF15 was associated with activation of the mitochondrial integrated stress response pathway in PTC patients. Circulating GDF15 levels were significantly higher in PTC patients than in the controls, and tumor expression of GDF15 was related to tumor aggressiveness. In vitro and in vivo knockdown of GDF15 in a thyroid cancer model showed decreased viability, migration, and invasion compared with the control cells via regulation of STAT3. Conclusions: In this study, we demonstrated that GDF15 is a mitokine induced in thyroid cancer cells upon mitochondrial stress. GDF15-induced STAT3 activation determined tumor progression in thyroid cancer. The GDF15-STAT3 signaling axis may be a target in aggressiveness of thyroid cancer.
Background: Mitochondrial stress is known to activate the mitochondrial unfolded protein response (UPRmt). The UPRmt results in the secretion of mitochondrial cytokines (mitokines), which can promote a hormetic response cell nonautonomously, and has been reported to be protumorigenic. Growth differentiation factor 15 (GDF15) is a well-characterized mitokine, which is reported to have a mitohormetic effect. Thus, we investigated whether GDF15 induction could prime a subpopulation of thyroid cancer cells to provide invasive advantages. Methods: The UPRmt, including mitokine expression, was assessed in the context of thyroid cancer in vitro and in vivo. GDF15 expression in 266 patients with papillary thyroid carcinoma (PTC) was determined by immunohistochemistry. The serum levels of GDF15 were measured in healthy subjects and PTC patients. In addition, our own and The Cancer Genome Atlas data were analyzed to determine the expression level of GDF15 in thyroid cancers. The role of GDF15 in tumor aggressiveness was investigated by observing the effects of GDF15 knockdown in BCPAP, TPC-1, 8505C, and FRO cells. Results: Pharmacological inhibition of mitochondrial oxidative phosphorylation function in thyroid cancer cells robustly increased GDF15 expression. The expression of GDF15 was associated with activation of the mitochondrial integrated stress response pathway in PTC patients. Circulating GDF15 levels were significantly higher in PTC patients than in the controls, and tumor expression of GDF15 was related to tumor aggressiveness. In vitro and in vivo knockdown of GDF15 in a thyroid cancer model showed decreased viability, migration, and invasion compared with the control cells via regulation of STAT3. Conclusions: In this study, we demonstrated that GDF15 is a mitokine induced in thyroid cancer cells upon mitochondrial stress. GDF15-induced STAT3 activation determined tumor progression in thyroid cancer. The GDF15-STAT3 signaling axis may be a target in aggressiveness of thyroid cancer.
Entities:
Keywords:
GDF15; STAT3; cancer; mitochondrial stress; mitochondrial unfolded protein response; thyroid cancer