Immunohistochemical analysis of C/EBPα in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: A correlative study of E3590

Costa, Daniel B.; Li, Sigui; Kocher, Olivier; Feins, Richard H.; Keller, Steven M.; Schiller, Joan H.; Johnson, David H.; Tenen, Daniel G.; Halmos, Balázs

doi:10.1016/j.lungcan.2006.11.023

Cited by 18 publications

(16 citation statements)

References 36 publications

(53 reference statements)

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“…Both the overexpression of Sox2 and the amplification of SOX2 were associated with improved prognosis in NSCLCs with squamous cell histology (11), whereas the expression of Sox2 in adenocarcinomas was a poor prognostic marker in early stage NSCLC (26). The downregulation of C/EBPα was not prognostic in our group’s study of stage II and III NSCLC (4). In the present cohort of 130 NSCLCs, we observed a trend towards improved prognosis in the subset of stage I adenocarcinomas with higher expression of Foxa2 when compared to the group with low or no expression of Foxa2.…”

Section: Discussionmentioning

confidence: 75%

Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

et al. 2012

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PURPOSE We sought to determine the mechanisms of downregulation of the airway transcription factor Foxa2 in lung cancer and the expression status of Foxa2 in non-small-cell lung cancer (NSCLC). METHODS A series of 25 lung cancer cell lines were evaluated for Foxa2 protein expression, FOXA2 mRNA levels, FOXA2 mutations, FOXA2 copy number changes and for evidence of FOXA2 promoter hypermethylation. In addition, 32 NSCLCs were sequenced for FOXA2 mutations and 173 primary NSCLC tumors evaluated for Foxa2 expression using an immunohistochemical assay. RESULTS Out of the 25 cell lines, 13 (52%) had undetectable FOXA2 mRNA. The expression of FOXA2 mRNA and Foxa2 protein were congruent in 19/22 cells (p=0.001). FOXA2 mutations were not identified in primary NSCLCs and were infrequent in cell lines. Focal or broad chromosomal deletions involving FOXA2 were not present. The promoter region of FOXA2 had evidence of hypermethylation, with an inverse correlation between FOXA2 mRNA expression and presence of CpG dinucleotide methylation (p<0.0001). In primary NSCLC tumor specimens, there was a high frequency of either absence (42/173, 24.2%) or no/low expression (96/173, 55.4%) of Foxa2. In 130 patients with stage I NSCLC there was a trend towards decreased survival in tumors with no/low expression of Foxa2 (HR of 1.6, 95%CI 0.9–3.1; p=0.122). CONCLUSIONS Loss of expression of Foxa2 is frequent in lung cancer cell lines and NSCLCs. The main mechanism of downregulation of Foxa2 is epigenetic silencing through promoter hypermethylation. Further elucidation of the involvement of Foxa2 and other airway transcription factors in the pathogenesis of lung cancer may identify novel therapeutic targets.

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Section: Discussionmentioning

confidence: 75%

Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

et al. 2012

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“…11,12,15,16 In all these examples, a role for impaired C/EBPa function in tumourigenesis was strengthened by the observation that C/EBPa re-expression is able to inhibit tumourigenesis both in vivo and in vitro. 15,16 In our study, we observed downregulation of C/EBPa in about 30% of GC cases.…”

Section: Discussionmentioning

confidence: 99%

“…9 C/EBPa may also have a role in other cancer models 10 such as lung cancer, where it was found downregulated by methylation. 11,12 However, the expression pattern and functional relevance of C/EBPa in normal stomach and in GC has never been described.…”

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C/EBPα expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis

Regalo

Resende

Wen

et al. 2010

Laboratory Investigation

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Transcription factors from the CCAAT/enhancer-binding protein (C/EBP) family are fundamental for the control of differentiation and proliferation of many adult tissues. C/EBPa has a crucial role in inducing terminal differentiation and is an established tumor suppressor gene in several cancer models. The objective of this study was to analyze the putative role of C/EBPa in gastric carcinoma (GC). We analyzed the expression of C/EBPa in normal and neoplastic gastric tissues, and assessed the role of C/EBPa on proliferation and differentiation of GC cells. In normal gastric mucosa, C/EBPa is expressed in the foveolar epithelium and co-localizes with the gastric differentiation marker trefoil factor 1 (TFF1). The expression of C/EBPa was found to be lost in 30% of GC cases. To evaluate the role of C/EBPa in cell proliferation and differentiation, we transfected GC cells with a full-length C/EBPa protein. We observed a significant decrease in proliferation in C/EBPa-transfected cells. This was accompanied by a decrease in Cyclin D1, an increase in P27 expression, and an increased expression of TFF1. Finally, we showed that inhibition of the Ras/MAPK pathway leads to increased C/EBPa and TFF1 expression, and decreased cell proliferation and cyclin D1 expression in GC cells. Our results suggest that C/EBPa (together with other members of the C/EBP family) has an active role in the control of differentiation and proliferation in normal gastric mucosa. In GC, loss of C/EBPa may be associated with the switch from a cellular differentiation to a cellular proliferation program, presumably as a consequence of Ras/MAPK pathway activation.

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“…In particular, expression of C/EBPα has been shown to be crucial for lung development, as knockout mice exhibit massive hyperproliferation of type II pneumocytes and do not survive after birth (Flodby et al , 1996). C/EBPα may act as a tumor suppressor in the lung, as its overexpression in lung tumor cells results in a dramatic decrease in cell proliferation (Halmos et al , 2002), and it is often downregulated in NSCLC (Halmos et al , 2002; Costa et al , 2007). Work done by Pear and colleagues showed that the human homolog of the Drosophila tribbles protein, TRIB2, associates with and inhibits the transcriptional activity of C/EBPα (Keeshan et al , 2006; Dedhia et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

Overexpression of TRIB2 in human lung cancers contributes to tumorigenesis through downregulation of C/EBPα

Grandinetti

Stevens

et al. 2011

Oncogene

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Lung cancer is the most common cause of cancer-related mortality worldwide. Here, we report elevated expression of tribbles homolog 2 (TRIB2) in primary human lung tumors and in non-small cell lung cancer cells that express low levels of differentiation-inducing transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα). In approximately 10–20% of cases, elevated TRIB2 expression resulted from gene amplification. TRIB2 knockdown was found to inhibit cell proliferation and in vivo tumor growth. In addition, TRIB2 knockdown led to morphological changes similar to C/EBPα overexpression and correlated with increased expression and activity of C/EBPα. TRIB2-mediated regulation of C/EBPα was found to occur through the association of TRIB2 with the E3 ligase TRIM21. Together, these data identify TRIB2 as a potential driver of lung tumorigenesis through a mechanism that involves downregulation of C/EBPα.

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Immunohistochemical analysis of C/EBPα in non-small cell lung cancer reveals frequent down-regulation in stage II and IIIA tumors: A correlative study of E3590

Cited by 18 publications

References 36 publications

Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

Frequent downregulation of the transcription factor Foxa2 in lung cancer through epigenetic silencing

C/EBPα expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis

Overexpression of TRIB2 in human lung cancers contributes to tumorigenesis through downregulation of C/EBPα

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