Regulation of mRNA and Protein Levels of β1 Integrin Variants in Human Prostate Carcinoma

Abstract

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.

Correlation between Beta1 integrin expression and prognosis in clinically localized prostate cancer

“…While there are data suggesting a role of β1 integrin in carcinogenesis, its precise functional role in PC is not well understood (21). Previous studies have indicated that β1 integrin and its splicing variants act by modulating cell adhesion, proliferation and survival (11,22).…”

“…Variant β1C normally maintains adhesion and inhibits cell cycle progression, thereby inhibiting cell proliferation and migration (10,22,25). It is expressed by normal prostate tissues and is downregulated in PC; Perlino et al evaluated 33 PC and 5 normal prostate tissues and observed a down regulation of the mRNA and protein levels of β1C in 94% and 100% of cancer cases, respectively (21). In contrast, variant A was maintained in PC where its translation rates had increased more than twofold, which supports its role in cell proliferation and cancer cell invasion (21-23).…”

Integrins in prostate cancer progression

“…Two variants, b 1C and b 1A , have been shown to be expressed in prostatic epithelium. b 1C is shown to be expressed at both protein and mRNA levels in normal prostatic epithelial cells, but is markedly downregulated in adenocarcinoma (Fornaro et al 1996, 1998, Perlino et al 2000. b 1A has been found to be consistently upregulated in human prostate cancer (Knox et al 1994, Murant et al 1997, Goel et al 2007 as well as in a mouse model designated TRAMP (transgenic adenocarcinoma of mouse prostate) (Goel et al 2005).…”

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…Changes in integrin levels have been reported to occur during tumorigenesis and metastasis of many tumors (Clezardin, 1998). In prostate cancer, the reported changes in integrins include increased expression levels of a3b1 and a6b1 (Schmelz et al, 2002), loss of b4 (Davis et al, 2001), and a decrease in a5b1c (Perlino et al, 2000) and a2b1 integrins (Dong et al, 1997). Integrins are implicated in regulating cellular processes such as adhesion, signaling, growth and differentiation, motility, survival, and gene expression (Miranti and Brugge, 2002).…”