Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation

Ropponen, Kirsi; Kellokoski, Jari; Pirinen, Risto; Moisio, Kaisa I.; Eskelinen, Matti; Alhava, Esko; Kosma, Veli‐Matti

doi:10.1136/jcp.54.7.533

Cited by 59 publications

(55 citation statements)

References 33 publications

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“…Others did detect AP-2a by immunohistochemistry in some prostate cancer specimens (Lipponen et al, 2000). In primary colorectal (Ropponen et al, 2001) and ovarian cancers (Anttila et al, 2000), AP-2a was detected in the nucleus or the cytoplasm of tumour cells. However, the presence of the transcription factor in the cytoplasm precludes its function in transcription.…”

Section: Discussionmentioning

confidence: 97%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185 c-erbB-2 levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185 c-erbB-2 and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells.

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Section: Discussionmentioning

confidence: 97%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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“…Many studies indicate that the activity of AP-2a results in cell cycle arrest and that its activity relates to tumor suppression, 1,7,57,58 while other studies suggest that overexpression of AP-2a is carcinogenic. 9,59-61 Several investigators examined the status of AP-2 proteins in human tumor tissues to uncover their role in oncogenesis and their prognostic value.…”

Section: Discussionmentioning

confidence: 99%

Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/neu gene in breast cancer

Wang

Hung

et al. 2005

Intl Journal of Cancer

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HER-2/neu proto-oncogene is overexpressed in about one fourth of human breast cancers. AP-2 transcription factors bind to the HER-2/neu gene promoter and activate its expression. In a striking concurrence, anomalous abundance of AP-2a protein or its homolog AP-2c is also detected with HER-2/neu protein in mammary tumor-derived cell lines. This suggests that the deregulation of AP-2 is the preceding pathogenic event and probably the pivotal one in this type of mammary carcinogenesis. We examined the process of AP-2a gene expression in mammary carcinoma cell lines to identify where the aberration had occurred. We found no amplification of the AP-2a gene. Its promoter was marginally upregulated; however, it did not significantly increase the mRNA levels. When the AP-2a protein was examined, a remarkable stability was seen in breast cancer cell lines MDA-MB-453 and SK-BR-3, with a half-life of over 30 hr. This is sharply higher than the approximate 1 hr observed in mammary epithelial cell line MCF-10A and murine cell line NIH 3T3. Treatment of MCF-10A and NIH 3T3 cells with the proteasome inhibitor MG-132 showed that AP-2a was ubiquitinated and its level significantly increased. Moreover, this increase was accompanied by elevated levels HER-2/neu protein. In contrast, weaker ubiquitination of AP-2a was seen in MDA-MB-453 and SK-BR-3 cancer cells, and MG-132 treatment did not raise the AP-2a level any further. These results uncover that unusual stability is the main mechanism that raises the levels of AP-2 proteins, and in addition, provide the first clue that defective ubiquitin-dependent proteasomal-degradation pathway is possibly the prime cause that affects the HER-2/neu gene and culminates in breast cancer. ' 2005 Wiley-Liss, Inc.

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“…AP-2 is one of the critical factors of neural gene expression (Mitchell et al, 1991) and various neural genes contain AP-2 binding sites in their regulatory regions. Loss of AP-2a expression has been associated with progression of melanoma , prostate cancer (Ruiz et al, 2004) and colorectal cancer (Ropponen et al, 1999(Ropponen et al, , 2001). In addition, immunohistochemical studies of human melanoma, breast and colorectal cancer specimens have revealed that loss of AP-2a coincides with poor prognosis (Karjalainen et al, 1998;Ropponen et al, 1999;Pellikainen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Transfection of AP-2a into hepatoblastoma and colon adenocarcinoma cell lines, which lack endogenous AP-2a expression, has resulted in negative cell cycle control and cell growth inhibition in vitro (Pellikainen et al, 2003). Immunohistochemical studies have shown that downregulated cytoplasmic AP-2a expression was consistently seen in high grade and advanced Duke's stage tumors (Ropponen et al, 2001). In addition, low cytoplasmic AP-2a expression was seen in high-grade carcinomas (Ropponen et al, 2001), corroborating previous reports in which low AP-2a expression was associated with higher tumor malignancy and poor survival (Karjalainen et al, 1998;Ropponen et al, 1999;Pellikainen et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Immunohistochemical studies have shown that downregulated cytoplasmic AP-2a expression was consistently seen in high grade and advanced Duke's stage tumors (Ropponen et al, 2001). In addition, low cytoplasmic AP-2a expression was seen in high-grade carcinomas (Ropponen et al, 2001), corroborating previous reports in which low AP-2a expression was associated with higher tumor malignancy and poor survival (Karjalainen et al, 1998;Ropponen et al, 1999;Pellikainen et al, 2003). However, the exact mechanism by which loss of AP-2a contributes to colon cancer progression is yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

et al. 2007

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Activator protein-2 (AP-2) is a transcription factor that regulates proliferation and differentiation in mammalian cells and has been implicated in the acquisition of the metastatic phenotype in several types of cancer. Herein, we examine the role of AP-2a in colon cancer progression. We provide evidence for the lack of AP-2a expression in the late stages of colon cancer cells. Re-expression of the AP-2a gene in the AP-2a-negative SW480 colon cancer cells suppressed their tumorigenicity following orthotopic injection into the cecal wall of nude mice. The inhibition of tumor growth could be attributed to the increased expression of E-cadherin and decreased expression and activity of matrix-metalloproteinase-9 (MMP-9) in the transfected cells, as well as a substantial loss of their in vitro invasive properties. Conversely, targeting constitutive expression of AP-2a in AP-2-positive KM12C colon cancer cells with small interfering RNA resulted in an increase in their invasive potential, downregulation of E-cadherin and increased expression of MMP-9. In SW480 cells, re-expression of AP-2a resulted in a fourfold increase in the activity of E-cadherin promoter, and a 5-14-fold decrease in the activity of MMP-9 promoter, indicating transcriptional regulation of these genes by AP-2a. Chromatin immunoprecipitation assay showed that re-expressed AP-2a directly binds to the promoter of E-cadherin, where it has been previously reported to act as a transcriptional activator. Furthermore, chromatin immunoprecipitation assay revealed AP-2a binding to the MMP-9 promoter, which ensued by decreased binding of transcription factor Sp-1 and changes in the recruitment of transcription factors to a distal AP-1 element, thus, contributing to the overall downregulation of MMP-9 promoter activity. Collectively, our data provide evidence that AP-2a acts as a tumor suppressor gene in colon cancer.

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Expression of transcription factor AP-2 in colorectal adenomas and adenocarcinomas; comparison of immunohistochemistry and in situ hybridisation

Abstract: (J Clin Pathol 2001;54:533-538)

Cited by 59 publications

References 33 publications

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Inefficient proteasomal‐degradation pathway stabilizes AP‐2α and activates HER‐2/neu gene in breast cancer

Loss of AP-2α results in deregulation of E-cadherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivo

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