Urologic Oncology: Seminars and Original Investigations
Original articleUp-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma☆
Introduction
Renal cell carcinoma (RCC) represents 2% to 3% of all cancers and is the most common malignant type of kidney cancer, accounting for 85% of kidney cancers. RCC encompasses different histologic subtypes that include the commonly prevalent clear-cell RCC with more than 70% of all RCC, papillary RCC representing 10% to 15%, chromophobe RCC comprising 5%, and other less common types. Currently, complete resection of the tumor is the only curative treatment of localized RCC tumors. However, about 30% of newly diagnosed patients with RCC already have a metastatic disease, and one-quarter of surgically cured patients would develop metastases subsequently despite chemotherapy, radiotherapy, or systemic therapies [1], [2].
Tumor progression resulting in cancer metastasis is a multistep process, which is dependent on dynamic changes in adhesive and migratory ability of tumor cells. Integrins are the major cell surface receptors mediating cell-to-extracellular matrix adhesion and are involved in the regulation of focal adhesion turnover and survival signaling, which are key events in the process of tumor growth and tumor cell migration [3]. Cooperatively with the integrins, cell adhesion is also organized by cell surface heparan sulfate proteoglycans, syndecans [4]. Of all 4 syndecan genes, syndecan-4 (SDC4) is the only ubiquitously expressed member and functions as an integrin co-receptor in cell adhesion–promoting mitogen-activated protein kinase signaling pathways [4], [5].
Tissue transglutaminase (TGM2) is another ubiquitously expressed protein shown to act as a potential binding partner for integrins and SDC4 [6], [7]. TGM2 is a multifunctional protein, which catalyzes not only calcium-dependent acyl-transfer reactions leading to the formation of stable multiprotein complexes resistant to proteolysis but also calcium-independent GTPase, protein disulfide isomerase, and kinase activities [8]. At the cell periphery, unless inactivated by its binding to fibronectin (FN) or heparan sulfate chains or both, TGM2 was implicated in the formation of a stable and insoluble matrix by cross-linking the deposited matrix proteins [8]. Upon binding to FN, TGM2 is recognized by SDC4 as an adhesion protein and drives RGD-independent cell adhesion and survival signaling in synergy with β1 integrins (ITGB1s) [5], [6], [9].
Although primary tumor cells exhibit decreased TGM2 expression compared with their metastatic counterparts [10], [11], elevated TGM2 expression levels are correlated with an increased metastatic potential in different cancer types, including breast cancer, melanoma, pancreatic adenocarcinoma, and ovarian cancer [11]. Accumulating evidence has implicated a strong correlation between aberrant TGM2 expression and β1/β5 integrins for tumor cell migration, invasion, and drug resistance leading to the development of metastatic phenotype [12], [13].
In the present study, we analyzed the expression levels of TGM2, ITGB1, and SDC4 genes in RCC cell lines and healthy and tumor tissues of 95 patients with RCC to investigate the role of TGM2 in the progression and metastasis of RCC. We showed, for the first time, that elevated expression of TGM2 along with ITGB1 and SDC4 up-regulation increased the risk of RCC metastasis independently from TGM2 activity. Similar results were obtained when established RCC cell lines were investigated for their expression of TGM2, ITGB1, and SDC4.
Section snippets
Patients and tissue specimens
This study comprises 95 patients with renal cancer who underwent radical nephrectomy at the Istanbul Faculty of Medicine, Department of Urology, between 2009 and 2011. The study protocol was approved by the Ethics Committee of Istanbul University and was in accordance with the Helsinki agreement. Histopathologic analysis, classification, staging, and Fuhrman grading of tumors were evaluated according to the previous description in the pathology department of Istanbul University, Istanbul
TGM2, ITGB1, and SDC4 gene expression in relation to clinicopathologic parameters of RCC
Given the increasingly important role of TGM2 in the progression and metastasis of various carcinomas, the basal level of TGM2 mRNA was analyzed in tumor samples from patients with RCC using quantitative real-time PCR. TGM2 was expressed in both tumor and control healthy tissue, and its expression was normalized with respect to 18S rRNA gene expression. Randomly selected paired samples (n = 23) showed no statistically significant differences in TGM2 expression levels when normalized against
Discussion
TGM2, a member of the transglutaminase family, is up-regulated or overactivated in specific clinical and physiologic situations, such as celiac disease, fibrosis, neurodegenerative disorders, and cancer [7]. The observation that reduction in TGM2 gene activity and expression is necessary for the initial progression of primary tumors, whereas high expression of TGM2 in association with ITGB1 leads to increased drug resistance and metastasis is intriguing, as it suggests that TGM2 and ITGB1
References (22)
- et al.
EAU guidelines on renal cell carcinoma: the 2010 update
Eur Urol
(2010) - et al.
Syndecans as cell surface receptors: unique structure equates with functional diversity
Matrix Biol
(2011) - et al.
Importance of syndecan-4 and syndecan -2 in osteoblast cell adhesion and survival mediated by a tissue transglutaminase-fibronectin complex
Exp Cell Res
(2011) - et al.
Fibronectin-tissue transglutaminase matrix rescues RGD-impaired cell adhesion through syndecan-4 and beta1 integrin co-signaling
J Biol Chem
(2008) - et al.
A novel RGD-independent cell adhesion pathway mediated by fibronectin-bound tissue transglutaminase rescues cells from anoikis
J Biol Chem
(2003) - et al.
Reassessing the current UICC/AJCC TNM staging for renal cell carcinoma
Eur Urol
(2009) - et al.
A microtiter plate transglutaminase assay utilizing 5-(biotinamido)pentylamine as substrate
Anal Biochem
(1992) - et al.
Regulated expression of tissue transglutaminase in Swiss 3T3 fibroblasts: effects on the processing of fibronectin, cell attachment, and cell death
Exp Cell Res
(1998) - et al.
Targeted-therapy in advanced renal cell carcinoma
Curr Med Chem
(2011) - et al.
Tissue transglutaminase in tumour progression: friend or foe?
Amino Acids
(2007)
Extracellular TG2: emerging functions and regulation
FEBS J
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This work was partially funded by Grant 109S431 from the Scientific & Technological Research Council of Turkey Health Sciences Division.