Prognostic significance of ras/p21 alterations in human ovarian cancer

Abstract

Summary Ras/p21 oncoprotein expression and K-ras mutations were analysed by Western blot and/or K-ras oligonucleotide hybridization in 78 primary ovarian cancers, 20 omental metastases, two low malignant potential tumours (LMP), nine benign ovarian tumours and 10 normal ovaries. A cut-off value of an integral of absorbance (i.a.) of 2.20, obtained by receiver operating characteristic (ROC) curve, was shown to be the best cut-off for defining p21 positivity. p21 levels were higher in malignant tumours than in benign tumours (median 2.10 i.a. vs median 1.22 i.a.; P= 0.014) and in omental metastases than in primary ovarian carcinomas (median 2.54 i.a. vs median 2.1 i.a.; P= 0.0089). p21 overexpression did not correlate with any of the clinicopathological parameters examined. Follow-up data were available for 63 patients. A significant relationship was shown between p21 positivity and a shorter overall survival (OS) (P < 0.03) and progression-free survival (PFS) (P< 0.03). In multivariate analysis only the presence of ascites, p21 levels and epidermal growth factor receptor status retained an independent prognostic role. K-ras gene mutations were frequently detected in benign and low malignant potential tumours (71.4%), which were mostly mucinous (P= 0.01 52).

Stimulation of urokinase-type plasminogen activator receptor expression by PMA requires JNK1-dependent and -independent signaling modules

“…Equally important, our studies show, for the ®rst time, that the u-PAR promoter is up-regulated by an activated c-Ha-ras and that this requires a JNK1-dependent signaling cascade. Considering the ®ndings by other investigators of the mutationactivation and/or overexpression of c-Ha-Ras/K-Ras in ovarian and other cancers (Bos, 1989;Chien et al, 1993;van Dam et al, 1994;Palejwala et al, 1996;Scambia et al, 1997), these latter observations may explain, in part, the observation of higher u-PAR levels in malignant ovarian tumors (Casslen et al, 1991).…”

“…Equally important, the up-regulation of u-PAR promoter activity brought about by a c-HaRas, which has been shown to be mutation-activated, or overexpressed, in a variety of malignancies including ovarian, colon, lung and pancreas cancers (Bos, 1989;Chien et al, 1993;van Dam et al, 1994;Palejwala et al, 1996;Scambia et al, 1997), is also dependent on a JNK1-dependent signaling cascade. Finally, our study serves to illustrate that the concept of linear signaling modules connecting the cell membrane to the nuclear transcriptional machinery is overly simplistic and probably unre¯ective of the complex regulation of inducible gene expression.…”

“…Since, both K-Ras and c-Ha-ras are overexpressed and/or mutationactivated in several malignancies including ovarian cancer and considering that this is predictive of recurrent or persistent disease (Bos, 1989;Chien et al, 1993;van Dam et al, 1994;Palejwala et al, 1996;Scambia et al, 1997) we therefore determined whether the JNK1 signaling module was required for stimulation of the u-PAR promoter by this oncogene. Towards this end, we ®rst transfected OVCAR-3 cells, which contain a wild type c-Ha-Ras, with the u-PAR promoter-driven CAT reporter and varying amounts of an expression construct encoding a mutation-activated c-Ha-Ras (Figure 8).…”

“…How small molecules, such as PMA, and c-Ha-ras that act at, or close to, the cell surface transduce their signal to the cell nucleus has been the subject of intense scrutiny. The latter is of particular interest since previous studies have implicated the overexpression of c-Ha-Ras/K-ras and/or its mutation-activation in several malignancies including ovarian and colon cancer (Bos, 1989;Chien et al, 1993;van Dam et al, 1994;Palejwala et al, 1996;Scambia et al, 1997). Recent studies have reported on parallel signaling cascades which connect the cell surface to the nucleus.…”

“…Increased u-PAR expression by PMA and c-Ha-ras is JNK1 dependentnancies including ovarian cancer (Bos, 1989;Chien et al, 1993;van Dam et al, 1994;Palejwala et al, 1996;Scambia et al, 1997).…”