Reduced hGC-1 Protein Expression Is Associated with Malignant Progression of Colon Carcinoma

Molecular and Clinical Hematology Branch, Digestive Disease Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
Clinical Cancer Research (Impact Factor: 8.72). 03/2008; 14(4):1041-9. DOI: 10.1158/1078-0432.CCR-07-4125
Source: PubMed

ABSTRACT hGC-1 (human granulocyte colony-stimulating factor-stimulated clone 1) is a gastrointestinal protein that is a member of the olfactomedin glycoprotein family. Its biological function remains poorly understood. Aberrant expression of hGC-1 in some human carcinomas has been recently reported. The purpose of this study was to examine hGC-1 expression in colon carcinoma and explore the relationship between hGC-1 expression and the clinicopathologic features of patients with colon cancer.
The expression of hGC-1 in colon adenocarcinoma tissues was examined by dot-blot analysis, in situ hybridization, and immunohistochemistry. The association of hGC-1 expression pattern with patient differentiation grade, tumor stage, metastasis, and survival were examined. To further investigate the involvement of hGC-1 in colon cancer progression, human colon carcinoma (HT-29) cells overexpressing hGC-1 were established and cell proliferation, adhesion, and migration were studied.
Compared with normal colon mucosa, the up-regulation of hGC-1 was more frequently detected in more differentiated colon cancers, whereas down-regulation or no expression was associated with poorly differentiated colon cancers. Interestingly, hGC-1 down-regulation was also found in late tumor-node-metastasis stage, metastasis, and in patients with shorter survival. The morphology and cortical actin distribution of HT-29 cells were altered by hGC-1 overexpression. However, this did not change cell proliferation, but decreased cell adhesion and migration.
Our findings indicate that hGC-1 is involved in colon cancer adhesion and metastasis, and that hGC-1 may be a useful marker for tumor differentiation and progression of human colon carcinoma.

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    • "Moreover, up-regulated OLFM4 showed a strong anti-apoptotic activity in mouse lymphoid vein endothelial SVEC cells and human adenocarcinoma HeLa cells [1,2], whereas recent findings suggested a proapoptotic effect of OLFM4 in human myeloid leukemia HL-60 cells [16]. Evidence from these studies strongly suggests that roles of OLFM4 in cell growth control and apoptosis may depend on the cell or tissue type [10,13-15]. To date, however, very limited data concerning the role of OLFM4 in the cell growth and apoptosis profiles of gastric cancer cells has been published. "
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    ABSTRACT: Human olfactomedin 4 (OLFM4) gene is a secreted glycoprotein more commonly known as the anti-apoptotic molecule GW112. OLFM4 is found to be frequently up-regulated in many types of human tumors including gastric cancer and it was believed to play significant role in the progression of gastric cancer. Although the function of OLFM4 has been indicated in many studies, recent evidence strongly suggests a cell or tissue type-dependent role of OLFM4 in cell growth and apoptosis. The aim of this study is to examine the role of gastric cancer-specific expression of OLFM4 in cell growth and apoptosis resistance. OLFM4 expression was eliminated by RNA interference in SGC-7901 and MKN45 cells. Cell proliferation, anchorage-independent growth, cell cycle and apoptosis were characterized in vitro. Tumorigenicity was analyzed in vivo. The apoptosis and caspase-3 activation in response to hydrogen peroxide (H2O2) or tumor necrosis factor-alpha (TNF α) were assessed in the presence or absence of caspase inhibitor Z-VAD-fmk. The elimination of OLFM4 protein by RNA interference in SGC-7901 and MKN45 cells significantly inhibits tumorigenicity both in vitro and in vivo by induction of cell G1 arrest (all P < 0.01). OLFM4 knockdown did not trigger obvious cell apoptosis but increased H2O2 or TNF α-induced apoptosis and caspase-3 activity (all P < 0.01). Treatment of Z-VAD-fmk attenuated caspase-3 activity and significantly reversed the H(2)O(2) or TNF α-induced apoptosis in OLFM4 knockdown cells (all P < 0.01). Our study suggests that depletion of OLFM4 significantly inhibits tumorigenicity of the gastric cancer SGC-7901 and MKN45 cells. Blocking OLFM4 expression can sensitize gastric cancer cells to H2O2 or TNF α treatment by increasing caspase-3 dependent apoptosis. A combination strategy based on OLFM4 inhibition and anticancer drugs treatment may provide therapeutic potential in gastric cancer intervention.
    Journal of Biomedical Science 04/2012; 19(1):38. DOI:10.1186/1423-0127-19-38 · 2.76 Impact Factor
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    • "Interestingly, Liu et al. recently demonstrated that OLFM4 down-regulates the innate immune response by influencing NOD1 and NOD2 mediated NF-κB activation in a mouse model of Helicobacter pylori infection [46]. Other reports implicate OLFM4 expression in tumour growth and, more specifically, in colon cancer [47], [48]. OLFM4 has also been shown to bind cell-surface lectins and cadherin [49]. "
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    ABSTRACT: Microarray analysis of RNA expression allows gross examination of pathways operative in inflammation. We aimed to determine whether genes expressed in whole blood early following initiation of intravenous corticosteroid treatment can be associated with response. From a prospectively accrued cohort of 128 pediatric patients hospitalized for intravenous corticosteroid treatment of severe UC, we selected for analysis 20 corticosteroid responsive (hospital discharge or PUCAI ≤45 by day 5) and 20 corticosteroid resistant patients (need for second line medical therapy or colectomy, or PUCAI >45 by day 5). Total RNA was extracted from blood samples collected on day 3 of intravenous corticosteroid therapy. The eluted transcriptomes were quantified on Affymetrix Human Gene 1.0 ST arrays. The data was analysed by the local-pooled error method for discovery of differential gene expression and false discovery rate correction was applied to adjust for multiple comparisons. A total of 41 genes differentially expressed between responders and non-responders were detected with statistical significance. Two of these genes, CEACAM1 and MMP8, possibly inhibited by methylprednisolone through IL8, were both found to be over-expressed in non-responsive patients. ABCC4 (MRP4) as a member of the multi-drug resistance superfamily was a novel candidate gene for corticosteroid resistance. The expression pattern of a cluster of 10 genes selected from the 41 significant hits were able to classify the patients with 80% sensitivity and 80% specificity. Elevated expression of several genes involved in inflammatory pathways was associated with resistance to intravenous corticosteroid therapy early in the course of treatment. Gene expression profiles may be useful to classify resistance to intravenous corticosteroids in children with severe UC and assist with clinical management decisions.
    PLoS ONE 09/2010; 5(9). DOI:10.1371/journal.pone.0013085 · 3.23 Impact Factor
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    • "However, in presently, the exact function of GW112 has yet to completely elucidated. Even though GW112 has been shown to facilitate cell adhesion in NIH3T3 and HEK293 cells and promote cell proliferation in prostate cancer, and to be correlative with invasion and metastasis [12,15–18], whereas the adhesion and migration suppression effects and unchanged cell proliferation were observed in GW112-over- expressing colon carcinoma HT-29 cells [48]. These controversial Fig. 5 – The effect of GRIM-19 on MMP-9, VEGF, u-PA and MMP-2 expression in SGC-7901 cells. "
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    ABSTRACT: Gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), as a novel IFN-beta/RA-inducible gene product, was identified as a potential tumor suppressor associated with growth inhibition and cell apoptosis. Recently, it has been reported that the apoptotic effects and apoptosis-related gene induction of GRIM-19 can be attenuated by GW112, indicating that GRIM-19 and GW112 are involved in a common signal transduction pathway. To investigate the signaling mechanisms that link GRIM-19 to GW112 and their functional role in tumor cell invasion and metastasis, we utilized adenovirus-mediated overexpression of GRIM-19 in the gastric cancer SGC-7901 cell line. We observed that enhanced expression of GRIM-19 not only downregulated GW112 but also decreased NF-small ka, CyrillicB binding activity. As a result, we found that tumor cell adhesion, migration, invasion and liver metastasis were inhibited. Additionally, upregulation of GRIM-19 also suppressed secretion of urokinase-type plasminogen activator (u-PA), matrix metalloproteinase (MMP)-2, 9 and vascular endothelial growth factor (VEGF). These results indicate that GRIM-19 acts as an upstream regulator of GW112 to block NF-small ka, CyrillicB binding activity, thereby inhibiting gastric cancer cell migration, invasion and metastasis. We conclude that adenoviral transfer of the GRIM-19 gene may be an efficacious approach to controlling the invasion and metastasis of human gastric cancer.
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