Up‐regulation of CD109 expression is associated with carcinogenesis of the squamous epithelium of the oral cavity

Abstract

CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein whose expression is up-regulated in squamous cell carcinomas (SCCs) of the lung, esophagus, and uterus. The purpose of this study was to evaluate CD109 expression in oral tumors, including premalignant lesions, and to assess the clinical application of CD109 in oral cancer. CD109 expression in oral normal and tumor tissues from 124 patients was examined by immunohistochemical staining with anti-CD109 antibody, and significant relations between clinical features and CD109 expression were statistically assessed. We found that high levels of CD109 expression were frequently detected in SCCs and premalignant lesions of the oral cavity, but not in normal squamous epithelia. The CD109 expression level was higher in well-differentiated SCCs than in poorly differentiated SCCs. Furthermore, premalignant lesions highly expressing CD109 showed higher risk to progress to SCCs. Oral SCC cell lines overexpressing CD109 exhibited accelerated cell growth in vitro compared with control cell lines. In addition, overexpression of CD109 impaired the transforming growth factor (TGF)-b1-mediated suppression of cell growth. These findings suggest that CD109 plays a role in the development of oral cancers, and is a useful prognostic marker to predict malignant transformation of premalignant lesions. (Cancer Sci 2008; 99: 1916-1923 U p-regulation or down-regulation of the expression of some genes, including oncogenes and tumor suppressor genes, trigger the development of human tumors; the products of these genes are potentially good molecular targets for cancer diagnosis and treatment. In oral cancers, despite the ease of clinical examination, most cancer patients are diagnosed with advanced-stage cancer and are difficult to treat because of the anatomic location of the lesions or because the treatment would impact on the patients' quality of life. Therefore, early diagnosis of high-risk premalignant lesions is most important for good prognosis.CD109 is a glycosylphosphatidylinositol (GPI)-anchored cellsurface glycoprotein and is a member of the α2-macroglobulin-C3, C4, and C5 family of thioester-containing proteins.(1-3) The CD109 protein was first identified as a cell-surface antigen detected by a monoclonal antibody raised against the primitive lymphoid/ myeloid cell line KG1a.(1) It has been reported that CD109 is expressed on a subset of fetal and adult CD34 + bone marrow mononuclear cells, mesenchymal stem cell subsets, phytohemagglutinin (PHA)-activated T lymphoblasts, thrombin-activated platelets, leukemic megakaryoblasts, endothelial cells, and some human tumor cell lines, but not on fresh peripheral leukocytes and normal bone marrow leukocytes.(1,2,4,5) It was also shown that CD109 carries the biallelic platelet-specific alloantigen Gov, which is implicated in refractoriness to platelet transfusion, post-transfusion purpura, and neonatal alloimmune thrombocytopenia. We identified CD109 as a gene up-regulated in cells overexpressing oncogenic RET tyrosine kinas...

CD109‐mediated degradation of TGF‐β receptors and inhibition of TGF‐β responses involve regulation of SMAD7 and Smurf2 localization and function

“…Deregulation of CD109 expression or mutation of CD109 gene occurs in many cancers [Hashimoto et al, 2004;Zhang et al, 2005;Sjoblom et al, 2006;Hasegawa et al, 2007;Sato et al, 2007;Hagiwara et al, 2008;Hasegawa et al, 2008], underscoring its potential relevance in vivo. We have previously shown that CD109 downregulates TGF-b signaling by promoting TGF-b receptor localization into the lipid raft/caveolae compartment and by enhancing TGF-b receptor degradation .…”

“…Moreover, CD109 forms a heteromeric complex with the TGF-b signaling receptors and negatively regulates TGF-b signaling in numerous cell types [Finnson et al, 2006]. The importance of CD109 in homeostasis is underscored by the observation that CD109 is mutated in colorectal cancer [Sjoblom et al, 2006] and that CD109 expression is deregulated in many cancers [Hashimoto et al, 2004;Zhang et al, 2005;Finnson et al, 2006;Hasegawa et al, 2007;Sato et al, 2007;Hagiwara et al, 2008;Hasegawa et al, 2008] and in psoriasis [Litvinov et al, 2011]. Given the potential significance of CD109 in regulating TGF-b signaling in various diseases, delineating its mechanism of action is important, as it may lead to the development of novel therapeutic strategies.…”

Processing of CD109 by furin and its role in the regulation of TGF-β signaling

“…In addition, the expression levels of the CD109 transcript were significantly increased in SCCs of esophagus, lung and uterus (Hashimoto et al, 2004;Zhang et al, 2005). Immunohistochemical analyses using an anti-CD109 antibody revealed that high levels of CD109 were frequently detected in lung and oral cavity SCCs compared with other types of carcinoma Hagiwara et al, 2008). On the other hand, CD109 immunoreactivity in normal tissues was detected in a restricted number of cell types, such as myoepithelial cells of the breast, salivary, lacrimal and bronchial secretary glands and basal cells of the prostate and bronchial epithelia Hagiwara et al, 2008;Hasegawa et al, 2007Hasegawa et al, , 2008.…”

“…Immunohistochemical analyses using an anti-CD109 antibody revealed that high levels of CD109 were frequently detected in lung and oral cavity SCCs compared with other types of carcinoma Hagiwara et al, 2008). On the other hand, CD109 immunoreactivity in normal tissues was detected in a restricted number of cell types, such as myoepithelial cells of the breast, salivary, lacrimal and bronchial secretary glands and basal cells of the prostate and bronchial epithelia Hagiwara et al, 2008;Hasegawa et al, 2007Hasegawa et al, , 2008. These findings suggested that CD109 may have a critical role in cancer development, especially in SCCs.…”

Genome-Wide Association Study of Copy Number Variations (CNVs) with Opioid Dependence

“…Its reciprocal CNV (deletion) of the same region was only identified in AA controls (P40.05), again consistently showing an opposite effect. This CNV is located between the CD109 and COL12A1 genes that were found to be associated with oral cancers (Hagiwara et al, 2008) and fibroma (Yasuda et al, 2009), respectively. We also observed a duplication on 6q26 with a suggestive protective effect (OR ¼ 0.35 (0.19-0.63) and P(Z) ¼ 0.0007 in the combined samples).…”