Effects of increased Kindlin-2 expression in bladder cancer stromal fibroblasts
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Jitao Wu1,*, Cuicui Yu2,*, Li Cai3, Youyi Lu1, Lei Jiang3, Chu Liu1, Yongwei Li1, Fan Feng1, Zhenli Gao1, Zhe Zhu4, Shengqiang Yu1, Hejia Yuan1 and Yuanshan Cui1
1Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
2Department of Anesthesiology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
3Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
4Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
*These authors contributed equally to this work
Shengqiang Yu, email: email@example.com
Hejia Yuan, email: firstname.lastname@example.org
Yuanshan Cui, email: email@example.com
Keywords: bladder cancer, Kindlin-2, cancer-associated fibroblasts, prognosis, invasion
Received: December 21, 2016 Accepted: March 31, 2017 Published: April 10, 2017
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.
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