Cathepsin B activity and protein levels in thyroid carcinoma, Graves' disease, and multinodular goiters

Cathepsin B (CB) is involved in the hydrolysis of thyroglobulin (Tg) and th ought to be regulated by thyroid stimulating hormone (TSH) in the normal th yroid. Our analyses of 91 thyroid tissues from 71 patients with Graves' dis ease (GD), multinodular goiter (MNG), papillary carcinoma (PC), or follicul ar carcinoma (FC), demonstrated a a-fold increase in expression of CB in GD and an average increase of 1.5-fold in MNG (varying from 10-fold below nor mal to 6-fold above normal in MNG nodules), as might be predicted by the al tered functional status of thyroid follicular cells in those diseases. Howe ver, CB activity was not downregulated in conjunction with the known "block ing effect" of malignancy on many thyroid functions, but rather increased o n average 9-fold in papillary carcinomas (rt = 33), and also showed a marke d increase in 2 follicular carcinomas. Activity measurements were confirmed by CB protein detection on Western blot with moderately increased CB prote in levels demonstrated in GD, variable expression in nodules of MNG, and ma rkedly increased protein expression in carcinomas. In all diseased states, increased protein was detected primarily as overexpression of the 27 kd hea vy chain of 2-chain mature CB and less frequently as overexpression of 31 k d single-chain mature CB. However, an additional 35 kd protein form was not ed in 3 of 9 PCs, 1 of 2 FCs, and 1 of 4 GD cases but in none of 10 MNG cas es. In conjunction with elevated CB activity plus additional protein bands on Western blots, altered patterns of CB immunohistochemical staining were observed, irrespective of the type of thyroid disease, suggesting certain c ommon changes in CB expression, posttranslational processing, and vesicular trafficking. In summary, GD and MNG thyroid tissues demonstrated altered C B expression in keeping with predicted functional changes in thyroid follic ular cells, while increased CB expression in carcinomas indicated a more pa thological role for CB in thyroid cancers, possibly related to the processe s of invasion or metastasis.