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.
BackgroundAlthough both thyroid histology and serum concentrations of hormones are known to change with age, only a few reports exist on the relationship between the age-related structural and functional changes of the thyroid follicles in both mice and humans. Our objectives were to investigate age-related histological changes of the thyroid follicles and to determine whether these morphological changes were associated with the functional activity of the follicles.MethodsThe thyroid glands of mice at 18 weeks and at 6, 15, and 30 months of age were histologically examined, and the serum levels of thyroid hormones were measured in 11-week-old and 20-month-old mice. Samples of human thyroid tissue from 10 women over 70 years old and 10 women between 30 and 50 years of age were analyzed in conjunction with serum thyroid hormone level.ResultsThe histological and functional changes observed in the thyroid follicles of aged mice and women were as follows: variable sizing and enlargement of the follicles; increased irregularity of follicles; Sanderson’s polsters in the wall of large follicles; a large thyroglobulin (Tg) globule or numerous small fragmented Tg globules in follicular lumens; oncocytic change in follicular cells; and markedly dilated follicles empty of colloid. Serum T3 levels in 20-month-old mice and humans were unremarkable.ConclusionsThyroid follicles of aged mice and women show characteristic morphological changes, such as cystic atrophy, empty colloid, and Tg globules.
Primary cilia are microtubule-based, dynamic organelles characterized by continuous assembly and disassembly. The intraflagellar transport (IFT) machinery, including IFT88 in cilia, is involved in the maintenance of bidirectional motility along the axonemes, which is required for ciliogenesis and functional competence. Cancer cells are frequently associated with loss of primary cilia and IFT functions. However, there is little information on the role of IFT88 or primary cilia in the metabolic remodeling of cancer cells. Therefore, we investigated the cellular and metabolic effects of the loss-of-function (LOF) mutations of IFT88/primary cilia in thyroid cancer cells. IFT88-deficient 8505C thyroid cancer cells were generated using the CRISPR/Cas9 system, and RNA-sequencing analysis was performed. LOF of the IFT88 gene resulted in a marked defect in ciliogenesis and mitochondrial oxidative function. Gene expression patterns in IFT88-deficient thyroid cancer cells favored glycolysis and lipid biosynthesis. However, LOF of IFT88/primary cilia did not promote thyroid cancer cell proliferation, migration, and invasion. The results suggest that IFT88/primary cilia play a role in metabolic reprogramming in thyroid cancer cells.
Our results suggest that Ang-1 can serve as a valuable prognostic biomarker for lymph node metastasis and invasiveness in patients with PTC.
Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.
Keloids are a common form of pathologic wound healing and are characterized by an excessive production of extracellular matrix. This study examined the major contributing mechanism of human keloid pathogenesis using transcriptomic analysis. We identified the upregulation of mitochondrial oxidative stress response, protein processing in the endoplasmic reticulum, and TGF-β signaling in human keloid tissue samples compared to controls, based on ingenuity pathway and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Electron microscopic examinations revealed an increased number of dysmorphic mitochondria and expanded endoplasmic reticulum (ER) in human keloid tissue samples than that in controls. Western blot analysis performed using human tissues suggested noticeably higher ER stress signaling in keloids than in normal tissues. Treatment with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, significantly decreased scar formation in rabbit models, compared to normal saline and steroid injections. In summary, our findings demonstrate the contributions of mitochondrial dysfunction and dysregulated ER stress signaling in human keloid formation and the potential of TUDCA in the treatment of keloids.
SummaryObjective Although the presence of oncocytic change in less than 75% of a tumour is not considered to indicate oncocytic variants of papillary thyroid carcinoma (PTC), we frequently observe partial oncocytic change, especially in obese PTC patients. Thus, we sought to investigate the relationship between the presence of oncocytic change of PTC and its prognosis. Design, setting and participants We retrospectively studied 142 patients with PTC who had undergone surgery between 2000 and 2005, and re-evaluated their PTC slides to record the proportion of oncocytic change in 10% increments from 0% to 100%. Major outcome measure We analysed the relationship between the proportion of oncocytic change and clinicopathological prognostic factors. Results Oncocytic change was found in 45Á8% (65/142) of PTC patients. The proportion of patients with oncocytic change was higher in obese patients than in lean patients and showed a significant correlation with the BMI (r = 0Á195, P = 0Á020). The PTC patients with oncocytic change showed a higher recurrence rate than PTC patients without oncocytic change (30Á8% vs 11Á7%, respectively; P = 0Á005). The presence of oncocytic change in PTC patients was associated with a shorter disease-free survival in a Kaplan-Meier analysis after a mean follow-up of 8Á9 years. Conclusion The patients with PTC with oncocytic change presented with a higher recurrence rate and were more likely to be obese. These findings suggest that presence of oncocytic change is a poor prognostic factor in PTC patients, even if the oncocytic change involves less than 75% of a tumour.
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