Loss of primary cilia promotes mitochondria-dependent apoptosis in thyroid cancer

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.

Trace Amine-Associated Receptor 1 Trafficking to Cilia of Thyroid Epithelial Cells

“…It is somewhat astonishing that especially KTC-1 cells, which are representatives of human thyroid carcinoma cells, exhibit cilia and maintain mTaar1-eGFP expression at them because in mice, papillary and follicular carcinoma are both correlated with cilia loss [ 3 , 7 ]. Nevertheless, in human thyroid tissue, the disappearance of cilia or their shortening has been associated with hyperactivity of the follicles [ 2 ].…”

“…Alterations of cilia or changes in their frequency are indicative of thyroid diseases, ranging from dysfunctional thyroid states to neoplastic pathologies [ 2 , 7 ]. While such correlations of thyroid pathologies with altered cilia length and numbers are important as diagnostic criteria in thyroid disease, little is known about the molecular mechanisms that connect cilia with altered thyroid states.…”

“…Using rat thyroid epithelial cell lines, we further showed that cell surface expression of rTaar1 in vitro depends on intact cilia, reminiscent of Taar1′s in situ localization in rodent thyroid tissue [ 1 , 4 ]. Since previous studies by us and others are further suggestive of an essential role of cilia in thyroid function regulation in man, mouse and rat, it is particularly important to better understand TAAR1/Taar1 trafficking to the cilia of thyroid epithelial cells [ 2 , 4 , 5 , 7 , 8 ].…”

The Role of Primary Cilia in Thyroid Cancer: From Basic Research to Clinical Applications

“…The loss of PC on ATC cells was associated with TC tumorigenesis and progression (10). However, a study from Junguee Lee et al demonstrated that loss of PC in PTCs results in increased apoptosis, and it is associated with reduced tumor aggressiveness (4). In this context, the loss of PC appears to select TC cells with more malignant features.…”

“…PC is well preserved in PTC and FTC, and their frequency and length appear similar to those of normal thyroid follicles. Interestingly, defects in PC genesis have been observed in ATC ( 4 ). Additionally, oncogenic alterations, coupled to specific intracellular downstream signaling pathways, lead to the development of different subtypes of TC.…”