Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer

Kuniyasu, Hiroki; Chihara, Yoshitomo; Kubozoe, Tadahiko; Takahashi, Tadateru

doi:10.3892/ijmm.10.3.333

Cited by 22 publications

(25 citation statements)

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“…Data from leukemia cells transfected with various CD44 variants showed, that cells expressing the CD44v3 variant show increased binding sites for heparin binding epidermal growth factor (HB-EGF) and basic fibroblast growth factor (b-FGF), known to stimulate autocrine tumor cell growth and angiogenesis (34). Co-expression of heparanase and CD44v3 was shown to be correlated with a more advanced, invasive and metastatic colon cancer disease (35). Recently, colonic cancer stem cells were characterized by specifc CD133 and CD44 expression, although the CD44 variant expressed in cancer stem cells associated with colon cancer have not yet been further analyzed (36).…”

Section: Discussionmentioning

confidence: 99%

Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas

Kopp¹,

Fichter²,

Schalhorn³

et al. 2009

Int J Mol Med

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Abstract. CD44 is a transmembrane glycoprotein involved in the interaction between cells and the extracellular matrix. A large variety of alternatively spliced CD44 variants are expressed by different tumors with possible implication for tumor progression, formation of metastasis and survival. In colon carcinomas, previous reports described higher molecular bands of CD44 transcripts in neoplastic colonic tissue, although a complete analysis of multiple combinations of CD44v transcripts were not performed. We therefore analyzed the pattern of CD44 standard and variant (v2-v10) transcripts in colorectal adenomas and carcinomas by exon-specific RT-PCR amplification and sought CD44v transcripts specific for colonic neoplasias. Our data indicate that CD44 standard transcripts, including the epithelial form (C-v8,v9,v10-C) corresponding to a 720 bp transcript, were detected in 2/38 (5.2%) samples of normal mucosa, 20/20 (100%) adenomas and in 21/33 (63%) colorectal carcinomas. High molecular CD44v3,v8-10 (673 bp) transcripts were found in 2/33 (6%) samples from normal mucosa, 19/20 (95%) from adenomas and in 29/31 from colorectal carcinomas (93%). Similar CD44v3,v8-10 transcripts were detected in five from seven colorectal liver metastases, while normal liver did not contain high molecular CD44v3 variants. The same CD44v3,v8-10 (673 bp) variant was detected in HT-29 human colon carcinoma cells. Direct sequencing of the CD44v3 (673 bp) transcript in samples from colorectal carcinomas and HT-29 cells confirmed the assumed CD44v (-C-v3-v8-v9-v10-C-) cDNA sequence. Analysis of other CD44 variant transcripts (v4-v10) using exon specific primers were less frequently associated with colorectal neoplasias. These data report for the first time frequent expression of neoplasia-associated CD44v3,v8-10 variants in colorectal adenomas and carcinomas supporting the role of increased CD44 variant expression as an early event in colorectal carcinogenesis. The described CD44v3,v8-10 (673 bp) variant might be relevant for diagnosis and treatment of colorectal cancer. IntroductionThe colonic adenoma-carcinoma sequence has been characterized by various changes in the expression of oncogenes, tumor suppressor genes, growth factors and DNA repair mechanisms (1-3). Adhesion molecules interacting with extracellular matrix molecules such as CD44 mediate interactions of the tumor cell with the microenvironment leading to tumor invasion and progression (4). The transmembrane glycoprotein CD44 and its splice variants are implicated in cell adhesion, proliferation, migration, tumor cell invasion and metastatic disease (5,6).CD44 is a transmembrane glycoprotein encoded by 20 exons, at least 10 of which are variably expressed due to alternative splicing ( Fig. 1) (7). CD44 functions as a receptor for hyaluronic acid and elements of the extracellular matrix including laminin and fibronectin (8,9). Furthermore, CD44 expression is involved in lymphocyte activation, hematopoiesis and stem cell differentiation (10). Alterations in the CD44 variant exp...

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Section: Discussionmentioning

confidence: 99%

Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas

Kopp¹,

Fichter²,

Schalhorn³

et al. 2009

Int J Mol Med

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“…A study by Brown et al showed that an EMT phenotype (mainly the CD44s isoform) and EMT induction in HMLE cells was associated with a switch from mainly CD44v isoform expression to CD44s predominance [34]. Numbers of studies suggest that expression of CD44 variants including CD44v3 and v6 are associated with metastatic lesions [21,[38][39][40][41]. The functional differences of CD44 molecules that possess single or multiple variant exons is not clear and needs further investigation in EOC.…”

Section: Discussionmentioning

confidence: 99%

Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

Chen

Yao

Sun

et al. 2017

Cell Physiol Biochem

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Background/Aims: Our study aims to investigate the role, effect and mechanisms of ESRP1 (epithelial splicing regulatory protein 1) in epithelial-mesenchymal transition (EMT) in epithelial ovarian cancer (EOC). Methods: Microarray and immunohistochemical analysis of ESRP1 expression were performed in EOC cases. The correlations between ESRP1 expression and clinical factors on EOC were assessed. Lentivirus-mediated RNA interference and EGFP vector which contains ESRP1 gene were used to down-regulate and up-regulate ESRP1 expression in human EOC cell lines. Roles of ESRP1 in cell growth, migration and invasion of EOC cells were also measured by Cell Counting Kit-8 and Transwell systems in vitro and by a nude mice intraperitoneal transplantation model in vivo. Results: By the analysis of Gene Expression Omnibus (GEO) (p<0.05) and our own microarray data (p<0.001), ESRP1 expression in EOC was significantly different from normal ovarian tissue. It was abundant in the nuclei of cancer cells and in malignant lesions. However, it was weakly expressed or negative in both normal and benign lesions. High ESRP1 expression in EOC was associated with poor clinical outcomes. Decreased ESRP1 expression significantly increased cell migration and invasion both in vivo and in vitro. Snail strongly repressed ESRP1 transcription through binding to the ESRP1 promoter in EOC cells. Furthermore, ESRP1 regulated the expression of CD44s. Down-regulated ESRP1 resulted in an isoform switching from CD44v to CD44s, which modulated epithelial-mesenchymal transition (EMT) program in EOC. Up-regulatin of ESRP1 was detected in mesenchymal to epithelial transition (MET) in vivo. Conclusions: ESRP1 regulates CD44 alternative splicing during the EMT process which plays an important role in EOC carcinogenesis. In addition, ESRP1 is associated with disease prognosis in EOC.Jie Tang, MD, Ph.D, Professor 283 Tongzipo Road, Yuelu District,

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“…Heparanase is an endoglycosidase cloned out by Vlodavsky et al in 1999, which degrades the HS chain of HSPGs [1,2] . Recently, protein or messenger RNA (mRNA) expression of heparanase has been identified in various cancer cells, and the overexpression of heparanase protein or mRNA in tumour cells has been reported to correlate with the metastatic potential of tumour cells in vitro and in vivo as well as with poor prognosis [4][5][6][7] . However its role in gastric carcinomas is still not clearly clarified.…”

Section: Introductionmentioning

confidence: 99%

Expression of heparanase gene, CD44v6, MMP-7 andnm23protein and their relationship with the invasion and metastasis of gastric carcinomas

Chen

Zhan²,

He³

et al. 2004

WJG

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AIM:To explore the expression of heparanase gene, CD44v6, MMP-7 and nm23 proteins in human gastric carcinoma as well as their relationship with the clinicopathological factors. METHODS:Reverse transcription polymerase chain reaction (RT-PCR) was used to measure the expressions of heparanase mRNA in 43 human gastric carcinomas and 10 adjacent normal gastric tissues. Streptavidin-peroxidase (S-P) two step method was used to measure the immunohistochemical expression of CD44v6, MMP-7 and nm23 protein in 43 human gastric carcinomas. RESULTS:The expression of heparanase gene was positive in 29 cases of gastric cancer with a positive rate of 67.4%, which was significantly higher than those in adjacent normal gastric tissues (P<0.05). The heparanase mRNA expression was significantly related to advanced stage of disease, serosal infiltration, lymph node metastasis and size of tumors (P<0.05), but not related to tumor location, gross and histological types of the cancer, peritoneal dissemination and liver metastasis (P>0.05). The positive rate of CD44v6, nm23 and MMP-7 proteins was 76.7%, 37.2% and 60.5%, respectively. The CD44v6 protein expression was significantly related to serosal infiltration, lymph node metastasis and TNM stage of disease (P<0.05). The nm23 protein expression was significantly related to the tumor gross appearance, lymph node and peritoneal metastasis (P<0.05). The MMP-7 protein expression was significantly related to serosal infiltration and TNM stage of disease (P<0.05). In an attempt to measure the association between these agents, we found that the expression of heparanase mRNA had significantly negative correlation with the expression of CD44v6 and MMP-7 protein (P<0.05), the expression of MMP-7 protein had significantly positive correlation with the expression of CD44v6 protein (r=0.568, P<0.05), the expression of MMP-7 protein had no correlation with the expression of nm23 protein (P>0.05), and the expression of nm23 protein had no correlation with the expression of CD44v6 protein (P>0.05). CONCLUSION:Despite their different mechanisms of action, heparanase, CD44v6 and nm23 may play important roles in the invasive infiltration and lymph node metastasis in gastric carcinomas. Instead of metastatic spreading, MMP-7 may be just related to the invasion of gastric carcinomas. However, co-detection of these factors may be important to predict metastatic spreading in such patients.

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Co-expression of CD44v3 and heparanase is correlated with metastasis of human colon cancer

Cited by 22 publications

References 0 publications

Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas

Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas

Snail Driving Alternative Splicing of CD44 by ESRP1 Enhances Invasion and Migration in Epithelial Ovarian Cancer

Expression of heparanase gene, CD44v6, MMP-7 andnm23protein and their relationship with the invasion and metastasis of gastric carcinomas

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