Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts

Abstract

// Jitao Wu 1, * , Cuicui Yu 2, * , Li Cai 3 , Youyi Lu 1 , Lei Jiang 3 , Chu Liu 1 , Yongwei Li 1 , Fan Feng 1 , Zhenli Gao 1 , Zhe Zhu 4 , Shengqiang Yu 1 , Hejia Yuan 1 and Yuanshan Cui 1 1 Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China 2 Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China 3 Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China 4 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA * These authors contributed equally to this work Correspondence to: Shengqiang Yu, email: [e-mail] Hejia Yuan, email: [e-mail] Yuanshan Cui, email: [e-mail] Keywords: bladder cancer, Kindlin-2, cancer-associated fibroblasts, prognosis, invasion Received: December 21, 2016      Accepted: March 31, 2017      Published: April 10, 2017 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.