Defective ciliogenesis in thyroid hürthle cell tumors is associated with increased autophagy

Abstract

Primary cilia are found in the apical membrane of thyrocytes, where they may play a role in the maintenance of follicular homeostasis. In this study, we examined the distribution of primary cilia in the human thyroid cancer to address the involvement of abnormal ciliogenesis in different thyroid cancers. We examined 92 human thyroid tissues, including nodular hyperplasia, Hashimoto's thyroiditis, follicular tumor, Hürthle cell tumor, and papillary carcinoma to observe the distribution of primary cilia. The distribution and length of primary cilia facing the follicular lumen were uniform across variable-sized follicles in the normal thyroid gland. However, most Hürthle cells found in benign and malignant thyroid diseases were devoid of primary cilia. Conventional variant of papillary carcinoma (PTC) displayed longer primary cilia than those of healthy tissue, whereas both the frequency and length of primary cilia were decreased in oncocytic variant of PTC. In addition, ciliogenesis was markedly defective in primary Hürthle cell tumors, including Hürthle cell adenomas and carcinomas, which showed higher level of autophagosome biogenesis. Remarkably, inhibition of autophagosome formation by Atg5 silencing or treatment with pharmacological inhibitors of autophagosome formation restored ciliogenesis in the Hürthle cell carcinoma cell line XTC.UC1 which exhibits a high basal autophagic flux. Moreover, the inhibition of autophagy promoted the accumulation of two factors critical for ciliogenesis, IFT88 and ARL13B. These results suggest that abnormal ciliogenesis, a common feature of Hürthle cells in diseased thyroid glands, is associated with increased basal autophagy.

Mixed signals from the cell's antennae: primary cilia in cancer

“…For example, tubulin glycylation was previously shown to control PC length in vitro . In addition, it has been reported that PC length can be altered in some human tumor tissues . Future studies will reveal whether PTM patterns in PC could serve as a biomarker and how altered length could modulate the function of PC during tumorigenesis.…”

Hürthle cell metaplasia in chronic lymphocytic thyroiditis: Role of age factor and review of literature on its molecular pathogenesis

“…In thyroid epithelial cells, primary cilia protrude from the apical surface into the follicular luminal space, which contains colloid; the primary cilia sense the environment of the follicular lumen and contribute to follicular function, including production of hormone . Whereas the distribution and length of cilia facing the follicular lumen are uniform across variable‐sized follicles in the normal thyroid gland, most HCs found in benign and malignant thyroid diseases are devoid of primary cilia . Intracytoplasmic lumen (ICL) is defined as cytoplasmic vacuoles with or without magenta material inside in Diff–Quik stained or vacuoles with or without greenish material inside Papanicolaou stained smears .…”

“…34 Whereas the distribution and length of cilia facing the follicular lumen are uniform across variable-sized follicles in the normal thyroid gland, most HCs found in benign and malignant thyroid diseases are devoid of primary cilia. 35 Intracytoplasmic lumen (ICL) is defined as cytoplasmic vacuoles with or without magenta material inside in Diff-Quik stained or vacuoles with or without greenish material inside Papanicolaou stained smears. 36 The cytoplasmic vacuoles demonstrate positive immunoreactions for thyroglobulin in both aspirate smears and tissue sections.…”

Targeting autophagy in thyroid cancers

“…Interestingly, although PTCs have long cilia, Hürthle cells found either in benign nodules or in malignant thyroid diseases were devoid of primary cilia (Lee et al 2016). Loss of cilia seemed to be a characteristic feature of Hürthle cells and was associated with high levels of autophagosome biogenesis, and inhibition of autophagy restored ciliogenesis in the Hürthle cell lines (Lee et al 2016).…”