Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling
Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling
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DOI：
10.1111/febs.12737
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发表时间：
2014-04-01
期刊：
影响因子：
5.4
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Fan, Yu;Shen, Bing;Liu, Yong
对于浸润性和晚期膀胱癌患者，化疗是膀胱切除术的合理替代方案。然而，膀胱癌细胞往往对这些疗法产生抗药性，类似于50%的晚期膀胱癌患者对化疗没有反应。最近的研究表明，长非编码RNA(LncRNA)参与了化疗耐药的发生。在此，我们研究了尿路上皮癌相关基因1(UCA1)在膀胱癌化疗期间顺铂耐药中的作用。我们发现，以顺铂为基础的化疗导致膀胱癌患者UCA1表达上调。同样，在对顺铂耐药的膀胱癌细胞中，UCA1水平也会增加。在顺铂治疗过程中，UCA1的过表达显著提高了细胞的存活率，而UCA1的过表达降低了顺铂治疗过程中的细胞存活率。抑制UCA1也部分克服了对顺铂耐药的T24细胞的耐药性。此外，我们还发现UCA1正向调节人膀胱癌细胞系中无翅型MMTV整合位点家族成员6(WNT6)的表达。UCA1和WNT6在体内的表达也呈正相关。UCA1的上调以WNT6依赖的方式激活WNT信号。最后，我们证明了UCA1通过增强Wnt6的表达增加了膀胱癌细胞对顺铂的耐药性，从而成为克服膀胱癌化疗耐药的潜在靶点。
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 similar to 50% of patients with advanced bladder cancer do not respond to chemotherapy. Recent studies have shown that long non-coding RNA (lncRNA) is involved in the development of chemoresistance. Here we investigated the role of the urothelial cancer-associated1 (UCA1) lncRNA in cisplatin resistance during chemotherapy for bladder cancer. We showed that cisplatin-based chemotherapy results in up-regulation of UCA1 expression in patients with bladder cancer. Similarly, UCA1 levels are increased in cisplatin-resistant bladder cancer cells. Over-expression of UCA1 significantly increases the cell viability during cisplatin treatment, whereas UCA1 knockdown reduces the cell viability during cisplatin treatment. UCA1 inhibition also partially overcomes drug resistance in cisplatin-resistant T24 cells. Furthermore, we showed that UCA1 positively regulates expression of wingless-type MMTV integration site family member6 (Wnt6) in human bladder cancer cell lines. UCA1 and Wnt6 expression is also positively correlated invivo. Up-regulation of UCA1 activates Wnt signaling in a Wnt6-dependent manner. We finally demonstrate that UCA1 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.