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  • 1
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    Oncotarget 5 (17), 7316-7327 
    Keywords: EXPRESSION ; TRANSCRIPTION FACTOR ; BINDING ; TARGET ; COLORECTAL-CANCER ; TRANSFORMATION ; OVEREXPRESSION ; cdk4 ; EPITHELIAL-MESENCHYMAL TRANSITION ; CENTROSOME AMPLIFICATION
    Abstract: AP4 represents a c-MYC-inducible bHLH-LZ transcription factor, which displays elevated expression in many types of tumors. We found that serum-starved AP4-deficient mouse embryo fibroblasts (MEFs) were unable to resume proliferation and showed a delayed S-phase entry after restimulation. Furthermore, they accumulated as tetraploid cells due to a cytokinesis defect. In addition, AP4 was required for c-MYC-induced cell cycle re-entry. AP4-deficient MEFs displayed decreased expression of CDK2 (cyclin-dependent kinase 2), which we characterized as a conserved and direct AP4 target. Activation of an AP4 estrogen receptor fusion protein (AP4-ER) enhanced proliferation of human diploid fibroblasts in a CDK2-dependent manner. However, in contrast to c-MYC-ER, AP4-ER activation was not sufficient to induce cell cycle re-entry or apoptosis in serum-starved MEFs. AP4-deficiency was accompanied by increased spontaneous and c-MYC-induced DNA damage in MEFs. Furthermore, c-MYC-induced apoptosis was decreased in AP4-deficient MEFs, suggesting that induction of apoptosis by c-MYC is linked to its ability to activate AP4 and thereby cell cycle progression. Taken together, these results indicate that AP4 is a central mediator and coordinator of cell cycle progression in response to mitogenic signals and c-MYC activation. Therefore, inhibition of AP4 function may represent a therapeutic approach to block tumor cell proliferation.
    Type of Publication: Journal article published
    PubMed ID: 25261373
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  • 2
    Keywords: GENES ; TRANSCRIPTION FACTOR ; fibroblasts ; INDUCED APOPTOSIS ; C-MYC ; PREMATURE SENESCENCE ; CELLULAR SENESCENCE ; EPITHELIAL-MESENCHYMAL TRANSITION ; FEEDBACK LOOP ; MYC TRANSGENIC MICE
    Abstract: Here we analyzed the function of the c-MYC-inducible basic helix-loop-helix leucine-zipper transcription factor AP4 in AP4-deficient mouse embryo fibroblasts (MEFs). Loss of AP4 resulted in premature senescence and resistance towards immortalization. Senescence was accompanied by induction of the cyclin-dependent kinase inhibitor-encoding genes p16, a known tumor suppressor, and p21, a previously described target for repression by AP4. Notably, AP4 directly repressed p16 expression via conserved E-box motifs in MEFs and human diploid fibroblasts. Senescence caused by AP4-deficiency was prevented by depletion of p16 and/or p21, demonstrating that these factors mediate senescence caused by AP4 loss. As senescence induced by the loss of AP4 was rescued by ectopic AP4, secondary lesions were not involved in causing premature senescence. Activation of c-MYC resulted in repression of p21 and p16 in AP4(+/+), but not in AP4(-/-) MEFs. Furthermore, after combined expression of c-MYC and mutant RAS in MEFs, AP4 was required for colony formation, anchorage-independent growth and tumor formation in mice. In addition, combined ectopic expression of AP4 and mutant RAS in MEFs resulted in colony formation. However, additional loss of the p53 tumor suppressor was necessary for anchorage-independent growth and tumor formation of MEFs by combined AP4 and mutant RAS expression. In conclusion, this study identified AP4 as an oncogenic antagonist of cellular senescence. AP4 achieves this effect by direct repression of p16 and p21, and may thereby critically contribute to c-MYC function and tumor progression.
    Type of Publication: Journal article published
    PubMed ID: 23949224
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  • 3
    Keywords: GENE-EXPRESSION ; TUMOR PROGRESSION ; METASTASIS ; COLORECTAL-CANCER ; beta-catenin ; EMBRYONIC STEM-CELLS ; TRANSCRIPTION FACTOR SNAIL ; WNT/BETA-CATENIN ; miR-200 family ; NEGATIVE FEEDBACK LOOP
    Abstract: Here, we show that expression of ZNF281/ZBP-99 is controlled by SNAIL and miR-34a/b/c in a coherent feed-forward loop: the epithelial-mesenchymal transition (EMT) inducing factor SNAIL directly induces ZNF281 transcription and represses miR-34a/b/c, thereby alleviating ZNF281 mRNA from direct down-regulation by miR-34. Furthermore, p53 activation resulted in a miR-34a-dependent repression of ZNF281. Ectopic ZNF281 expression in colorectal cancer (CRC) cells induced EMT by directly activating SNAIL, and was associated with increased migration/invasion and enhanced beta-catenin activity. Furthermore, ZNF281 induced the stemness markers LGR5 and CD133, and increased sphere formation. Conversely, experimental down-regulation of ZNF281 resulted in mesenchymal-epithelial transition (MET) and inhibition of migration/invasion, sphere formation and lung metastases in mice. Ectopic c-MYC induced ZNF281 protein expression in a SNAIL-dependent manner. Experimental inactivation of ZNF281 prevented EMT induced by c-MYC or SNAIL. In primary CRC samples, expression of ZNF281 increased during tumour progression and correlated with recurrence. Taken together, these results identify ZNF281 as a component of EMT-regulating networks, which contribute to metastasis formation in CRC.
    Type of Publication: Journal article published
    PubMed ID: 24185900
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  • 4
    Keywords: TYROSINE KINASE ; LUNG-CANCER ; HEPATOCELLULAR-CARCINOMA ; GASTROINTESTINAL STROMAL TUMORS ; ACUTE MYELOID-LEUKEMIA ; ACUTE MYELOBLASTIC-LEUKEMIA ; BREAST-CANCER CELLS ; COLORECTAL-CARCINOMA CELLS ; KINASE INHIBITOR STI571 ; FACTOR RECEPTOR/C-KIT
    Abstract: The c-Kit receptor tyrosine kinase is commonly over-expressed in different types of cancer. p53 activation is known to result in the down-regulation of c-Kit. However, the underlying mechanism has remained unknown. Here, we show that the p53-induced miR-34 microRNA family mediates repression of c-Kit by p53 via a conserved seed-matching sequence in the c-Kit 3'-UTR. Ectopic miR-34a resulted in a decrease in Erk signaling and transformation, which was dependent on the down-regulation of c-Kit expression. Furthermore, ectopic expression of c-Kit conferred resistance of colorectal cancer (CRC) cells to treatment with 5-fluorouracil (5-FU), whereas ectopic miR-34a sensitized the cells to 5-FU. After stimulation with c-Kit ligand/stem cell factor (SCF) Colo320 CRC cells displayed increased migration/invasion, whereas ectopic miR-34a inhibited SCF-induced migration/invasion. Activation of a conditional c-Kit allele induced several stemness markers in DLD-1 CRC cells. In primary CRC samples elevated c-Kit expression also showed a positive correlation with markers of stemness, such as Lgr5, CD44, OLFM4, BMI-1 and beta-catenin. On the contrary, activation of a conditional miR-34a allele in DLD-1 cells diminished the expression of c-Kit and several stemness markers (CD44, Lgr5 and BMI-1) and suppressed sphere formation. MiR-34a also suppressed enhanced sphere-formation after exposure to SCF. Taken together, our data establish c-Kit as a new direct target of miR-34 and demonstrate that this regulation interferes with several c-Kit-mediated effects on cancer cells. Therefore, this regulation may be potentially relevant for future diagnostic and therapeutic approaches.
    Type of Publication: Journal article published
    PubMed ID: 24009080
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  • 5
    Keywords: CELL LUNG-CANCER ; DNA ; MARKER ; UP-REGULATION ; MUTATION ; COLORECTAL-CANCER ; p53 ; HOMOLOG ; TUMOR-SUPPRESSOR ; MicroRNAs
    Abstract: PURPOSE: Here, we determined whether epigenetic inactivation of miR-34a and miR-34b/c genes may serve as a prognostic marker for distant metastases in colon cancer. EXPERIMENTAL DESIGN: Using a case-control study design of 94 primary colon cancer samples with and without liver metastases, we determined CpG methylation frequencies of miR-34a and miR-34b/c promoters, expression of miR-34a, and its targets c-Met, Snail, and beta-catenin and their prognostic value. RESULTS: miR-34a methylation was detected in 45.1% (n = 42 of 93) of the samples and strongly associated with metastases to the liver (P = 0.003) and lymph nodes (P = 0.006). miR-34b/c methylation was detected in 91.9% of the samples (n = 79/86). A significant inverse correlation between miR-34a methylation and expression of mature miR-34a (P = 0.018) was detected. Decreased miR-34a expression was associated with upregulation of c-Met, Snail, and beta-catenin protein levels (P = 0.031, 0.132, and 0.004), which were associated with distant metastases (P = 0.001, 0.017, and 0.005). In a confounder-adjusted multivariate regression model miR-34a methylation, high c-Met and beta-catenin levels provided the most significant prognostic information about metastases to the liver (P = 0.014, 0.031, and 0.058) and matched pairs showed a higher prevalence of these risk factors in the samples with distant spread (P = 0.029). Finally, we obtained statistical evidence indicating that the simultaneous detection of these three markers has the highest prognostic value. CONCLUSIONS: Silencing of miR-34a and upregulation of c-Met, Snail, and beta-catenin expression is associated with liver metastases of colon cancer. Detection of miR-34a silencing in resected primary colon cancer may be of prognostic value, especially in combination with detection of c-Met and beta-catenin expression.
    Type of Publication: Journal article published
    PubMed ID: 23243217
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  • 6
    Keywords: EXPRESSION ; proliferation ; TUMOR PROGRESSION ; STEM-CELLS ; PROGNOSTIC-SIGNIFICANCE ; beta-catenin ; microenvironment ; E-cadherin ; TUMORIGENESIS ; WNT ACTIVITY
    Abstract: Colonic crypts are stereotypical structures with distinct stem cell, proliferating, and differentiating compartments. Colorectal cancers derive from colonic crypt epithelia but, in contrast, form morphologically disarrayed glands. In this study, we investigated to which extent colorectal cancers phenocopy colonic crypt architecture and thus preserve structural organization of the normal intestinal epithelium. A subset of colon cancers showed crypt-like compartments with high WNT activity and nuclear beta-Catenin at the leading tumor edge, adjacent proliferation, and enhanced Cytokeratin 20 expression in most differentiated tumor epithelia of the tumor center. This architecture strongly depended on growth conditions, and was fully reproducible in mouse xenografts of cultured and primary colon cancer cells. Full crypt-like organization was associated with low tumor grade and was an independent prognostic marker of better survival in a collection of 221 colorectal cancers. Our findings suggest that full activation of preserved intestinal morphogenetic programs in colon cancer requires in vivo growth environments. Furthermore, crypt-like architecture was linked with less aggressive tumor biology, and may be useful to improve current colon cancer grading schemes.
    Type of Publication: Journal article published
    PubMed ID: 25111606
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  • 7
    Keywords: EXPRESSION ; IN-VITRO ; TUMOR PROGRESSION ; COLON-CANCER ; STEM-CELLS ; beta-catenin ; C-MYC ; SMALL-INTESTINE ; TRANSCRIPTIONAL REPRESSION ; E-cadherin
    Abstract: The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c-MYC target gene and displays up-regulation concomitantly with c-MYC in colorectal cancer (CRC) and numerous other tumor types. Here a genome-wide characterization of AP4 DNA binding and mRNA expression was performed using a combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic analyses. Thereby, hundreds of induced and repressed AP4 target genes were identified. Besides many genes involved in the control of proliferation, the AP4 target genes included markers of stemness (LGR5 and CD44) and epithelial-mesenchymal transition (EMT) such as SNAIL, E-cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7. Accordingly, activation of AP4 induced EMT and enhanced migration and invasion of CRC cells. Conversely, down-regulation of AP4 resulted in mesenchymal-epithelial transition and inhibited migration and invasion. In addition, AP4 induction was required for EMT, migration, and invasion caused by ectopic expression of c-MYC. Inhibition of AP4 in CRC cells resulted in decreased lung metastasis in mice. Elevated AP4 expression in primary CRC significantly correlated with liver metastasis and poor patient survival. These findings imply AP4 as a new regulator of EMT that contributes to metastatic processes in CRC and presumably other carcinomas.
    Type of Publication: Journal article published
    PubMed ID: 23752226
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  • 8
    Keywords: ANGIOGENESIS ; EXPRESSION ; CELL ; GENES ; TUMOR PROGRESSION ; PATHOGENESIS ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; MicroRNAs ; MIR-16 FAMILY ; P53 NETWORK
    Abstract: The transcription factor AP4 mediates epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) but its control in this setting is not fully understood. Here we report the definition of a double-negative feedback loop involving AP4 and miR-15a/16-1 that regulates EMT and metastatic progression. In CRC cells, AP4 was downregulated by DNA damage in a p53-dependent manner. AP4 downregulation by p53 was mediated indirectly by the tumor suppressive microRNAs miR-15a and miR-16-1, which targeted the 3'-UTR of AP4 mRNA, induced mesenchymal-epithelial transition (MET) and promoted CRC cell migration. However, miR-15a/16-1 also acted downstream of p53 to induce MET and limit CRC cell migration. This latter pathway acted as a negative feedback on AP4, the downregulation of which relied upon MET induction by miR-15a/16-1. In tumor xenoplants, ectopic miR-15a/16-1 suppressed formation of lung metastases whereas ectopic AP4 suppressed expression of miR-15a/16-1. In clinical specimens of colorectal cancer, miR-15a levels inversely correlated with AP4 protein levels shown previously to correlate with distant metastasis and poor survival. In summary, our results define a double-negative feedback loop involving miR-15a/16-1 and AP4 that stabilizes epithelial and mesenchymal states, respectively, that may determine metastatic prowess.
    Type of Publication: Journal article published
    PubMed ID: 24285725
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  • 9
    Keywords: DOWN-REGULATION ; CELL-SURVIVAL ; TUMOR PROGRESSION ; COLON-CANCER ; MOUSE MODEL ; beta-catenin ; C-MYC ; inflammation ; EPITHELIAL-MESENCHYMAL TRANSITION ; COLITIS-ASSOCIATED CANCER
    Abstract: Members of the miR-34 family are induced by the tumor suppressor p53 and are known to inhibit epithelial-to-mesenchymal transition (EMT) and therefore presumably suppress the early phases of metastasis. Here, we determined that exposure of human colorectal cancer (CRC) cells to the cytokine IL-6 activates the oncogenic STAT3 transcription factor, which directly represses the MIR34A gene via a conserved STAT3-binding site in the first intron. Repression of MIR34A was required for IL-6-induced EMT and invasion. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a conserved, direct miR-34a target. The resulting IL-6R/STAT3/miR-34a feedback loop was present in primary colorectal tumors as well as CRC, breast, and prostate cancer cell lines and associated with a mesenchymal phenotype. An active IL-6R/STAT3/miR-34a loop was necessary for EMT, invasion, and metastasis of CRC cell lines and was associated with nodal and distant metastasis in CRC patient samples. p53 activation in CRC cells interfered with IL-6-induced invasion and migration via miR-34a-dependent downregulation of IL6R expression. In Mir34a-deficient mice, colitis-associated intestinal tumors displayed upregulation of p-STAT3, IL-6R, and SNAIL and progressed to invasive carcinomas, which was not observed in WT animals. Collectively, our data indicate that p53-dependent expression of miR-34a suppresses tumor progression by inhibiting a IL-6R/STAT3/miR-34a feedback loop.
    Type of Publication: Journal article published
    PubMed ID: 24642471
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