Introduction of antisense CD44s cDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells

Harada, Nobuhiko; Mizoi, Takayuki; Kinouchi, Makoto; Hoshi, Kosei; Ishii, Seiichi; Shiiba, Ken Ichi; Sasaki, Iwao; Matsuno, Seiki

doi:10.1002/1097-0215(20010101)91:1<67::aid-ijc1011>3.0.co;2-d

Cited by 88 publications

(69 citation statements)

References 27 publications

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“…The relatively low incidence of metastasis obtained following inoculation of parental HT29 cells may be explained by the fact that this cell line is not highly metastatic as are HM7 cells, which are able to produce 100% metastasis incidence after only 6 weeks. Harada et al (2001) findings further support our study: they show that mice intrasplenically injected with LS174T cell transfectants with antisense CD44s vectors were completely free of metastasis as compared to mice injected with the parental LS174T cells. Trans- fected cells with antisense CD44s inhibited the overall expression of CD44 variants, an effect that in our study we achieve following treatment with butyrate.…”

Section: Discussionsupporting

confidence: 84%

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line

et al. 2002

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Over-expression of the adhesion molecule CD44 and its splice variants, especially CD44v6, is associated with poor prognosis and metastasis. We aimed at regulating the expression of CD44 in the highly metastatic human colon cancer cell line HM7 and thereby affecting its metastatic ability. HM7 cells show constitutive expression of CD44 standard and variants isoforms, which were significantly down-regulated by treatment with butyrate. Butyrate significantly inhibited transcription of the CD44 gene and abolished epidermal growth factor-mediated up-regulation of the reporter gene luciferase subcloned upstream to the CD44 promoter ( -1.1 kb) and transfected to HM7 cells. Nuclear proteins from butyrate-treated cells bound to an epidermal growth factor receptor element motif present in the CD44 promoter. Epidermal growth factor receptor elementsite directed mutations eliminated the inducibility of the luciferase reporter gene and did not allowed binding of nuclear proteins harvested from butyrate-treated cells. Butyrate induced CD44 gene repression by specifically interacting with an epidermal growth factor receptor element nuclear transcriptional factor. This interaction affects CD44 transcriptional activity vis-à-vis in vivo metastatic ability of HM7 cells. These results provide additional insight into the anticarcinogenic properties of butyrate.

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Section: Discussionsupporting

confidence: 84%

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line

et al. 2002

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“…No staining was observed on CD44 siRNA-transduced cell lysate, confirming the silencing of all forms of CD44 by siRNA. The growth rate of LS174T cells under normal culture conditions was not affected by siRNA or vector transduction (data not shown) in agreement with a prior study using antisense to target CD44 expression (26).…”

Section: Transduction Of Ls174t Cells With Cd44 Sirna Leads To Specifsupporting

confidence: 91%

“…Numerous published reports have shown that CD44 plays a critical role(s) in the metastatic potential of a variety of cancers, including colon, breast, lung, and ovarian cancers (26,(32)(33)(34)(35). Moreover, it has been reported that decreasing overall CD44 (standard and variant isoforms) expression (26) or increasing the expression of sCD44 in colon cancer cells blunts metastasis to liver and tumor growth in vivo (36,37).…”

Section: Discussionmentioning

confidence: 99%

HCELL Is the Major E- and L-selectin Ligand Expressed on LS174T Colon Carcinoma Cells

Burdick

Chu

Godar

et al. 2006

Journal of Biological Chemistry

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When confined to a primary site (early stage disease), the five-year survival rate from colon cancer is ϳ90%. However, when disseminated from primary sites (metastatic), survival drops precipitously to 8%. These dramatic survival statistics underscore the need to define the pathobiology of the metastatic process to devise novel interventions to prevent or inhibit colon cancer spread. Hematogenous metastasis occurs as a highly regulated cascade of events, initiated by the escape of tumor cells from the primary site into the blood stream and culminating in the formation of secondary colonies in distant organs. This process critically involves the binding of circulating colon cancer cells to the endothelium of target tissue(s) under fluid shear conditions, as well as the dynamic formation of leukocyte/cancer cell emboli, each of which are directed by selectin-selectin ligand interactions.The selectin family of adhesion molecules, E-, P-, and L-selectin, are Ca 2ϩ -dependent lectins that bind sialofucosylated carbohydrate structures, the prototypes of which are sialyl Lewis X (sLe x ) and sialyl Lewis A (sLe a ) (1, 2). E-and P-selectin are typically inducible endothelial molecules (P-selectin is also expressed on activated platelets), and L-selectin expression is restricted to leukocytes (3). There are multiple reports that tumor cell expression of E-selectin ligand(s) promotes the metastatic spread of numerous cancer types in vivo, including colon cancer (4 -10). Colon carcinoma cells also tether and roll under dynamic flow conditions on E-selectin purified and immobilized on plastic (11, 12), as well as E-selectin presented by cytokine-stimulated human umbilical vein endothelial cells (HUVEC) 2 (11-13). Independently, L-selectin has been shown to promote colon cancer metastasis in vivo (14), presumably mediated by the physical association of leukocytes with tumor cells resulting in leukocyte-colon cancer cell emboli (15, 16). Although expression of E-selectin ligand(s) on tumor cells itself promotes metastasis, one model holds that selectins work cooperatively to promote the spread of cancer; leukocyte L-selectin engagement of relevant tumor ligand(s) mediates the formation of leukocyte-tumor aggregates, which possess heightened binding capacity to endothelium in an E-selectindependent manner (16).Colon carcinoma cells express selectin ligands, and there is abundant evidence that selectin-dependent adhesive events are central to the metastatic process (4 -10,14). However, these selectin ligands have yet to be fully characterized or identified other than by general classifications (e.g. mucins). We recently identified the sialofucosylated hematopoietic cell E-and L-selectin ligand (HCELL) glycoform of CD44 on the LS174T colon carcinoma cell line and demonstrated its function as a high affinity E-and L-selectin ligand using the blot rolling assay (17, 18). However, these studies did not specifically address the relative contribution(s) of HCELL to the observed potent E-and L-selectin ligand activity of intact LS174...

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“…The expression of CD44 splice variants (CD44v) on tumor cells, coupled with evidence that upregulation of CD44v confers metastatic potential in vivo and results in poor prognosis (69)(70)(71), has focused attention on CD44v in the biology of various human malignancies. However, the direct role of CD44v in the metastatic process has remained obscure.…”

Section: Discussionmentioning

confidence: 99%

CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer

Okayama

Kumamoto²,

Saitou³

et al. 2009

Oncol Rep

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Abstract. The aim of this study was to examine the expression of CD44v6, CD54, Cdx2, CXCL5, Cyclin B1, MMP-7, nm23, RCAS1 and Survivin in primary gastric cancer and to investigate whether these molecules were useful in predicting the lymph node status. They were selected as candidates for indicators of lymph node metastasis from various kinds of cancer-associated genes reported previously. In 135 cases of radically resected primary gastric adenocarcinoma, we investigated the association between the expression of these molecules and clinocopathologic factors by immunohistochemistry. The results revealed that the expression of CD44v6 and MMP-7 were significantly associated with lymph node status. By contrast, nuclear Cdx2 expression was found to be inversely correlated with lymph node metastasis. Moreover, multivariate analysis demonstrated that CD44v6, MMP-7 and nuclear Cdx2 were independent predictors for lymph node status. In conclusion, our results suggest that positive expression of both CD44v6 and MMP-7, and negative expression of nuclear Cdx2 may serve as powerful predictors of lymph node metastasis in gastric cancer. Combined evaluation of these markers could be further useful to predict lymph node status clinically.

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Introduction of antisense CD44s cDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells

Cited by 88 publications

References 27 publications

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line

Butyrate down-regulates CD44 transcription and liver colonisation in a highly metastatic human colon carcinoma cell line

HCELL Is the Major E- and L-selectin Ligand Expressed on LS174T Colon Carcinoma Cells

CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer

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