RESTORED EXPRESSION OF TRANSFORMING-GROWTH-FACTOR BETA-TYPE-II RECEPTOR IN K-RAS-TRANSFORMED THYROID-CELLS, TGF-BETA-RESISTANT, REVERTS THEIR MALIGNANT PHENOTYPE

Transforming growth factor beta 1 (TGF beta 1) inhibits the growth of normal rat epithelial thyroid cells (FRTL-5 strain) by counteracting t hyrotropin (TSH)-stimulated DNA synthesis and by slowing the cells in the G1 phase of the cell cycle. Here, we have studied two clones oi FR TL-5 thyroid cell line transformed by the wild type (wt) v-k-ras oncog ene (K.M.A1, K.M.A2) and one clone (A6) transformed by a temperature-s ensitive (ts) v-k-ras mutant. Anchorage-dependent as well as anchorage -independent growth of these k-ras-transformed cells was not inhibited by TGF beta 1. TGF beta 1 resistance appeared to be dependent by a fu nctional p21 k-ras, because A6 cell growth was partially inhibited at the nonpermissive temperature (39 degrees C). To determine the basis f or TGF beta 1 resistance in k-ras-transformed thyroid cells, we looked for possible defects in the expression of type I (T beta R-I/ALK5) an d type Ii TGF beta receptors (T beta R-II). Lower levels of type II re ceptors were present in all of the k-ras-transformed clones, as reveal ed by both Northern blot and crosslinking experiments. A partial rever sion of the malignant phenotype of the wt k-ras-transformed clone was obtained in two clones isolated after transfection of the malignant th yroid cells (K.M.A1) with a T beta R-II expression vector. These two c lones also showed restored levels of exogenous T beta R-II mRNA and pr otein, and both clones showed a partially reacquired sensitivity to TG F beta 1. Similarly, the reversion of the malignant phenotype of the A 6 clone grown at the nonpermissive temperature was accompanied by a re stored expression of the T beta R-II receptors. These data indicate th at active k-ras oncogene can induce TGF beta 1 resistance in rat thyro id felts and suggest that one of the possible mechanisms of escape fro m TGF beta 1 growth control in k-ras-induced thyroid carcinogenesis in volves a reduced expression of T beta R-II receptors. (C) 1997 Wiley-L iss, Inc.