β-Catenin Up-Regulates the Expression of the Urokinase Plasminogen Activator in Human Colorectal Tumors

Hiendlmeyer, Elke; Regus, Susanne; Wassermann, Stella; Hlubek, Falk; Haynl, Angela; Dimmler, Arno; Koch, Claudia; Knoll, Claudia; Beest, Moniek van; Reuning, Ute; Brabletz, Thomas; Kirchner, Thomas; Jung, Andreas

doi:10.1158/0008-5472.can-3627-2

Cited by 79 publications

(69 citation statements)

References 18 publications

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“…In our system, the two cell lines that have a folate-depletion-induced elevation of E-cadherin (HCEC and NCM460) are also the ones that display an increase in urokinase. Regulation of urokinase has also been attributed to SMAD-4 [55] and β-catenin [56]. Furthermore, SMAD-4 is an inducer of Ecadherin transcription [57], and in our system, the changes in these two genes are paralleled, with a trend for increase in HCEC and NCM460 and decrease in NCM356 during folate depletion.…”

Section: Discussionsupporting

confidence: 60%

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

Crott

Liu

Keyes

et al. 2008

The Journal of Nutritional Biochemistry

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Folate deficiency may affect gene expression by disrupting DNA methylation patterns or by inducing base substitution, DNA breaks, gene deletions and gene amplification. Changes in expression may explain the inverse relationship observed between folate status and risk of colorectal cancer. Three cell lines derived from the normal human colon, HCEC, NCM356 and NCM460, were grown for 32-34 days in media containing 25, 50, 75 or 150 nM folic acid, and the expression of genes involved in cell-cycle checkpoints, intracellular signaling, folate uptake and cell adhesion and migration was determined. Expression of Folate Receptor 1 was increased with decreasing media folate in all cell lines, as was p53, p21, p16 and β-catenin. With decreasing folate, the expression of both E-cadherin and SMAD-4 was decreased in NCM356. APC was elevated in NCM356 but unchanged in the other lines. No changes in global methylation were detected. A significant increase in p53 exon 7-8 strand breaks was observed with decreasing folate in NCM460 cells. The changes observed are consistent with DNA damage-induced activation of cell-cycle checkpoints and cellular adaptation to folate depletion. Folate-depletion-induced changes in the Wnt/APC pathway as well as in genes involved in cell adhesion, migration and invasion may underlie observed relationships between folate status and cancer risk.

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Section: Discussionsupporting

confidence: 60%

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

Crott

Liu

Keyes

et al. 2008

The Journal of Nutritional Biochemistry

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“…In addition to migratory activity, proteolytic lysis of Matrigel is required for cells to penetrate the membrane in the invasion assay we used. The canonical Wnt pathway may be responsible for this process, because it involves several extracellular proteinases such as urokinase-type plasminogen activator (uPA) (Hiendlmeyer et al, 2004), uPA receptor (Mann et al, 1999), CD44 (Wielenga et al, 1999), matrix metalloproteinase (MMP)-7 (Brabletz et al, 1999) and MT1-MMP/MMP-14 (Takahashi et al, 2002). It is also known that the b-catenin/Tcf target gene fra-1 directly induces MMP-1 and MMP-9 promoter activity (Belguise et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

et al. 2009

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BACKGROUND: The canonical Wnt signalling pathway is activated in most sporadic colorectal cancers (CRCs). We previously reported that FZD7 functions as a receptor for the canonical Wnt signalling pathway in colon cancer cells. METHODS AND RESULTS: In this study, we examined the function of FZD7 in survival, invasion and metastatic capabilities of colon cancer cells. FZD7_siRNA transfection decreased cell viability of HT-29 and HCT-116 colon cancer cells. Expression of c-Jun, phosphorylation of JNK and c-Jun, and activation of RhoA were suppressed after FZD7_siRNA transfection into HCT-116 cells. In vitro invasion activity and Wnt target gene expression were also reduced in HCT-116 cells transfected with FZD7_siRNA. Liver metastasis of stable FZD7_siRNA HCT-116 cell transfectants in scid mice was decreased to 40 -50% compared to controls. The mRNA levels of FZD7 in 135 primary CRC tissues were examined by real-time PCR. FZD7 mRNA levels were significantly higher in stage II, III or IV tumours than in non-tumour tissues (Po0.005), and overall survival was shorter in those patients with higher FZD7 expression (Po0.001). CONCLUSION: These data suggest that FZD7 may be involved in enhancement of survival, invasion and metastatic capabilities of colon cancer cells through non-canonical Wnt signalling pathways as well as the canonical pathway.

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“…32 Protein expression of uPA is observed predominantly at the invasive tumor front and is correlated strongly with IHC expression of nuclear b-catenin, implicating uPA in Wnt pathway activation. 33 Moreover, the uPA gene appears to act as a direct target gene of b-catenin.…”

Section: Discussionmentioning

confidence: 99%

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

Zlobec

Minoo

Baumhoer

et al. 2007

Cancer

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BACKGROUND. The heterogeneity of stage II colon cancer underlines the need for identifying high‐risk, lymph node‐negative patients. The objective of this study was to define a multimarker prognostic model of 5‐year survival in patients with lymph node‐negative, mismatch repair (MMR)‐proficient colorectal cancer (CRC). METHODS. Immunohistochemistry for 13 tumor markers was performed on 587 lymph node‐negative, MMR‐proficient CRC samples by using a tissue microarray. Immunoreactivity was evaluated semiquantitatively. A receiver‐operating characteristic‐based approach was used to detect clinically relevant tumor markers and to determine cutoff scores for tumor positivity. Univariate and multivariate analyses stratified by pathologic T3 (pT3) or pT4 tumor classification were performed. RESULTS. In univariate analysis, the absence of CD8+ tumor infiltrating lymphocytes (TILs) (P < .001), loss of p27 (P = .006), positive urokinase‐type plasminogen activator (uPA) expression (P = .002), and positive uPA receptor (uPAR) expression (P = .037) were associated with an adverse prognosis. In multivariate analysis, CD8 (P = .001), p27 (P = .031), and uPA (P = .014) were independent prognostic factors. The multimarker phenotype of negative CD8, loss of p27, and positive uPA expression led to significantly worse survival compared with all other combinations of these features. Stratified by pT3 or pT4 stage, CD8 (P = .006) and uPA (P = .011) had independent prognostic value. Combined CD8 negativity and uPA positivity led to a more adverse prognosis in both patients with pT3 tumors and patients with pT4 tumors (P < .001). No difference was observed in the length of survival between patients with pT3 tumors who had CD8 negativity and uPA positivity and patients with pT4 tumors (P = .267). CONCLUSIONS. The multimarker phenotype of the absence of CD8+ TILs, loss of p27, and positive uPA expression was predictive of an adverse prognosis in patients with lymph node‐negative, MMR‐proficient CRC. The current findings suggested that a subgroup of patients with high‐risk, lymph node‐negative pT3 tumors should be considered for adjuvant therapy. Cancer 2008. © 2007 American Cancer Society.

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β-Catenin Up-Regulates the Expression of the Urokinase Plasminogen Activator in Human Colorectal Tumors

Cited by 79 publications

References 18 publications

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells

Multimarker phenotype predicts adverse survival in patients with lymph node‐negative colorectal cancer

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