Brand S, Dambacher J, Beigel F, Olszak T, Diebold J, Otte JM, Goke B, Eichhorst STCXCR4 and CXCL12 are inversely expressed in colorectal cancer cells and modulate cancer cell migration, invasion and MMP-9 activation. Exp Cell Res 310: 117-130
Department of Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Germany. Experimental Cell Research
(Impact Factor: 3.25).
11/2005; 310(1):117-30. DOI: 10.1016/j.yexcr.2005.07.006
Colorectal cancer (CRC) is characterized by a distinct metastatic pattern resembling chemokine-induced leukocyte trafficking. This prompted us to investigate expression, signal transduction and specific functions of the chemokine receptor CXCR4 in CRC cells and metastases. Using RT-PCR analysis and Western blotting, we demonstrated CXCR4 and CXCL12 expression in CRC and CRC metastases. Cell differentiation increases CXCL12 mRNA levels. Moreover, CXCR4 and its ligand are inversely expressed in CRC cell lines with high CXCR4 and low or not detectable CXCL12 expression. CXCL12 activates ERK-1/2, SAPK/JNK kinases, Akt and matrix metalloproteinase-9. These CXCL12-induced signals mediate reorganization of the actin cytoskeleton resulting in increased cancer cell migration and invasion. Moreover, CXCL12 increases vascular endothelial growth factor (VEGF) expression and cell proliferation but has no effect on CRC apoptosis. Therefore, the CXCL12/CXCR4 system is an important mediator of invasion and metastasis of CXCR4 expressing CRC cells.
Available from: Burkhard Göke
- "Two recent studies demonstrated that SAPK/JNK-1/2 is activated in Crohn's disease (CD) , . Importantly, the activation of ERK-MAP kinases and Akt has been linked to cell migration , , and in previous studies, we demonstrated that activation of Akt and STAT proteins by various cytokines modulates IEC proliferation and migration , , , , . Similarly, our experiments demonstrated that OSM receptor activation results in increased IEC migration and epithelial wound healing which could be blocked using a MEK-1 kinase inhibitor (PD98059) and by siRNA-mediated STAT3 inhibition. "
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ABSTRACT: Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.
OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays.
The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p≤0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories "immunity and defense" (p = 2.1×10-7), "apoptosis" (p = 3.7×10-4) and "JAK/STAT cascade" (p = 3.4×10-6). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9×10-5). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD).
OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.
Available from: Mingder Shi
- "Colorectal cancer has been seen as a disease with a polygenic background, where oncogenes and tumor suppressor genes and signaling pathways participate [30, 31]. In addition, CXCL12 and its receptor, CXCR4, crosstalk has been found to be crucial for tumor metastasis in colorectal and breast cancer models by inducing chemotactic and invasive responses [32, 33]. Previous studies have noted a trend showing higher CXCR4 expression with higher stages of CRC [3, 34, 35]. "
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ABSTRACT: The chemokine CXCL12, designated stromal cell-derived factor-1 (SDF-1), plays a significant role in many cancer metastases. Previous studies have shown that CXCL12-G801A, a single nucleotide polymorphism (SNP) in the 3' untranslated region, correlates with breast and lung cancer in Iran. The aim of this study was to evaluate the association of the gene variant CXCL12-G801A with colorectal cancer (CRC) in a Taiwanese cohort.
In this study, we used a denaturing high performance liquid chromatography (DHPLC) method to analyze the frequencies of CXCL12-G801A polymorphic variants between CRC patients (n = 258) and healthy controls (n = 300) in Taiwan.
The SNP distribution was higher in CRC patients with TNM stage II (117/258) than healthy controls (52/300). We observed a significant increase in the G/A plus A/A genotype of the CXCL12-G801A polymorphism in CRC patients (45.35%) compared with healthy controls (17.33%). The analysis of allelic frequencies in both groups revealed that CRC patients have a higher frequency of A allele (23.45%) than healthy controls (8.67%). Furthermore, among older CRC patients, the frequency of the CXCL12-G801A genotype was significantly increased (p = 0.0148).
Our observations suggest that the CXCL12-G801A genotype may be associated with some clinical manifestations in CRC patients in Taiwan.
Available from: Kangyu Lin
- "Our results suggest that miR-133b suppresses CRC metastasis by regulating the migratory and invasive abilities of CRC cells through CXCR4. To further reveal the potential signaling pathway that underlies the miR-133b/CXCR4 interaction, we investigate the expression of the CXCR4 downstream genes vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9)[37,38]. The results showed that their expressions were affected by the miR-133b mimics and inhibitor in the SW-480 and SW-620 cell lines (Figure 6), that miR-133b regulates CXCR4 to affect its classic underlying pathway. "
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ABSTRACT: MicroRNA-133b (miR-133b), which is a muscle-specific microRNA, has been reported to be downregulated in human colorectal carcinoma (CRC) when compared to adjacent non-tumor tissue. However, its diagnostic value and role in CRC have yet to be described. CXC chemokine receptor-4 (CXCR4), which participates in multiple cell processes such as cell invasion-related signaling pathways, was predicted to be a potential target of miR-133b. The aim of this study was to investigate the associations and functions of miR-133b and CXCR4 in CRC initiation and invasion.
Mature miR-133b and CXCR4 expression levels were detected in 31 tumor samples and their adjacent, non-tumor tissues from patients with CRC, as well as in 6 CRC cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate CXCR4 as a putative target gene of miR-133b. Regulation of CXCR4 expression by miR-133b was assessed using qRT-PCR and Western blot analysis, and the effects of exogenous miR-133b and CXCR4 on cell invasion and migration were evaluated in vitro using the SW-480 and SW-620 CRC cell lines.
A significant downregulation of miR-133b was observed in 93.55% of CRC tissues, and the expression of miR-133b was much lower in metastatic tumors (stage C and D, stratified by the Modified Dukes Staging System) than in primary tumors (stage A and B). In contrast, CXCR4 protein expression significantly increased in 52.63% of CRC samples, and increased CXCR4 expression in CRC was associated with advanced tumor stage. CXCR4 was shown to be a direct target of miR-133b by luciferase reporter assays, and transfection of miR-133b mimics inhibited invasion and stimulated apoptosis of SW-480 and SW-620 CRC cells.
Our study demonstrated that downregulated miR-133b contributed to increased cell invasion and migration in CRC by negatively regulating CXCR4. These findings may be significant for the development of therapy target for CRC.
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