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Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype
- Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Cancer Research
medicine.medical_specialty
Carcinogenesis
Endocrinology, Diabetes and Metabolism
Mice, Transgenic
Biology
medicine.disease_cause
Article
Cell Line
03 medical and health sciences
Endocrinology
stem cells
Cell Movement
Cell Line, Tumor
Internal medicine
thyroid cancer
medicine
Animals
Humans
mouse models
Thyroid Neoplasms
Thyroid cancer
Cell Proliferation
Wound Healing
Gene knockdown
Electron Transport Complex II
Thyroid
Membrane Proteins
DNA Methylation
succinate dehydrogenase
medicine.disease
Phenotype
Citric acid cycle
Protein Subunits
030104 developmental biology
medicine.anatomical_structure
Oncology
Cancer research
SDHD
Stem cell
metabolism
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....86a5f669e611714d0b15b5ce8505b16c