GENETIC INTEGRITY OF TRANSFORMING-GROWTH-FACTOR-BETA (TGF-BETA) RECEPTORS IN CERVICAL-CARCINOMA CELL-LINES - LOSS OF GROWTH SENSITIVITY BUTCONSERVED TRANSCRIPTIONAL RESPONSE TO TGF-BETA

Transforming growth factor beta (TGF-beta) exerts an inhibitory effect on the growth of most epithelial cell types, and the loss of responsi veness to this growth inhibition has been implicated in the developmen t of a variety of human cancers. The genetic alteration of TGF-beta re ceptors is known to play a critical role in this escape from growth re gulation. We asked whether there is a correlation between TGF-beta sen sitivity and the genetic status of TGF-beta type I and type II recepto rs (RI and RII, respectively) in human cervical carcinoma cell lines. Among 8 cell lines examined, 3 (ME-180, C-33A and HeLaS3) showed resis tance to TGF-beta and 3 (SiHa, CaSki and HeLa229) showed minimal respo nse to the growth inhibitory effect of TGF-beta; the other cell lines (HeLa and HT-3) were sensitive. Northern blot analysis revealed that t he RII mRNA was not expressed in 2 TGF-beta-resistant cell lines (ME-1 80 and C-33A) but was expressed in the other cell lines. Southern blot analysis of RI and RII revealed a homozygous deletion of the entire T GF-beta RII gene in the cell line ME-180. We then asked whether the ot her TGF-beta-resistant or refractory cell lines had microsatellite ins tability and/or poly-adenine tract mutations of RII. We also checked f or point mutations in the individual exons of the entire RII using pol ymerase chain reaction-single-strand conformational polymorphism (PCR- SSCP). Although C-33A exhibited poly-adenine microsatellite instabilit y, its RII gene showed no signs of mutation. The molecular integrity o f the TGF-beta receptors in all cell lines, except ME-180 and C-33A, c ould be confirmed by examining the distinct transcriptional induction of plasminogen activator inhibitor-I (PAI-I), p21(WAFI/CIPI) and, in s ome cases, the accompanying downregulation of c-myc in response to TGF -beta. Our observations, taken together, indicate that inactivation of the RII contributes to the resistance to TGF-beta of some cervical ca rcinoma cell lines. Loss of or attenuated sensitivity to TGF-beta grow th inhibition in other cells may be attributed to the disruption of di stal components in the TGF-beta signal pathway, but not to the recepto r system. Int. J. Cancer 77:620-625, 1998. (C) 1998 Wiley-Liss, Inc.