Wu Liang1, Zheng Hao2, Jin-Li Han1, Ding-Jun Zhu1, Zhao-Feng Jin1, Wen-Lian Xie3. 1. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China. 2. Department of Urology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhu-Hai, Guangdong Province, P.R. China. 3. Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, P.R. China. Electronic address: wenlianxie@sina.com.
Abstract
BACKGROUND: The epithelial-to-mesenchymal transition (EMT) is a critical step in tumor metastasis. CAV-1 has been shown to be an oncogene in bladder cancer. However, little is known about the relationship between CAV-1 and EMT in bladder cancer metastasis. METHODS: Immunohistochemical analysis was carried out retrospectively on tumor samples from patients treated for bladder cancer. CAV-1 and E-cadherin expression levels were measured and correlated with clinical features of tumor grade and metastasis. EMT was assessed in bladder cancer cell lines (T24, UMUC3, HT1376, and 5637) using wound healing and in vitro transwell invasion assays, and small interfering RNA was used to knock down CAV-1 and Slug expression. RESULTS: In this study, we show that increased CAV-1 expression induces bladder cancer cell migration and promotes the EMT, which was determined by the reduction of E-cadherin expression and the induction of N-cadherin and vimentin expression. Knockdown of CAV-1 expression with specific small interfering RNA reduced cell migration and EMT. Mechanistically, CAV-1-induced expression of the transcription factor, Slug. Slug knockdown abolished the CAV-1-induced EMT in bladder cancer cells. We further show that Slug expression is mediated by the CAV-1 regulation of the PI3K/AKT signaling. In addition, positive CAV-1 expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in bladder cancer tissues. CONCLUSIONS: Our results suggest that CAV-1 promotes invasive phenotypes in bladder cancer cells by inducing EMT through up-regulation of Slug expression, which occurs through activation of the PI3K/AKT signaling pathway. This new role for CAV-1 in promoting bladder cancer metastasis presents CAV-1 and related pathways as potential therapeutic targets in invasive bladder cancer.
BACKGROUND: The epithelial-to-mesenchymal transition (EMT) is a critical step in tumor metastasis. CAV-1 has been shown to be an oncogene in bladder cancer. However, little is known about the relationship between CAV-1 and EMT in bladder cancer metastasis. METHODS: Immunohistochemical analysis was carried out retrospectively on tumor samples from patients treated for bladder cancer. CAV-1 and E-cadherin expression levels were measured and correlated with clinical features of tumor grade and metastasis. EMT was assessed in bladder cancer cell lines (T24, UMUC3, HT1376, and 5637) using wound healing and in vitro transwell invasion assays, and small interfering RNA was used to knock down CAV-1 and Slug expression. RESULTS: In this study, we show that increased CAV-1 expression induces bladder cancer cell migration and promotes the EMT, which was determined by the reduction of E-cadherin expression and the induction of N-cadherin and vimentin expression. Knockdown of CAV-1 expression with specific small interfering RNA reduced cell migration and EMT. Mechanistically, CAV-1-induced expression of the transcription factor, Slug. Slug knockdown abolished the CAV-1-induced EMT in bladder cancer cells. We further show that Slug expression is mediated by the CAV-1 regulation of the PI3K/AKT signaling. In addition, positive CAV-1 expression was significantly correlated with negative E-cadherin expression, as determined by immunohistochemistry analysis in bladder cancer tissues. CONCLUSIONS: Our results suggest that CAV-1 promotes invasive phenotypes in bladder cancer cells by inducing EMT through up-regulation of Slug expression, which occurs through activation of the PI3K/AKT signaling pathway. This new role for CAV-1 in promoting bladder cancer metastasis presents CAV-1 and related pathways as potential therapeutic targets in invasive bladder cancer.
Authors: Teijo Pellinen; Sami Blom; Sara Sánchez; Katja Välimäki; John-Patrick Mpindi; Hind Azegrouz; Raffaele Strippoli; Raquel Nieto; Mariano Vitón; Irene Palacios; Riku Turkki; Yinhai Wang; Miguel Sánchez-Alvarez; Stig Nordling; Anna Bützow; Tuomas Mirtti; Antti Rannikko; María C Montoya; Olli Kallioniemi; Miguel A Del Pozo Journal: Sci Rep Date: 2018-02-05 Impact factor: 4.379