Abnormally High Expression of Proteasome Activator-γ in Thyroid Neoplasm

Abstract

PA28-gamma 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-gamma 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-gamma expression was estimated by immunohistochemical staining and Western blotting. In all of the papillary adenocarcinoma samples, PA28-gamma 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-gamma was predominantly distributed in nucleus rather than in the cytoplasm of cancer cells. On the other hand, no obvious PA28-gamma expression was observed in the adjacent normal thyroid follicular cells. In multinodular goiter, the expression of PA28-gamma was relatively low compared with papillary adenocarcinoma. In anaplastic carcinoma, PA28-gamma was expressed at the highest level, especially in poorly differentiated regions such as squamous metaplasia of anaplastic cancer tissue. Therefore, the PA28-gamma 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, alpha-subunit of 20S proteasome, and proliferating cell nuclear antigen are similarly overexpressed in this region. Thus, PA28-gamma 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 beta-lactone. These results demonstrate that PA28-gamma is overexpressed in thyroid cancer, especially in its growth-accelerated cells.

Upregulation of nuclear PA28γ expression in cirrhosis and hepatocellular carcinoma

“…This finding is in agreement with a recent study that showed increased expression of PA28γ protein during cancer progression and its correlation with PCNA labeling index (19). Thus, the results suggest the possible involvement of PA28γ in HCC progression.…”

“…These results are contradictory to those from other studies on other types of cancer, such as thyroid carcinoma; the nuclear PA28γ level was higher in these tumors compared to non-tumor tissues (19). While the exact reason for Table II.…”

Regulation of c-Myc protein stability by proteasome activator REGγ

“…Indeed, studies indicated that REGγ is absent in breast cancers but upregulated in thyroid cancers. 7,45 Our study revealed that the oncoprotein c-Myc is a novel substrate of REGγ. We found that c-Myc protein is negatively regulated by REGγ in several cancer cell lines, including HeLa, MCF7 and MEFs.…”

Expression of Proteasome Activator REGγ in Human Laryngeal Carcinoma and Associations with Tumor Suppressor Proteins

“…Increasing evidence has also suggested that overexpressed REGγ could positively contribute to cell cycle progression in the development of various human cancers. For instance, REGγ has been reported to be highly expressed in thyroid cancer (Okamura et al, 2003) and in colorectal cancer serum (Roessler et al, 2006). Recently, the overexpressed REGγ has been also found in human breast cancer cells and the metastatic lymph nodes (Wang et al, 2009).…”