Truncated Notch receptors have transforming activity in vitro and in vivo. However, the role of wild-type Notch signaling in neoplastic transformation remains unclear. Ras signaling is deregulated in a large fraction of human malignancies and is a major target for the development of novel cancer treatments. We show that oncogenic Ras activates Notch signaling and that wild-type Notch-1 is necessary to maintain the neoplastic phenotype in Ras-transformed human cells in vitro and in vivo. Oncogenic Ras increases levels and activity of the intracellular form of wild-type Notch-1, and upregulates Notch ligand Delta-1 and also presenilin-1, a protein involved in Notch processing, through a p38-mediated pathway. These observations place Notch signaling among key downstream effectors of oncogenic Ras and suggest that it might be a novel therapeutic target.
Notch receptor signaling has been implicated in cellular transformation. Notch-1 receptor expression is increased during the progression from cervical intraepithelial lesions (CIN) to invasive cervical carcinoma. Moreover, the main cellular localization of Notch-1 protein changes from cytoplasmic to nuclear with the transition from CIN III to microinvasive carcinoma. Since the E6 and E7 proteins encoded by human papilloma virus (HPV) are a causative agent of cervical carcinoma, this study determined whether E6 and E7 protein expression causes the observed upregulation in Notch-1 expression. Mouse and human primary cell lines were transfected with HPV16 E6 and E7 and Notch-1 expression and activity were analyzed. We show that Notch-1 expression and activity are upregulated by E6 and E7 independently. This was due to both transcriptional and post-transcriptional mechanisms. A protein involved in Notch processing, Presenilin-1 (PS-1), was also upregulated by E6 and E7. In the presence of E6 and E7, Notch-1 protein expression is localized in the cytoplasm. Downregulation of Notch-1 expression in a human cervical carcinoma cell line expressing E6/E7 caused striking inhibition of proliferation in vitro and tumorigenicity in vivo. These data suggest that E6- and E7-mediated upregulation of Notch signaling may contribute to disruption of regular cell growth in cervical cancer.
Purpose: To evaluate if serum cytokine levels could be used as diagnostic or prognostic markers in ovarian cancer. Experimental Design: A cytokine bead array was done to simultaneously analyze 14 cytokines in the sera of 187 ovarian cancer patients with complete clinicopathologic data and follow-up, 45 patients with benign ovarian tumors, and 50 healthy controls. Serum levels of the well-known serum tumor marker CA-125 were routinely measured in all patients. Results: Serum levels of CA-125, interleukin 6 (IL-6), IL-7, and IL-10 were elevated in ovarian cancer patients compared with patients with benign ovarian tumors. Analyzing the cytokines in combination with CA-125 showed that a combination of IL-7 and CA-125 serum levels could accurately predict 69% of the ovarian cancer patients, without falsely classifying patients with benign pelvic mass. The cytokines IL-6, IL-7, IL-8, IL-10, monocyte chemotactic protein-1 (MCP-1), and IP-10 and CA-125 were associated with disease-free and overall survival in univariate analysis. In multivariate analysis, IL-7 and IP-10 were independent predictors of overall survival, although after inclusion of the clininopathologic parameters, only stage and residual disease remained as independent predictors of survival. Conclusions: IL-7 levels were found to be strongly associated with ovarian cancer and could be used in combination with CA-125 to distinguish between malignant and benign ovarian tumors.
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