The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

Mikula, Mario; Gotzmann, Josef; Fischer, Andreas; Wolschek, Markus; Thallinger, Christiane; Schulte‐Hermann, Rolf; Beug, Hartmut; Mikulits, Wolfgang

doi:10.1038/sj.onc.1206781

Cited by 70 publications

(59 citation statements)

References 77 publications

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“…JUN can homodimerise to form the AP-1 transcription factor, which activates the expression of a number of genes involved in cell cycle regulation, including cyclin D1 (Albanese et al, 1995). However, an elevated cFos expression can also lead to apoptosis in hepatoma cells (Kalra and Kumar, 2004) and hepatocytes (Mikula et al, 2003). Furthermore, recent studies have shown that cFos transcriptionally represses the key antiapoptotic gene c-FLIP(L), greatly sensitising prostate cancer cells to TRAIL-induced apoptosis (Li et al, 2007;Zhang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues during embryonic development. They are also known to behave as oncogenes in some haematological malignancies. In this study, we show that the expression of many of the HOX genes is highly elevated in primary non-small-cell lung cancers (NSCLCs) and in the derived cell lines A549 and H23. Furthermore, blocking the activity of HOX proteins by interfering with their binding to the PBX co-factor causes these cells to undergo apoptosis in vitro and reduces the growth of A549 tumours in vivo. These findings suggest that the interaction between HOX and PBX proteins is a potential therapeutic target in NSCLC. The HOX genes are a family of homeodomain-containing transcription factors that determine the identity of cells and tissues in early development (Iimura and Pourquié, 2007), and also have key regulatory roles in adult haematopoietic stem cells and their descendants (Abramovich and Humphries, 2005). In addition, HOX genes are often overexpressed in malignant cells and are known to act as oncogenes in some haematopoietic malignancies (Eklund, 2007).Repeated duplication events have given rise to 39 HOX genes in mammals, divided into four groups (A -D) in tightly linked clusters on different chromosomes (Hoegg and Meyer, 2005). The HOX genes are also divided into paralogue groups -genes that have the equivalent position in each cluster (1 -13) -thus HOXA1, for example, is the 3 0 most gene in cluster A (Scott, 1993). Whereas some HOX genes have distinct functions in specific contexts, many others have overlapping or redundant functions, both during early development (McIntyre et al, 2007) and in malignant cells (Eklund, 2007). This redundancy in HOX function is based in part upon the binding of similar DNA sequences and also on the interaction of HOX proteins with a common set of co-factors including PBX and MEIS. PBX and MEIS modify the DNA-binding specificity of HOX proteins, influence the regulation of transcription and are required for many aspects of HOX function (Moens and Selleri, 2006).In addition to haematological malignancies, the HOX genes are also expressed at high levels in many other solid malignancies, although with the exception of melanoma (Morgan et al, 2007), they are not known to have an oncogenic function. A number of studies, focusing on small groups of HOX genes, have shown that some are upregulated in lung cancer (Abe et al, 2006), but the functional significance of this is unknown. Here we present a comprehensive analysis of HOX expression in non-small-cell lung cancer (NSCLC) that reveals that many of the HOX genes have strongly elevated expression in malignant cells. Further, we show that antagonising HOX/PBX binding in the NSCLC cell lines A549 (Lieber et al, 1976) and H23 (Little et al, 1983) induces apoptosis in vitro and causes significant tumour shrinkage in A549 nude mouse models.

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Section: Discussionmentioning

confidence: 99%

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

et al. 2009

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“…Induction of c-Fos results in apoptosis in murine hepatocytes that conditionally express c-Fos (Mikula et al, 2003). Fos À/À tp53 À/À double-knockout mice develop highly invasive and proliferative rhabdomyosarcoma, a tumour rarely observed in tp53 À/À knockout-mice (Fleischmann et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of c-Fos was found to inhibit cell cycle progression, stimulated murine hepatocyte cell death and strongly suppressed tumour formation in vivo (Mikula et al, 2003). A functional involvement of c-Fos in apoptosis has been shown by its regulatory involvement during remodelling and stress response in various tissues in mouse development (Jochum et al, 2001).…”

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confidence: 99%

C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma

et al. 2008

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Members of the Fos protein family dimerise with Jun proteins to form the AP-1 transcription factor complex. They have a central function in proliferation and differentiation of normal tissue as well as in oncogenic transformation and tumour progression. We analysed the expression of c-Fos, FosB, Fra-1 and Fra-2 to investigate the function of Fos transcription factors in ovarian cancer. A total of 101 patients were included in the study. Expression of Fos proteins was determined by western blot analysis, quantified by densitometry and verified by immunohistochemistry. Reduced c-Fos expression was independently associated with unfavourable progression-free survival (20.6, 31.6 and 51.2 months for patients with low, moderate and high c-Fos expression; P ¼ 0.003) as well as overall survival (23.8, 46.0 and 55.5 months for low, moderate and high c-Fos levels; P ¼ 0.003). No correlations were observed for FosB, Fra-1 and Fra-2. We conclude that loss of c-Fos expression is associated with tumour progression in ovarian carcinoma and that c-Fos may be a prognostic factor. These results are in contrast to the classic concept of c-Fos as an oncogene, but are supported by the recently discovered tumour-suppressing and proapoptotic function of c-Fos in various cancer types.

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“…C-Jun and c-Fos are members of the AP-1 complex [12,15] . A number of studies found that COBRA1 may be associated with the AP-1 complex via physical binding to c-Fos on the promoter proximal region of its target genes in breast cancer and UGC [8,11] .…”

Section: Protein Expression Levels Of C-fos and C-jun In Different Hcmentioning

confidence: 99%

“…The c-Fos protein is transiently up-regulated in the early stages of hepatocarcinogenesis and then declines in the later stages of tumor progression. This temporary overexpression is needed for priming hepatocytes for migration and tissue invasion [15] . In contrast, the c-Jun protein is involved in tumor cell survival and apoptosis [16] .…”

Section: Introductionmentioning

confidence: 99%

The potential involvement of the cofactor of BRCA1 in hepatocellular carcinoma pathogenesis

et al. 2016

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<p>The cofactor of BRCA1 (COBRA1), which also refers to negative elongation factor polypeptide B (NELF-B), is a negative elongation factor (NELF) subunit that has been implicated in the development and progression of several cancers. While reduced COBRA1 expression has been associated with metastatic breast cancer, COBRA1 negatively regulates the activator protein-1 (AP-1) complex, leading to the down-regulation of trefoil factor-1 (TFF1) expression in gastric cancer cell lines. The involvement of COBRA1 in hepatocellular carcinoma (HCC) tumor formation and progression is not known. Here, we investigated the expression of COBRA1, the AP-1 complex, and TFF1 in several HCC cell lines; ranging from low- to high-grade HCC cell lines generated from patients with different stages of the disease. Our results showed that the COBRA1 protein was highly expressed in the low-grade HCC cell line, while significantly down-regulated in high-grade HCC cell lines. TFF1, previously regarded as a COBRA1 target gene, was only expressed in the low-grade HCC cell line and the control cells. Our results suggest that COBRA1 may play a role in HCC pathogenesis and progression. The TFF1 mRNA expression profile was uncorrelated to that of the AP-1 complex subunit proteins, which suggests the involvement of other regulatory pathways in TFF1 expression; however, this requires further study.</p>

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The proto-oncoprotein c-Fos negatively regulates hepatocellular tumorigenesis

Cited by 70 publications

References 77 publications

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer)

C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma

The potential involvement of the cofactor of BRCA1 in hepatocellular carcinoma pathogenesis

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