Alterations of integrin expression levels in cancer cells correlate with changes in invasiveness, tumor progression, and metastatic potential. The beta1C integrin, an alternatively spliced form of the human beta1 integrin, has been shown to inhibit prostate cell proliferation. Furthermore, beta1C protein levels were found to be abundant in normal prostate glandular epithelium and down-regulated in prostatic adenocarcinoma. To gain further insights into the molecular mechanisms underlying abnormal cancer cell proliferation, we have studied beta1C and beta1 integrin expression at both mRNA and protein levels by Northern and immunoblotting analysis using freshly isolated neoplastic and normal human prostate tissue specimens. Steady-state mRNA levels were evaluated in 38 specimens: 33 prostatic adenocarcinomas exhibiting different Gleason's grade and five normal tissue specimens that did not show any histological manifestation of benign prostatic hypertrophy. Our results demonstrate that beta1C mRNA is expressed in normal prostate and is significantly down-regulated in neoplastic prostate specimens. In addition, using a probe that hybridizes with all beta1 variants, mRNA levels of beta1 are found reduced in neoplastic versus normal prostate tissues. We demonstrate that beta1C mRNA down-regulation does not correlate with either tumor grade or differentiation according to Gleason's grade and TNM system evaluation, and that beta1C mRNA levels are not affected by hormonal therapy. In parallel, beta1C protein levels were analyzed. As expected, beta1C is found to be expressed in normal prostate and dramatically reduced in neoplastic prostate tissues; in contrast, using an antibody to beta1 that recognizes all beta1 variants, the levels of beta1 are comparable in normal and neoplastic prostate, thus indicating a selective down-regulation of the beta1C protein in prostate carcinoma. These results demonstrate for the first time that beta1C and beta1 mRNA expression is down-regulated in prostate carcinoma, whereas only beta1C protein levels are reduced. Our data highlight a selective pressure to reduce the expression levels of beta1C, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.

Integrins are ubiquitous cell adhesion molecules that are involved in maintaining normal tissue morphology and have been implicated in the aggressive behavior of several malignancies. beta 1C integrin is an alternatively spliced variant of the beta 1A integrin subunit that, at variance with beta 1A, inhibits epithelial cell proliferation. beta 1C integrin is expressed in non-proliferative, benign prostatic epithelium and is down-regulated in prostatic adenocarcinoma. In the current study, we examined beta 1C expression at mRNA and protein levels in 18 endometrial adenocarcinoma and in 20 endometrial hyperplastic tissues, using Northern and Western blotting analysis and immunohistochemistry. The pattern of integrin expression was compared to that of the endometrium of 14 normal cycling women. The results of this study document inhibited beta 1C integrin expression in endometrial adenocarcinoma, both at the mRNA and protein levels, at variance with significantly up-regulated beta 1C mRNA expression in endometrial hyperplasia, in comparison with normal proliferative endometria. Our data suggest a key role of the regulation of beta 1C integrin expression in the pathogenesis of endometrial proliferative diseases: beta 1C integrin may act as growth modulator in cancer cells, playing a role in downstream intracellular signaling.

beta(1C) and beta(1A) integrins are alternatively spliced variants of the human beta(1)-subunit; the former has been shown to inhibit cell proliferation, and the latter to promote it. Although some components of the beta(1) integrin subfamily are expressed in human endometrial and decidual cells during the menstrual cycle and early pregnancy, to date no information is available about the expression of beta(1C) integrin in endometrial and decidual tissues and its possible roles during implantation and pregnancy. To gain further insight on this subject, we have explored beta(1C) integrin expression in endometrial (proliferative, secretory, and atrophic) and decidual (from the first and third trimesters of pregnancy) tissue samples at both gene and protein levels by Northern and Western blotting analyses and by immunohistochemistry. beta(1A) protein levels were also measured in the same tissues as a control. The results of this study demonstrate that both beta(1C)- and beta(1A)-subunits are expressed in the endometrium and decidua. In the former, maximal beta(1C) expression was detected in atrophic endometria, whereas beta(1A) expression levels were increased in secretive and decreased in atrophic endometrial tissues compared with proliferative endometria. In addition, whereas beta(1A) levels were significantly increased in decidual tissues, compared with proliferative endometria, beta(1C) expression was dramatically reduced in the same tissues, thus pointing to selective down-regulation of beta(1C) expression in the decidua. These data suggest that the expression of beta(1C) integrin, a very efficient inhibitor of cell proliferation, may be modulated by the maternal microenvironment and may play a fundamental role in mediating trophoblast outgrowth and migration during pregnancy.

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