CD109 Is a Potential Biomarker for Malignant Tumors
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American Journal of Translational Medicine Vol 4, Issue 3, September. 2020. ISSN 2474-7378 (P) & 2474-7386 (O) A REVIEW J T M CD109 is a potential biomarker for 2 malignant tumors 0 2 Yanan Zhang 1, Li Xu2, Na Song 2,Jiabei Tong3, Guotao Jia4， 0 Ronggui Li 1, Fabin Han 1,2,3*. 1 College of Life Sciences, Qingdao University, Qingdao 266071, China; 2The Institute for Tissue Engineering and Regenerative, Liaocheng University/Liaocheng People's Hospital, Liaocheng 252000, China; 3Shandong MeiJia Theraputics Biotechnology Co., Ltd. Jinan 250101, China 4Departmentof Pathology, Liaocheng People's Hospital, Liaocheng 252000, China *Correspondence: Dr. Han Fabin. Email: [email protected] ABSTRACT CD109 is a surface antigen of cells, which is highly expressed in several types of human cancers including various squamous cell carcinomas and adenocarcinomas. CD109 functions to regulate cell proliferation and differentiation through TGF-β signaling pathway, JAK-STAT, and epidermal growth factor receptor (EGFR) signaling. In recent years, studies have indicated that CD109 is highly expressed in malignant tumors and associated with the metastasis of cancer into other tissues and organs, and related to poor prognosis after treatment with chemotherapy. Therefore, to understand the expression and function of CD109 as a biomarker for the molecular diagnosis and treatment of malignant cancers. Here, we reviewed the recent advances in the biological function and expression of CD109 and its application as a biomarker for the diagnosis and targeted therapy of malignant cancers. (Am J Transl Med 2020. 4:111-121). Keywords: CD109; Expression; Malignant tumor, breast cancer; proliferation, differentiation (Manuscript received May 29, 2020, accepted July 05, 2020; published online July 25, 2020) first named as CDw109 as early as 1993 and was INTRODUCTION later renamed as CD109 in 1996. In 2002, CD109 cDNA was isolated from the human CD34+ acute CD109 is a glycosylphosphatidylinositol-anchored myeloid leukemia cell line KG1a and endothelial glycoprotein that was recently identified to be a cell cells. The CD109 protein is about 170 kD, and it surface antigen in malignant tumors such as breast contains 1,445 amino acids (Giesert et al., 2003; cancer and lung cancer (Schuh et al., 2002). It was Schuh et al., 2002). As a member of co-receptor, 111 ã Hawaii Gangze Inc., PublisHer, Honolulu, USA American Journal of Translational Medicine Vol 4, Issue 3, September. 2020. ISSN 2474-7378 (P) & 2474-7386 (O) CD109 is manly involved in cell proliferation and CD109 regulates cell proliferation and differentiation by negatively regulating TGF-β differentiation through different signaling pathways signal pathway, participates in JAK-STAT signaling and epidermal growth factor receptor (EGFR) 1. Regulating TGF-β signaling pathway pathways (Finnson et al., 2006). CD109 is reported to be closely related to the occurrence and TGF-β signaling is playing important roles in cell progression of cancer as it is highly expressed in homeostasis and development of cancer. The TGF-β some tumors such as a glioma, squamous cell superfamily is composed of several growth factors carcinoma, and adenocarcinoma (Sato et al., 2007; that can induce different cellular processes and Shiraki et al., 2017). responses. Hashimoto et al. have shown that CD109 is a TGF-β co-receptor and involved in suppressing Early studies showed that CD109 exists in the the TGF-β-mediated signal pathway by formation of CD34+ cell subset of hematopoietic stem cells, a receptor complex with receptors of TGF-βR1 and which indicates that CD109 may be one of the TGF-βR2 on the cell surface of human keratinocytes. original hematopoietic stem cell markers (Murray et It was shown that soluble CD109 can bind to TGF-β al., 1999). Ertel et al. found that the CD109 was also and antagonize the downstream cell responses of expressed in a subset of platelets and endothelial TGF-β signaling. Some studies have found that cells. The Gov antigen, a human platelet alloantigen, CD109 is involved in TGF-β signaling. There are was also found on CD109-positive cells (Ertel et al., new co-receptors in the β/Smads signaling pathway 2005; Li et al., 2014; Rappold et al., 1997). In recent which can regulate the activity of TGF-β signaling years, more studies have shown that CD109 is receptors (Bernabeu et al., 2009; Finnson et al., highly expressed in certain malignant tumors such 2006; Hashimoto et al., 2004; Li et al., 2016; as squamous cell carcinoma, glioma, and basal Mokrosinski and Krajewska, 2008). cell-like breast cancer, but not in some human normal tissues such as glandular ducts and acinus of Bizet et al. found that the combination of CD109 breast and prostate and secretory cells, suggesting and caveolin-1 can promote the internalization and that CD109 may be used as a biomarker for certain degradation of the TGF-β receptor, and showed that tumors (Hasegawa et al., 2007). TGF-β1 ligand binds to CD109 and induces formation of a TGF-β receptor heteromeric complex, The incidence of cancer has been increasing in which is mediated by caveolae and signal pathways recent years; searching for effective and specific further mediated by Smad7 / Smurf2 to inhibit biomarkers is not only useful in early diagnosis, but TGF-β signaling and response. In addition, Tsai et al. more importantly can be used to identify a also showed that on the cell surface: CD109 blocked therapeutic target marker to effectively reduce the TGF-β signaling by promoting the internalization of mortality of patients with cancer. We mainly focused TGF-β receptors; thereby, disrupting its binding and on the biological function of CD109 and use CD109 activation with Smad2 (Bizet et al., 2011; Bizet et al., as a potential molecular diagnosis and therapeutic 2012; Tsai et al., 2018). CD109 affects TGF-β / target of malignant tumors including breast cancer Smad signaling by controlling p-smad2; thereby, and other cancers (Solomon et al., 2004; Sutherland mediating the growth and metastasis of liver cancer et al., 1991). cells (Zong et al., 2016). 112 ã Hawaii Gangze Inc., PublisHer, Honolulu, USA American Journal of Translational Medicine Vol 4, Issue 3, September. 2020. ISSN 2474-7378 (P) & 2474-7386 (O) Importantly, it was recently found that CD109 can signaling pathway regulate TGF-β-induced ALK1-Smad1/5 and ALK5- Smad2/3 pathways in different ways. On the one Signal transducer and activator of transcription hand, activation of TGF-β signaling can inhibit factor (STAT) signaling pathway is mediated by proliferation and migration of endothelial cells. In Janus kinase (JAK) known as JAK-STAT Signaling contrast, TGF-β signaling also enhances these pathway which is involved in regulating cell processes through ALK1-Smad1/5. It was shown proliferation, differentiation, migration, apoptosis, that CD109 is co-localized with ALK1 in cell and tumorigenesis (Levy and Darnell, 2002; surface, and that overexpressing CD109 in the Shinagawa et al., 2017). Kusaba et al. found that mouse epidermis enhanced ALK1-Smad1/5 after activation, STAT3 is phosphorylated by signaling, but reduced ALK5-Smad2/3 signaling as non-receptor protein tyrosine kinase JAK2, which shown in Figure 1 (Mii et al., 2019; Vorstenbosch et then leads to the formation and transfer of STAT3 al., 2017). dimer to the nucleus (Kusaba et al., 2005). Litvinov et al. showed that exogenous CD109 or recombinant CD109 induced STAT3 phosphorylation to activate JAK-STAT signaling pathway in human keratinocytes. It was found that transfection of CD109 siRNA downregulates STAT3 and disrupts CD109 from the cell surface of cultured human keratinocytes (Litvinov et al., 2011). Other studies also showed that CD109 regulates the differentiation of keratinocytes through signal transduction pathways involved in STAT3. The STAT3 phosphorylation was significantly increased in CD109-deficient mice than that in the wild type mice; indicating that up-regulation of STAT3 signaling is associated with increased proliferation and impaired differentiation of keratinocytes (Mii et al., 2012). Chuang et al. pointed out that STAT3 is a key effector of CD109 to promote lung cancer metastasis (Chuang et al., 2017). At the same time, Figure 1: CD109 is involved in regulating TGF-β CD109-induced phosphorylation of STAT3 depends signaling. TGF-β binds the TGF-βR2 to induce on JAK kinase activity, but its specific induction phosphorylation of the TGF-βR1. Activated TGF-βR1 mechanism is still unclear. phosphorylate Smad2 and Smad3 to activate the downstream signal pathways involving R-SMADs, 3. CD109 is involved in EGFR pathway: Smad4, and transcription factors to regulate cell transcription function in proliferating cells. Epidermal growth factor receptor (EGFR) -mediated activation pathway also plays important roles in 2. CD109 is involved in JAK-STAT promoting cell migration, survival, and proliferation 113 ã Hawaii Gangze Inc., PublisHer, Honolulu, USA American Journal of Translational Medicine Vol 4, Issue 3, September. 2020. ISSN 2474-7378 (P) & 2474-7386 (O) in malignant tumors (Singh et al., 2016). After the THE MOLECULAR ligand binds to epidermal growth factor (EGF), EGFR will be activated to form a homodimer or MECHANISM OF CD109 IN heterodimer with HER2 and another member of the ErbB family (Jedlinski et al., 2017). The dimerized THE OCCURRENCE AND receptors are autophosphorylated with each other, then phosphorylation of non-receptor tyrosine c-Src TREATMENT OF BREAST kinase occurs, which leads to the activation of STAT3 (Levy and Darnell, 2002). EGFR CANCER overexpression is reported to be associated with the invasion and prognosis of malignant tumors (Jedlinski et al., 2017). CD109 directly interacts 1. Molecular pathological classification of with EGFR and enhances EGF signaling to increase breast cancer: cell migration and invasion of malignant tumors; indicating changes in CD109 expression are related In 2000, Perou et al. (Perou et al., 2000) conducted to the progression of malignant tumors (Zhang et al., the gene expression study and obtained the 2015).