Abstract
Kindlin-2 is a focal adhesion protein highly expressed in bladder cancer stromal fibroblasts. We investigated the prognostic significance of Kindlin-2 in bladder cancer stromal fibroblasts and evaluated the effects of Kindlin-2 on the malignant behaviors of tumor cells. Immunohistochemical staining of 203 paraffin-embedded bladder cancer tissues showed that Kindlin-2 expression correlated with advanced stage, high grade, and relapse of bladder cancer. Kaplan-Meier survival analysis demonstrated that patients exhibiting high Kindlin-2 expression had shorter survival times than those with low Kindlin-2 expression (p < 0.01). Multivariate analysis revealed that high Kindlin-2 expression leads to poor prognosis in bladder cancer. Using cancer-associated fibroblasts (CAFs) isolated from human bladder cancer tissue, we observed that Kindlin-2 knockdown decreased CAFs activation, resulting in decreased expression of α-smooth muscle actin (α-SMA) and the extracellular matrix protein fibronectin. Kindlin-2 suppression also reduced CAF-induced bladder cancer cell migration and invasion. Moreover, we found that Kindlin-2 activates CAFs and promotes the invasiveness of bladder cancer cells by stimulating TGF-β-induced epithelial-mesenchymal transition. These results support targeting Kindlin-2 and the corresponding activated CAFs in bladder cancer therapy.
Highlights
Bladder cancer is the second most common cancer of the genitourinary tract [1], and therapy fails in 33–75% of patients due to tumor recurrence and distant metastases [2]
The staining of Kindlin-2 was moderate in the stromal fibroblasts of lowgrade tumor tissues (Figure 1C), but strong in high-grade tissues (Figure 1D)
Kindlin-2 is a focal adhesion protein found in a variety of tissues [13,14,15,16], and can promote cancer invasion and metastasis [18,19,20, 23, 24]
Summary
Bladder cancer is the second most common cancer of the genitourinary tract [1], and therapy fails in 33–75% of patients due to tumor recurrence and distant metastases [2]. Tumor stromal cells promote cancer cell migration and metastasis [3, 4]. Tumor tissue is composed of cancer cells and various types of stromal cells, such as fibroblasts, macrophages, and endothelial cells [3, 5, 6]. Cytokines produced by CAFs promote the epithelial–mesenchymal transition (EMT), which is a major risk factor for metastasis [9, 10]. Schulte et al reported a correlation between CAFs and EMT markers in bladder cancer by immunohistochemistry (IHC) [11]. EMT is a process that allows an epithelial cell to acquire a mesenchymal phenotype through multiple biochemical changes, resulting in an increased migratory capacity [12]
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