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From the Center of Study on Mitochondria and Energy
Metabolism,*
Consiglio Nazionele delle Ricerche, Bari,
Italy; the Chair of Urology
and the
Institute of Pathological Anatomy,§
School of
Medicine, University of Bari, Bari, Italy; and the Department of
Pathology,
Yale University School of Medicine,
New Haven, Connecticut
Alterations of integrin expression levels in cancer cells correlate with changes in invasiveness, tumor progression, and metastatic potential. The ß1C integrin, an alternatively spliced form of the human ß1 integrin, has been shown to inhibit prostate cell proliferation. Furthermore, ß1C 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 ß1C and ß1 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 ß1C mRNA is expressed in normal prostate and is significantly down-regulated in neoplastic prostate specimens. In addition, using a probe that hybridizes with all ß1 variants, mRNA levels of ß1 are found reduced in neoplastic versus normal prostate tissues. We demonstrate that ß1C mRNA down-regulation does not correlate with either tumor grade or differentiation according to Gleason’s grade and TNM system evaluation, and that ß1C mRNA levels are not affected by hormonal therapy. In parallel, ß1C protein levels were analyzed. As expected, ß1C is found to be expressed in normal prostate and dramatically reduced in neoplastic prostate tissues; in contrast, using an antibody to ß1 that recognizes all ß1 variants, the levels of ß1 are comparable in normal and neoplastic prostate, thus indicating a selective down-regulation of the ß1C protein in prostate carcinoma. These results demonstrate for the first time that ß1C and ß1 mRNA expression is down-regulated in prostate carcinoma, whereas only ß1C protein levels are reduced. Our data highlight a selective pressure to reduce the expression levels of ß1C, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.
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