Expression of Transcription Factor E2F-1 in Pancreatic Ductal Carcinoma: An Immunohistochemical Study

Yamazaki, Kazuto; Yajima, Takayuki; Nagao, Toshitaka; Shinkawa, Hiroki; Kondo, Fukuo; Hanami, Kyota; Asoh, Akira; Sugano, Isamu; Ishida, Yasuo

doi:10.1078/0344-0338-00348

Cited by 42 publications

(35 citation statements)

References 19 publications

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“…E2F-1 immunohistochemical expression was correlated with increased tumor cell apoptosis, suggesting that E2F-1 may have an oncosuppressor role in HCC. An apoptosis promoting tumor suppressor role for E2F-1 has also been demonstrated in adenocarcinoma of Barrett esophagus, in carcinomas of colon, prostate, and bladder, and more recently, in osteosarcoma [8,9,[20][21][22]. In contrast, E2F-1 appears to act as an oncogene, promoting tumor growth, in lung cancer, esophageal squamous cell carcinoma, and carcinomas of the breast, pancreas, and ovary [9,23,24].…”

Section: Discussionmentioning

confidence: 86%

E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

et al. 2012

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E2F-1 is a transcription factor involved in DNA synthesis and repair, cell proliferation, and apoptosis. Hyposphorylated pRb represses E2F-1 action in early G1 phase, while in late G1, pRb hyperphosphorylation leads to E2F-1 release and activation. In vitro studies have shown that E2F-1 may act either as oncogene or as tumor suppressor gene. We evaluated immunohistochemical expression of E2F-1 protein in chronic viral liver disease and hepatocellular carcinoma (HCC) and correlated this with clinicopathological parameters, cell proliferation, apoptosis, and the expression of E2F-1-regulators, pRb, and phospho-pRb (Ser795). In liver biopsies from 30 patients with chronic viral hepatitis, including 22 with cirrhosis without HCC, and 57 with cirrhosis with HCC, E2F-1 expression was assessed by immunohistochemistry. In chronic hepatitis and cirrhosis, hepatocytes and cholangiocytes demonstrated mild cytoplasmic and/or nuclear membrane E2F-1 immunostaining. In contrast, all HCC (100 %) showed strong nuclear E2F-1 immunostaining, with or without membrane accentuation, while a minority demonstrated additional moderate cytoplasmic immunostaining. Abnormally low pRb and phospho-pRb expression was seen in 70 % and 67.9 % of HCC, respectively. In HCC, nuclear E2F-1 expression was inversely correlated with phospho-pRb expression (p = 0.001) and positively related to tumor apoptotic index (p = 0.025). No significant correlation was found between E2F-1 expression and patient demographics, HCC etiology, tumor grade, pRb, p53 expression, or cell proliferation. In conclusion, we show that the increased expression of E2F-1 protein in human HCC is correlated with enhanced tumor cell apoptosis supporting a pro-apoptotic role of E2F-1 in human HCC.

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Section: Discussionmentioning

confidence: 86%

E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

et al. 2012

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“…In previous studies, E2F1 was shown to promote breast cancer cell and hepatocarcinoma cell proliferation, and conferred antiestrogen resistance to breast cancer cells (Arakawa et al, 2004;Louie et al, 2004). Transgenic models with E2F1 overexpression (Lee et al, 2004) and clinical data from patients with different types of cancer (Gorgoulis et al, 2002;Yamazaki et al, 2003;Imai et al, 2004;Lee et al, 2004;Onda et al, 2004) have further supported the role of E2F1 in oncogenesis. Under normal circumstances, E2F1 gene expression is tightly regulated, and its protein product is rapidly degraded.…”

Section: Discussionmentioning

confidence: 93%

“…The protein has been shown to be essential for c-Mycinduced carcinogenesis both in vitro and in vivo (Baudino et al, 2003). Recent clinical studies have shown that E2F1 is correlated with tumor progression and shorter survival time in patients with pancreatic and nonsmall cell lung carcinomas (Gorgoulis et al, 2002;Yamazaki et al, 2003). The number of known E2F1 target genes has recently been increased using microarray technology, and now includes genes involved in mitosis, chromosome segregation, mitotic spindle checkpoints, DNA repair, chromatin assembly/ condensation, differentiation, embryonic development and apoptosis (Mundle and Saberwal, 2003).…”

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confidence: 99%

Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

et al. 2005

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Although previous studies suggested that the tumorigenicity of mouse double minute 2 (MDM2) was due to its negative regulation of p53, the p53-independent interactions may be equally as important. During recent studies utilizing MDM2 inhibitors, we noted that E2F transcription factor 1 (E2F1) was downregulated upon inhibition of MDM2, regardless of the p53 status of the cancer. The present study investigated the mechanisms responsible for the MDM2-mediated increase in E2F1 expression. MDM2 prolongs the half-life of the E2F1 protein by inhibiting its ubiquitination. MDM2 displaces SCF SKP2 , the E2F1 E3 ligase. Direct binding between MDM2 and E2F1 is necessary for the negative effects of MDM2 on E2F1 ubiquitination, and deletion of the MDM2 nuclear localization signal does not result in loss of the ability to increase the E2F1 protein level. The downregulation of E2F1 upon MDM2 inhibition was not due to either pRB or p14Arf . In addition, E2F1 was responsible for at least part of the inhibition of cell proliferation induced by MDM2 knockdown. In conclusion, the present study provides evidence that stabilization of the E2F1 protein is likely another p53-independent component of MDM2-mediated tumorigenesis. More knowledge about the MDM2-E2F1 interaction may be helpful in developing novel anticancer therapies.

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“…The expression levels of E2F1, E2F2, and E2F8 were elevated in the ovarian cancer cells (27). Besides, E2F1 was overexpressed in breast cancers (28), pancreatic ductal carcinoma (29), and gastric cancer (30). E2F5 was also overexpressed in breast cancer (31).…”

Section: Discussionmentioning

confidence: 99%

E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

Deng

Wang²,

Zong³

et al. 2010

Cancer Research

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The E2F family member of transcription factors includes the atypical member E2F8, which has been little studied in cancer. We report that E2F8 is strongly upregulated in human hepatocellular carcinoma (HCC), where it was evidenced to contribute to oncogenesis and progression. Ectopic overexpression of E2F8 promoted cell proliferation, colony formation, and tumorigenicity, whereas E2F8 knockdown inhibited these phenotypes, as documented in Huh-7, Focus, Hep3B, and YY-8103 HCC cell lines. Mechanistic analyses indicated that E2F8 could bind to regulatory elements of cyclin D1, regulating its transcription and promoting accumulation of S-phase cells. Together, our findings suggest that E2F8 contributes to the oncogenic potential of HCC and may constitute a potential therapeutic target in this disease. Cancer Res; 70(2); 782-91. ©2010 AACR.

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Expression of Transcription Factor E2F-1 in Pancreatic Ductal Carcinoma: An Immunohistochemical Study

Cited by 42 publications

References 19 publications

E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

E2F-1 is overexpressed and pro-apoptotic in human hepatocellular carcinoma

Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway

E2F8 Contributes to Human Hepatocellular Carcinoma via Regulating Cell Proliferation

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