The Role of Cell Cycle Regulatory Protein, Cyclin D1, in the Progression of Thyroid Cancer

Abstract

Cell cycle progression is facilitated by cyclindependent kinases that are activated by cyclins including cyclin D1 and inactivated by cyclindependent kinase inhibitors (CDKIs) such as p27. Our previous studies have demonstrated decreased p27 expression in both papillary and more aggressive carcinomas of the thyroid compared to thyroid adenoma and almost similar level of cyclin D1 expression between thyroid adenoma and papillary carcinoma. These results indicate that CDKIs may have an important role in the carcinogenesis of the thyroid and that they probably have a limited role in malignant progression of the thyroid cancer. The role of cyclin D1 in malignant progression of thyroid carcinoma has yet to be established. We studied the expression of cyclin D1 by immunohistochemistry in 34 cases of conventional papillary carcinoma (CPC), 10 cases of minimally invasive follicular carcinoma (MIFC), and 32 cases of more aggressive thyroid carcinoma (ATC), which included 11 tall cell variants, one columnar cell variant of papillary carcinoma, seven insular carcinomas, and 13 anaplastic carcinomas. Cyclin D1 staining was classified by staining score as 0, negative; 1؉, less than 25%; 2؉, 25 to 50%; and 3؉, more than 50% tumor cells staining positive. Kruskal-Wallis oneway ANOVA and Wilcoxon Rank Sum/MannWhitney U Test was used to assess the difference in the expression of cyclin D1 between the study groups. Twenty-eight out of the 34 CPCs were cyclin D1 positive, 24 (70%) were 1؉, 3 (9%) were 2؉, and one (3%) were 3؉ positive. Seven of 10 MIFCs were cyclin D1 positive, five (71%) were 1؉, and the remaining two (29%) were 2؉ positive. On the other hand, 28 of 32 ATCs showed cyclin D1 immunostaining. Of these, three (9%) were 1؉, five (13%) were 2؉, and 20 (63%) were 3؉ positive. This study demonstrates a significant overexpression of cyclin D1 in ATC compared CPC (P < .001) and MIFC (P < .005), suggesting that the cyclin D1 expression may play a role in tumor progression and may have prognostic significance in thyroid cancer.

Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma

“…11,27 Mutations of candidate genes such as TP53 and CTNNB1, the gene encoding b-catenin, and abnormal cell cycle regulation, proliferation, and apoptosis are associated with aggressive neoplasms and have been suggested as markers of thyroid tumor progression. [28][29][30][31][32] Columnar cell carcinoma is a recognized variant of well-differentiated papillary thyroid carcinoma that is associated with an uncertain clinical course. Small size, encapsulation, and tumor circumscription are associated with a more favorable prognosis, whereas large size, extrathyroidal extension, and metastasis confer a worse prognosis.…”

“…57,58 A positive correlation between the nuclear overexpression of cyclin D1, cellular proliferation, and the proliferation marker, Ki-67, with tumor stage and aggressive biological behavior was reported previously. 31,32,39,[59][60][61][62][63][64] An alteration in the gene encoding cyclin D1 has not been reported in thyroid neoplasia, but a link between aberrant b-catenin expression and upregulation of cyclin D1 has been shown in a variety of neoplasms. [65][66][67] In this study, the nuclear expression of cyclin D1 was markedly increased in the vast majority of indolent and aggressive neoplasms.…”

Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis

“…With regard to cyclin D1, it is a well-known regulator of cell cycle and its overexpression plays an important role in tumour progression (Hall and Peters, 1996;Wang et al, 2000). Cyclin D1 forms a multimeric complex with cyclin-dependent kinase, which facilitate transition through the restriction point of cell cycle by inactivation of the retinoblastoma tumour-suppressor protein (pRb).…”

“…Cyclin D1 forms a multimeric complex with cyclin-dependent kinase, which facilitate transition through the restriction point of cell cycle by inactivation of the retinoblastoma tumour-suppressor protein (pRb). Constitutive overexpression of cyclin D1, caused by chromosomal abnormalities, gene amplification or other posttranslational mechanisms has been reported in different types of tumours including thyroid cancer (Hall and Peters, 1996;Wang et al, 2000). For these reasons, the concurrent expression of galectin-3, HBME-1, c-met protein and cyclin D1 observed in some suspicious lesions in the context of HTs strongly suggests the presence of transformed thyrocytes.…”

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

“…It suggests that Cyclin D1 expression in thyroid epithelium of the E7 cells is inhibited by a negative feedback of the Cyclin D1-RB1-E2F1 axis. The cyclin D1 staining of stromal cells (not seen in WT and RET/PTC3 thyroids) is puzzling and not reported in human thyroid carcinomas (Wang et al, 2000). However, we have identified such features in human thyroid goitres, and in malignant tumours with 'E7 like' cellular features.…”