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Genetic integrity of transforming growth factor β (TGF‐β) receptors in cervical carcinoma cell lines: loss of growth sensitivity but conserved transcriptional response to TGF‐β
Author(s) -
Kang Shin H.,
Won Kyungshick,
Chung HwanWook,
Jong HyunSoon,
Song YongSang,
Kim SeongJin,
Bang YungJue,
Kim Noe K.
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980812)77:4<620::aid-ijc23>3.0.co;2-8
Subject(s) - biology , microsatellite instability , microbiology and biotechnology , cell culture , transforming growth factor beta , transforming growth factor , receptor , cell growth , point mutation , gene , mutation , endocrinology , genetics , microsatellite , allele
Transforming growth factor β (TGF‐β) 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‐β receptors is known to play a critical role in this escape from growth regulation. We asked whether there is a correlation between TGF‐β sensitivity and the genetic status of TGF‐β 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‐β and 3 (SiHa, CaSki and HeLa229) showed minimal response to the growth inhibitory effect of TGF‐β; the other cell lines (HeLa and HT‐3) were sensitive. Northern blot analysis revealed that the RII mRNA was not expressed in 2 TGF‐β‐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‐β RII gene in the cell line ME‐180. We then asked whether the other TGF‐β‐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‐β 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‐β. Our observations, taken together, indicate that inactivation of the RII contributes to the resistance to TGF‐β of some cervical carcinoma cell lines. Loss of or attenuated sensitivity to TGF‐β growth inhibition in other cells may be attributed to the disruption of distal components in the TGF‐β signal pathway, but not to the receptor system. Int. J. Cancer 77:620–625, 1998. © 1998 Wiley‐Liss, Inc.