RT Journal Article
T1 Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype.
A1 Ashtekar, Amruta
A1 Huk, Danielle
A1 Magner, Alexa
A1 La Perle, Krista
A1 Zhang, Xiaoli
A1 Piruat, José I
A1 López-Barneo, José
A1 Jhiang, Sissy M
A1 Kirschner, Lawrence S
K1 metabolism
K1 mouse models
K1 stem cells
K1 succinate dehydrogenase
K1 thyroid cancer
AB Mutations in genes encoding enzymes in the tricarboxylic acid cycle (TCA, also known as the Krebs cycle) have been implicated as causative genetic lesions in a number of human cancers, including renal cell cancers, glioblastomas and pheochromocytomas. In recent studies, missense mutations in the succinate dehydrogenase (SDH) complex have also been proposed to cause differentiated thyroid cancer. In order to gain mechanistic insight into this process, we generated mice lacking the SDH subunit D (Sdhd) in the thyroid. We report that these mice develop enlarged thyroid glands with follicle hypercellularity and increased proliferation. In vitro, human thyroid cell lines with knockdown of SDHD exhibit an enhanced migratory capability, despite no change in proliferative capacity. Interestingly, these cells acquire stem-like features which are also observed in the mouse tumors. The stem-like characteristics are reversed by α-ketoglutarate, suggesting that SDH-associated tumorigenesis results from dedifferentiation driven by an imbalance in cellular metabolites of the TCA cycle. The results of this study reveal a metabolic vulnerability for potential future treatment of SDH-associated neoplasia.
YR 2017
FD 2017-09-19
LK http://hdl.handle.net/10668/11592
UL http://hdl.handle.net/10668/11592
LA en
DS RISalud
RD Apr 6, 2025