Long non‐coding <scp>RNA UCA</scp>1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling

<jats:p>Chemotherapy is a reasonable alternative to cystectomy in patients with invasive and advanced bladder cancer. However, bladder cancer cells often develop drug resistance to these therapies, and ~ 50% of patients with advanced bladder cancer do not respond to chemotherapy. Recent studies have shown that long non‐coding <jats:styled-content style="fixed-case">RNA</jats:styled-content> (lnc<jats:styled-content style="fixed-case">RNA</jats:styled-content>) is involved in the development of chemoresistance. Here we investigated the role of the urothelial cancer‐associated 1 (<jats:styled-content style="fixed-case">UCA</jats:styled-content>1) lnc<jats:styled-content style="fixed-case">RNA</jats:styled-content> in cisplatin resistance during chemotherapy for bladder cancer. We showed that cisplatin‐based chemotherapy results in up‐regulation of <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 expression in patients with bladder cancer. Similarly, <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 levels are increased in cisplatin‐resistant bladder cancer cells. Over‐expression of <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 significantly increases the cell viability during cisplatin treatment, whereas <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 knockdown reduces the cell viability during cisplatin treatment. <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 inhibition also partially overcomes drug resistance in cisplatin‐resistant T24 cells. Furthermore, we showed that <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 positively regulates expression of wingless‐type <jats:styled-content style="fixed-case">MMTV</jats:styled-content> integration site family member 6 (Wnt6) in human bladder cancer cell lines. <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 and Wnt6 expression is also positively correlated <jats:italic>in vivo</jats:italic>. Up‐regulation of <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 activates Wnt signaling in a Wnt6‐dependent manner. We finally demonstrate that <jats:styled-content style="fixed-case">UCA</jats:styled-content>1 increases the cisplatin resistance of bladder cancer cells by enhancing the expression of Wnt6, and thus represents a potential target to overcome chemoresistance in bladder cancer.</jats:p>