ALTERATIONS IN THE EXPRESSION OF ALPHA-6-BETA-4 INTEGRIN AND P21 WAF1/CIP1 IN N-NITROSOMETHYLBENZYLAMINE-INDUCED RAT ESOPHAGEAL TUMORIGENESIS/

Integrin alpha 6 beta 4 is altered in many neoplastic cells, but no da ta exist to show this happens in esophageal neoplasms. To examine the expression of this integrin in rat esophageal tumorigenesis induced by N-nitrosomethylbenzylamine (NMBA), alpha 6 and beta 4 expression was evaluated in normal esophageal epithelium, in NMBA-induced preneoplast ic lesions, and in papillomas by quantitative reverse transcription (R T)-polymerase chain reaction (PCR) and immunohistochemical analysis. B ecause the beta 4 subunit of this integrin has been found to cause cel l-cycle arrest by the induction of p21/WAF1/Cip1, the expression of p2 7/WAF1/Cip1 was also analyzed by RT-PCR. Compared with the levels in n ormal epithelium, the alpha 6A, alpha 6B, and beta 4 integrin levels i n esophageal papillomas were 1.9-, 2.2-, and 2.1-fold lower, respectiv ely. RT-PCR analysis showed no significant differences in integrin lev els between preneoplastic and normal samples, and northern blot analys is of the beta 4 integrin produced results in agreement with the RT-PC R results. The p21/WAF1/Cip1 level was decreased 1.6-fold in preneopla stic tissues and 3.1-fold in papilloma samples when compared with the mRNA levels in normal epithelium. Immunostaining showed that alpha 6 b eta 4 integrin was localized at the basolateral surface of the basal c ells in normal esophageal epithelium. In preneoplastic lesions, howeve r, the expression of this integrin was not polarized and was expressed in basal cells as well as in suprabasal cells. beta 4 expression was significantly reduced and alpha 6A expression was decreased and deloca lized in papillomas. These findings suggest that alteration in alpha 6 beta 4 integrin and p21/WAF1/Cip1 expression may be an important biom arker for tumor progression in NMBA-induced rat esophageal tumorigenes is. (C) 1998 Wiley-Liss, Inc.