Heterogeneous cross-talk of E2F family members is crucially involved in growth modulatory effects of interferon-γ and EGF

Reimer, Daniel; Sadr, Susann; Wiedemair, Annemarie; Concin, Nicole; Hofstetter, Gerda; Marth, Christian; Zeimet, Alain G.

doi:10.4161/cbt.5.7.2750

Cited by 17 publications

(13 citation statements)

References 21 publications

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“…Nonetheless, we cannot completely rule out that a higher stroma to epithelial cell ratio is responsible for the low E2F expression levels detected in control tissue. On the other hand, overexpression of proliferation-promoting E2F transcription factors in ovarian cancers is corroborated by our recent in vitro findings, showing that E2F1 and predominantly E2F2 were significantly up-regulated in ovarian cancer cell lines compared with normal human peritoneal mesothelial cells (21). Furthermore, E2F1 and E2F2 correlated significantly with grade 3 tumors and residual disease >2 cm in diameter after primary debulking surgery, suggesting a pivotal role of these proliferation-promoting E2F transcription factors in the biology of fast-growing ovarian carcinomas.…”

Section: Discussionsupporting

confidence: 78%

“…As gene expression profile of epithelial mucinous ovarian cancers was found to be very similar to that of intestinal carcinomas (27) and hereditary nonpolyposis colorectal cancers are frequently associated with mutations of the E2F4 gene (28), it is tempting to speculate that alterations in the E2F4 gene could also play a significant role in mucinous cancers of the ovary, and through the lack of the inhibitory property of mutated E2F4 on E2F2 transcription, overexpression of E2F2 especially in this histologic subtype could be explained. This hypothesis is furthermore supported by our recent data obtained in IFN-g-treated ovarian cancer cell lines showing a direct inhibitory E2F4-pocket protein effect on the E2F1 and especially E2F2 promoters (21). Moreover, E2F4 was reported to act as a critical regulator of the E2F1 gene in the Burkitt's lymphoma cell line Daudi treated with IFN-a (29).…”

Section: Discussionsupporting

confidence: 70%

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Clinical Relevance of E2F Family Members in Ovarian Cancer—An Evaluation in a Training Set of 77 Patients

Reimer

Sadr

Wiedemair

et al. 2007

Clinical Cancer Research

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Purpose: The major obstacle in treating ovarian cancer is the rapid development of platinum resistance during therapy. Deregulation of members of the E2F family of transcription factors is crucially involved in carcinogenesis and probably in mechanisms underlying platinum resistance. We therefore investigated the relevance of the whole set of E2F family members in predicting clinical outcome and their significance in predicting platinum resistance. Experimental Design: Real-time PCR of all E2F family members was done from 77 ovarian carcinomas, defined as our training set, and 8 healthy control samples. The correlation with clinicopathologic characteristics, platinum resistance, and survival was investigated. Furthermore, the cross-talk of E2F family members was assessed for its value in predicting survival and platinum resistance. Results: The proliferation-promoting E2F1and E2F2 were associated with grade 3 tumors and residual disease >2 cm in diameter after initial surgery. Survival analyses showed low expression of E2F1or E2F2 to be significantly associated with favorable disease-free and overall survival (E2F1, P = 0.039 and 0.047, respectively; E2F2, P = 0.009 and 0.006, respectively). In contrast, high expression of inhibiting E2F4 or E2F7 predicted favorable disease-free and overall survival (E2F4, P = 0.047 and 0.042, respectively; E2F7, P = 0.048 and 0.042, respectively). A high E2F2 to E2F4 ratio was the most valuable prognostic variable for disease-free survival in multivariate analysis (hazard ratio, 6.494; P = 0.002). Tumors considered platinum resistant were associated with lower E2F4 and E2F7 expression (P = 0.012 and 0.009, respectively) compared with platinumsensitive tumors. Again, ratios of E2F1 or E2F2 to E2F7 were the most favorable variables in predicting platinum resistance. Conclusions: We here show that deregulation of both proliferation-promoting and proliferationinhibiting E2F transcription factors and their cross-talk is crucially involved in the tumor biology of ovarian cancer and influences clinical outcome. Furthermore, down-regulation of E2F7 may contribute to mechanisms underlying platinum resistance, and calculation of ratios of proliferationpromoting E2F1to E2F7 could serve as a putative predictor of platinum resistance.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionsupporting

confidence: 70%

Clinical Relevance of E2F Family Members in Ovarian Cancer—An Evaluation in a Training Set of 77 Patients

Reimer

Sadr

Wiedemair

et al. 2007

Clinical Cancer Research

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“…Furthermore, a positive correlation between E2F1, a proliferation-promoting transcription factor involved in the Rb pathway, and soluble CAR expression was observed. Moreover, tumors with p53 mutations have been found to be associated with high expression levels of E2F1 [Reimer et al, submitted for publication], and in ovarian cancer cells interferon-g treatment resulted in down-regulation of E2F1 31 followed by a significant decline in hCAR and its soluble variants (unpublished data). These findings tempt us to speculate that E2F1 may be directly involved in the regulation of CAR.…”

Section: Discussionmentioning

confidence: 99%

“…31 Human peritoneal mesothelial cells (HPMC) and ovarian surface epithelial cells (OSE) served as control and were obtained from patients during surgery for other than inflammatory or malignant disease.…”

Section: Cell Linesmentioning

confidence: 99%

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

Reimer

Steppan

Wiedemair

et al. 2007

Intl Journal of Cancer

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The coxsackie‐adenovirus receptor (hCAR) has been extensively studied in context of adenoviral‐based gene therapy for cancer. However, there is strong evidence that besides its decisive role in coxsackie and adenovirus cell‐entry, hCAR is a component of epithelial tight junctions and involved in cell‐cell adhesions in normal and cancer cells. Furthermore, this adhesion molecule behaves like a cell surface receptor endowed with tumor suppressive properties via signal transduction. Moreover, 3 truncated soluble isoforms of hCAR were recently identified. We investigated the quantitative expression of all known CAR isoforms in a training set of 140 ovarian cancer samples and 21 controls by RT‐PCR. The expression levels of the various isoforms were compared with clinicopathologic parameters and their prognostic significance was assessed. Expression levels of all CAR isoforms were elevated in ovarian carcinomas as compared with those of non‐malignant controls. mRNA‐expression correlated with protein levels. Moreover, expression of the soluble isoforms CAR 3/7 and CAR 4/7 but not that of hCAR was significantly increased in advanced ovarian cancer as revealed by a highly significant correlation with FIGO stage and residual disease > 2 cm in diameter after debulking surgery. High expression of CAR 3/7 and 4/7 was shown to be of independent prognostic relevance for progression‐free (CAR 4/7) and overall survival (CAR 3/7 and CAR 4/7). In conclusion, soluble CAR isoforms 3/7 and 4/7 may play a pivotal role in ovarian cancer biology, possibly by counteracting migration‐ and growth‐inhibitory properties of the membranous hCAR and thus favoring cancer cell dissemination throughout the peritoneal cavity. © 2007 Wiley‐Liss, Inc.

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“…Established ovarian cancer cell lines and the mesothelioma cell line CRL-5820 (American Type Culture Collection/LGC Promochem GmbH) were cultured in serum-free medium as previously described (15). Ovarian surface epithelial (OSE) and human peritoneal mesothelial cells (HPMC) were obtained from postmenopausal patients during surgery for other than inflammatory or malignant conditions.…”

Section: Cell Culture Experimentsmentioning

confidence: 99%

E2F3a Is Critically Involved in Epidermal Growth Factor Receptor–Directed Proliferation in Ovarian Cancer

et al. 2010

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We describe for the first time a new integral molecular pathway, linking transcription factor E2F3a to epidermal growth factor receptor (EGFR) activation in ovarian cancer cells. Investigations on the role of E2F family members in EGFR-mediated mitogenic signaling revealed that E2F3a was selectively upregulated following EGFR activation, whereas all other E2F family members remained unaffected. In contrast, EGF treatment of healthy ovarian surface epithelial and mesothelial cells yielded a selective upregulation of proliferation-promoting E2F1 and E2F2 without influencing E2F3a expression. In ovarian cancer cell lines, the extent of EGF-induced proliferative stimulus was closely related to the magnitude of E2F3a increase, and proliferation inhibition by E2F3a knockdown was not overcome by EGF exposure. Furthermore, the EGFR-E2F3a axis was found to be signal transducer and activator of transcription 1/3 dependent and the ratio of IFN-regulatory factor (IRF)-1 to IRF-2 was shown to be determinative for E2F3a control. In a pilot study on 32 primary ovarian cancer specimens, a highly significant correlation between activated EGFR and E2F3a expression was disclosed. This new integral pathway in the EGFR-driven mitogenic cell response, which through its key player E2F3a was found to be essential in triggering proliferation in ovarian cancer cells, provides new insights into EGFR signaling and could represent the basis for appealing new therapeutic approaches in ovarian cancer. Cancer Res; 70(11); 4613-23. ©2010 AACR.

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Heterogeneous cross-talk of E2F family members is crucially involved in growth modulatory effects of interferon-γ and EGF

Cited by 17 publications

References 21 publications

Clinical Relevance of E2F Family Members in Ovarian Cancer—An Evaluation in a Training Set of 77 Patients

Clinical Relevance of E2F Family Members in Ovarian Cancer—An Evaluation in a Training Set of 77 Patients

Soluble isoforms but not the transmembrane form of coxsackie‐adenovirus receptor are of clinical relevance in epithelial ovarian cancer

E2F3a Is Critically Involved in Epidermal Growth Factor Receptor–Directed Proliferation in Ovarian Cancer

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