p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis

Ropponen, Kirsi; Kellokoski, Jari; Lipponen, P; Pietiläinen, Timo; Eskelinen, Matti; Alhava, Esko; Kosma, Veli‐Matti

doi:10.1038/sj.bjc.6690662

Cited by 63 publications

(59 citation statements)

References 36 publications

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“…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: Introductionsupporting

confidence: 87%

“…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%

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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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Section: Introductionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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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“…In clinical specimens of invasive breast cancer, a correlation between low AP-2 expression and disease progression was demonstrated, suggesting a tumor suppressor-like role for AP-2 (Gee et al, 1999). In colorectal carcinoma, AP-2 expression correlates with p21/WAF1 expression and recurrence-free survival (Ropponen et al, 1999). These observations indicate that AP-2 plays multiple roles in both normal development and the development/ progression of cancer.…”

mentioning

confidence: 67%

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

2003

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To determine treatment strategies and predict the clinical outcome of patients with melanoma it is important to understand the etiology of this disease. Recently, there has been some insight into molecular basis of melanoma including identification of a few of the regulatory factors and genes involved in this disease. For instance, the transcription factor AP-2 plays a tumor suppressor-like role in melanoma progression by regulating genes involved in tumor growth and metastasis. Previously, we have shown that the progression of human melanoma to the metastatic phenotype is associated with loss of AP-2 expression and deregulation of target genes such as MUC18/MCAM, c-KIT, and MMP-2. Increasing evidence demonstrates that the thrombin receptor (proteaseactivated receptor-1, PAR-1) plays a major role in tumor invasion and contributes to the metastatic phenotype of human melanoma. This review focuses on the role of the thrombin receptor in melanoma and its regulation by AP-2. We show that loss of AP-2 expression in metastatic melanoma cells correlates with overexpression of the thrombin receptor. Our analysis of AP-2/Sp1 complexes within the regulatory region of the thrombin receptor demonstrates that AP-2 binds the proximal 3 0 region of the promoter and diminishes PAR-1 expression. Levels of AP-2 and Sp1 proteins in a panel of melanoma cell lines demonstrated a marked decrease in the ratio of AP-2/ Sp1, a decrease that correlated with overexpression of PAR-1 in metastatic melanoma cells. We propose that loss of AP-2 results in increased expression of the thrombin receptor, which subsequently contributes to the metastatic phenotype of melanoma by upregulating the expression of adhesion molecules, proteases, and angiogenic molecules.

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“…Increased p21 expression has also been seen in several types of malignant tumors (Baekelandt et al, 1999;Barboule et al, 1998), and a higher level of p21 has been correlated with higher 5-year survival rate (Kuwahara et al, 1999;Natsugoe et al, 1999;Ropponen et al, 1999). To evaluate p15 PAF 's potential function in tumor development, p15 PAF expression level was measured using tumor blots (Invitrogen).…”

Section: P15 Paf Expression Is Increased In Tumor Tissuesmentioning

confidence: 99%

p15PAF, a novel PCNA associated factor with increased expression in tumor tissues

et al. 2001

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Proliferating cell nuclear antigen (PCNA) is an essential protein in both DNA replication and DNA damage repair. A novel 15 kD protein, p15 PAF , was identi®ed as a PCNA-associated factor in a yeast two-hybrid screen using PCNA as the bait. p15 PAF is localized primarily in the nucleus. p15 PAF shares the conserved PCNA binding motif with several other PCNA binding proteins including CDK inhibitor p21. Overexpression of p15 PAF competes with p21-PCNA binding. Mutation of this motif in p15 PAF abolished its PCNA-binding activity. Notably, p15 PAF expression in several types of tumor tissues was signi®cantly increased, especially in esophageal tumors. Like PCNA, p15 PAF may possess prognostic signi®cance in a broad array of human cancers. Oncogene (2001) 20, 484 ± 489.

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p21/WAF1 expression in human colorectal carcinoma: association with p53, transcription factor AP-2 and prognosis

Cited by 63 publications

References 36 publications

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

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

Role and regulation of the thrombin receptor (PAR-1) in human melanoma

p15PAF, a novel PCNA associated factor with increased expression in tumor tissues

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