Transforming growth factor  (TGF-) exerts an inhibitory effect on the growth of most epithelial cell types, and the loss of responsiveness to this growth inhibition has been implicated in the development of a variety of human cancers. The genetic alteration of TGF- receptors is known to play a critical role in this escape from growth regulation. We asked whether there is a correlation between TGF- sensitivity and the genetic status of TGF- type I and type II receptors (RI and RII, respectively) in human cervical carcinoma cell lines. Among 8 cell lines examined, 3 (ME-180, C-33A and HeLaS3) showed resistance to TGF- and 3 (SiHa, CaSki and HeLa229) showed minimal response to the growth inhibitory effect of TGF-; the other cell lines (HeLa and HT-3) were sensitive. Northern blot analysis revealed that the RII mRNA was not expressed in 2 TGF--resistant cell lines (ME-180 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 TGF- RII gene in the cell line ME-180. We then asked whether the other TGF--resistant or refractory cell lines had microsatellite instability and/or poly-adenine tract mutations of RII. We also checked for point mutations in the individual exons of the entire RII using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP). Although C-33A exhibited poly-adenine microsatellite instability, its RII gene showed no signs of mutation. The molecular integrity of the TGF- receptors in all cell lines, except ME-180 and C-33A, could be confirmed by examining the distinct transcriptional induction of plasminogen activator inhibitor-1 (PAI-1), p21 WAF1/CIP1 and, in some cases, the accompanying downregulation of c-myc in response to TGF-. Our observations, taken together, indicate that inactivation of the RII contributes to the resistance to TGF- of some cervical carcinoma cell lines. Loss of or attenuated sensitivity to TGF- growth inhibition in other cells may be attributed to the disruption of distal components in the TGF- signal pathway, but not to the receptor system. Int.
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