Abstract
The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma. Specific thyroid cancers such as Hürthle cell carcinoma, oncocytic variant of papillary thyroid carcinoma (PTC), and PTC with Hashimoto’s thyroiditis show reduced biogenesis of primary cilia; these cancers are often associated the abnormalities in mitochondrial function. Here, we examined the association between primary cilia and the mitochondria-dependent apoptosis pathway. Tg-Cre;Ift88flox/flox mice (in which thyroid follicles lacked primary cilia) showed irregularly dilated follicles and increased apoptosis of thyrocytes. Defective ciliogenesis caused by deleting the IFT88 and KIF3A genes from thyroid cancer cell lines increased VDAC1 oligomerization following VDAC1 overexpression, thereby facilitating upregulation of mitochondria-dependent apoptosis. Furthermore, VDAC1 localized with the basal bodies of primary cilia in thyroid cancer cells. These results demonstrate that loss-of-function of primary cilia results in apoptogenic stimuli, which are responsible for mitochondrial-dependent apoptotic cell death in differentiated thyroid cancers. Therefore, regulating primary ciliogenesis might be a therapeutic approach to targeting differentiated thyroid cancers.
Highlights
The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma
The frequency of ciliated thyroid cancer cells is markedly lower in Hürthle cell carcinoma, oncocytic variant of papillary carcinoma (PTCov), and papillary thyroid carcinoma (PTC) with Hashimoto’s thyroiditis (PTC-HT), which are usually associated with mitochondrial d ysfunction[2]
We found that mice lacking primary cilia in thyroid follicular cells showed upregulated apoptotic cell death, resulting in altered follicular structure, and that inhibiting ciliogenesis in thyroid cancer cell lines resulted in VDAC1 oligomerization following VDAC1 overexpression, leading to apoptosis
Summary
The primary cilium is well-preserved in human differentiated thyroid cancers such as papillary and follicular carcinoma Specific thyroid cancers such as Hürthle cell carcinoma, oncocytic variant of papillary thyroid carcinoma (PTC), and PTC with Hashimoto’s thyroiditis show reduced biogenesis of primary cilia; these cancers are often associated the abnormalities in mitochondrial function. Tg-Cre;Ift88flox/flox mice (in which thyroid follicles lacked primary cilia) showed irregularly dilated follicles and increased apoptosis of thyrocytes. VDAC1 localized with the basal bodies of primary cilia in thyroid cancer cells These results demonstrate that loss-of-function of primary cilia results in apoptogenic stimuli, which are responsible for mitochondrial-dependent apoptotic cell death in differentiated thyroid cancers. The relationship between primary cilia and cell death via activation of the mitochondrial apoptotic pathway is unclear
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