Restored expression of transforming growth factor β type II receptor in k-ras-transformed thyroid cells, TGFβ-resistant, reverts their malignant phenotype

✍ Scribed by Anna Coppa; Gabriella Mincione; Davide Lazzereschi; Annalisa Ranieri; Alessandra Turco; Barbara Lucignano; Susanna Scarpa; Maria Ragano-Caracciolo; Giulia Colletta

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 308 KB
• Volume: 172
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/(sici)1097-4652(199708)172:2<200::aid-jcp7>3.0.co;2-s

✦ Synopsis

Transforming growth factor b1 (TGFb1) inhibits the growth of normal rat epithelial thyroid cells (FRTL-5 strain) by counteracting thyrotropin (TSH)-stimulated DNA synthesis and by slowing the cells in the G1 phase of the cell cycle. Here, we have studied two clones of FRTL-5 thyroid cell line transformed by the wild type (wt) v-k-ras oncogene (K.M.A1, K.M.A2) and one clone (A6) transformed by a temperature-sensitive (ts) v-k-ras mutant. Anchorage-dependent as well as anchorage-independent growth of these k-ras-transformed cells was not inhibited by TGFb1. TGFb1 resistance appeared to be dependent by a functional p21 k-ras, because A6 cell growth was partially inhibited at the nonpermissive temperature (39ЊC). To determine the basis for TGFb1 resistance in k-ras-transformed thyroid cells, we looked for possible defects in the expression of type I (TbR-I/ALK5) and type II TGFb receptors (TbR-II). Lower levels of type II receptors were present in all of the k-ras-transformed clones, as revealed by both Northern blot and crosslinking experiments.

A partial reversion of the malignant phenotype of the wt k-ras-transformed clone was obtained in two clones isolated after transfection of the malignant thyroid cells (K.M.A1) with a TbR-II expression vector. These two clones also showed restored levels of exogenous TbR-II mRNA and protein, and both clones showed a partially reacquired sensitivity to TGFb1. Similarly, the reversion of the malignant phenotype of the A6 clone grown at the nonpermissive temperature was accompanied by a restored expression of the TbR-II receptors.

These data indicate that active k-ras oncogene can induce TGFb1 resistance in rat thyroid cells and suggest that one of the possible mechanisms of escape from TGFb1 growth control in k-ras-induced thyroid carcinogenesis involves a reduced expression of TbR-II receptors.