Positive Correlation between Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition and its Association with Clinical Outcome in Bladder Cancer Patients

Abstract

Involvement of matrix metalloproteinases (MMPs) in the pathogenesis of urothelial carcinoma elects them to be sensitive marker for clinical and prognostic implications. MMPs regulate tumor growth and invasion by inducing epithelial-to-mesenchymal transition (EMT) which is characterized by the complex reprogramming of epithelial cells and ultimately bring about major changes in the structural organization of bladder urothelium. The present study has been undertaken to evaluate the clinical relevance of MMPs in two distinct types of bladder cancer disease. Expression analysis of MMPs namely MMP-2, MMP-7, MMP-9 and EMT markers including epithelial marker, E-cadherin; mesenchymal markers, N-cadherin and Vimentin; and EMT-activating transcriptional factors (EMT-ATFs), Snail, Slug, Twist and Zeb was done in 64 cases of bladder tumor tissues [{Non-muscle invasive bladder cancer (NMIBC): 35 cases} and {Muscle invasive bladder cancer (MIBC): 29 cases}] by real-time quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry (IHC) staining was done in matched bladder tumor tissues to evaluate the protein expression and localization of E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Our data showed overexpression of MMP-2, MMP-7 and MMP-9 at transcriptome level in 32.8%, 25% and 37.5% bladder tumor cases respectively. These tumor tissues were examined for higher expression of mesenchymal markers (N-cadherin and Vimentin) at mRNA and protein level and exhibited statistical association with tumor stage and tumor grade (p = 0.02, p = 0.04, Mann-Whitney test). Significant statistical correlation in tumor tissues with overexpressed MMPs has also been observed between gain of transcriptional factors and weak expression of E-cadherin with tumor stage, grade, gender, presence of hematuria and smoking history of the patients. Gene expression patterns of EMT markers in bladder tumors with overexpressed MMPs and their significant association with clinical profile validate the important role of MMPs in the pathogenesis of urothelial carcinoma of bladder (UCB). Increased expression of specific MMPs may affect several downstream EMT programs and thus may improve its diagnostic and prognostic utility in clinical setting.

Targeted inhibition of β-catenin alleviates airway inflammation and remodeling in asthma via modulating the profibrotic and anti-inflammatory actions of transforming growth factor-β1

“…New evidence suggests that the airway epithelium can contribute to airway remodeling through the process of EMT [31]. The hallmark trait of EMT is the downregulation of the epithelial marker E-cadherin, the upregulation of the mesenchymal markers α-SMA and Fn, and the increased expression of EMT-activating transcription factors such as Snail and MMP-7 [22,[31][32]. By comparison, broblasts can contribute to airway remodeling via accumulating in subepithelial regions, differentiating into myo broblasts, and secreting ECM components [33].…”

Signaling Pathways Induced by Leptin during Epithelial–Mesenchymal Transition in Breast Cancer

“…EMT involves a modification of the classic epithelial phenotype and morphology to a fibroblastoid phenotype, as it favors an increase of cell migration, invasion, and resistance to anoikis and chemotherapy [ 54 , 55 ]. In the molecular context, cells undergo changes in gene expression, function, and/or activation of proteins involved in this transition [ 56 , 57 , 58 ]. EMT is characterized by the loss of the cell–cell junctions and the reorganization of the cytoskeleton, which results in the loss of apicobasal polarity and the decrease in the expression of canonical epithelial markers such as E-cadherin, cytokeratins, ZO-1 [ 59 ].…”

“…EMT is characterized by the loss of the cell–cell junctions and the reorganization of the cytoskeleton, which results in the loss of apicobasal polarity and the decrease in the expression of canonical epithelial markers such as E-cadherin, cytokeratins, ZO-1 [ 59 ]. This is followed by a gain of mesenchymal markers such as N-cadherin, vimentin, fibronectin, α-SMA, as well as an increase in the expression and activation of the TFs that regulate EMT, such as Twist, Snail, Slug, ZEB, and β-catenin [ 57 , 60 ]. These TFs regulate the expression of genes that favors cell migration and invasive processes [ 60 , 61 ] and contribute to the disruption of cell junctions by transcriptionally repressing CDH1 , OCLN , and CLDN [ 62 , 63 , 64 ].…”

The regulatory roles of lncRNAs in the process of breast cancer invasion and metastasis

“…MMPs act important roles in tissue remodeling associated with various biology processes such as morphogenesis, angiogenesis, tissue repair, and metastasis. MMPs are also important components of cells invasion capable of degrading a range of ECMs proteins allowing cancer cells to migrate and invade [ 30–32 ]. Recent researches confirmed that lncRNAs regulate tumor invasion and metastasis partly because of their abilities to influence the expressions of MMPs.…”