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Abnormally High Expression of Proteasome Activator- in Thyroid Neoplasm

First Department of Internal Medicine (T.Ok., S.T., T.Oh., A.Y., H.S., H.F., Y.U., I.H., C.S.), Department of Bioscience (M.S.), and Second Department of Surgery (H.M.), Tottori University Faculty of Medicine, Yonaga 683-8504, Japan

Address all correspondence and requests for reprints to: Shin-ichi Taniguchi, M.D., Ph.D., First Department of Internal Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan. E-mail: stani{at}grape.med.tottori-u.ac.jp.

PA28- is the activator of 20S proteasome, the ATP-dependent proteolytic system that plays an important role in cell cycle progression in various cell types. In this paper, we show the abnormally high expression of PA28- in various thyroid neoplasms. Thyroid samples were obtained from patients with normal thyroid (4 cases) and with the following diseases: papillary adenocarcinoma (13 cases), multinodular goiter (4 cases), and anaplastic carcinoma (1 case). PA28- expression was estimated by immunohistochemical staining and Western blotting. In all of the papillary adenocarcinoma samples, PA28- was abnormally overexpressed, especially in cancer cells existing at the peripheral region of the cancer mass or in cancer cells invading the capsular region surrounding the cancer mass. In cancer cells of these areas, PA28- was predominantly distributed in nucleus rather than in the cytoplasm of cancer cells. On the other hand, no obvious PA28- expression was observed in the adjacent normal thyroid follicular cells. In multinodular goiter, the expression of PA28- was relatively low compared with papillary adenocarcinoma. In anaplastic carcinoma, PA28- was expressed at the highest level, especially in poorly differentiated regions such as squamous metaplasia of anaplastic cancer tissue. Therefore, the PA28- expression seems to be restricted to thyroid cancer cells, especially in the region where the growth rate of cancer cells is accelerated. This result is further confirmed by the fact that C2, -subunit of 20S proteasome, and proliferating cell nuclear antigen are similarly overexpressed in this region. Thus, PA28- might be involved in the regulatory system for the cell cycle. Moreover, the growth of thyroid cancer cell lines was affected by the proteasome inhibitor, clasto-lactacystin ß-lactone. These results demonstrate that PA28- is overexpressed in thyroid cancer, especially in its growth-accelerated cells.

This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, and Culture (no. 12671088).

Abbreviations: BrdU, 5-Bromo-2'-deoxy-uridine; C2, -subunit of the 20S proteasome; PCNA, proliferating cell nuclear antigen.

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