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Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis.

ABSTRACT: Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer of thyroid C-cells, for which few treatment options are available. We have recently reported a role for cyclin-dependent kinase 5 (CDK5) in MTC pathogenesis. We have generated a mouse model, in which MTC proliferation is induced upon conditional overexpression of the CDK5 activator, p25, in C-cells, and arrested by interrupting p25 overexpression. Here, we identify genes and proteins that are differentially expressed in proliferating versus arrested benign mouse MTC. We find that downstream target genes of the tumor suppressor, retinoblastoma protein, including genes encoding cell cycle regulators such as CDKs, cyclins and CDK inhibitors, are significantly upregulated in malignant mouse tumors in a CDK5-dependent manner. Reducing CDK5 activity in human MTC cells down-regulated these cell cycle regulators suggesting that CDK5 activity is critical for cell cycle progression and MTC proliferation. Finally, the same set of cell cycle proteins was consistently overexpressed in human sporadic MTC but not in hereditary MTC. Together these findings suggest that aberrant CDK5 activity precedes cell cycle initiation and thus may function as a tumor-promoting factor facilitating cell cycle protein expression in MTC. Targeting aberrant CDK5 or its downstream effectors may be a strategy to halt MTC tumorigenesis.

SUBMITTER: Pozo K

PROVIDER: S-EPMC4494924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Calcitonin receptor expression in medullary thyroid carcinoma.

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miR‑592 acts as an oncogene and promotes medullary thyroid cancer tumorigenesis by targeting cyclin‑dependent kinase 8.

Project description:Medullary thyroid carcinoma (MTC) is a relatively rare subtype of thyroid cancer, accounting for 5‑10% of all cases of thyroid cancer worldwide. Due to the current lack of knowledge regarding the tumorigenesis of MTC, the clinical treatment of MTC remains a challenge. It has been reported that microRNAs (miRNAs) regulate the progression of MTC; however, the regulatory network of miRNAs and the exact underlying mechanisms are not completely understood. In the present study, an miRNA expression profile (GSE40807), consisting of 80 samples, was downloaded and analyzed using Gene Expression Omnibus‑2R to identify differentially expressed miRNAs between MTC and normal samples. miR‑592 expression levels were significantly increased in MTC tissues and cell lines compared with normal tissues and cell lines. Patients with high miR‑592 expression levels exhibited a less favorable prognosis compared with patients with low miR‑592 expression. The results suggested that miR‑592 overexpression promoted TT and MZ‑CRC‑1 cell proliferation in vitro. In addition, miR‑592 negatively regulated cyclin‑dependent kinase 8 (CDK8) via targeted binding in MTC cells. Moreover, co‑transfection of CDK8 overexpression plasmid and miR‑592 mimic reversed miR‑592‑mediated MTC cell proliferation. In conclusion, miR‑592 may serve as an oncogene in MTC by decreasing the expression of CDK8, indicating that the miR‑592/CDK8 axis might serve as a promising therapeutic target for MTC.

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