Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Pediatric Surgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510000, China.
Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
Mol Ther. 2019 Feb 6;27(2):326-341. doi: 10.1016/j.ymthe.2018.12.015. Epub 2019 Jan 9.
The prognosis for patients with bladder cancer (BCa) with lymph node (LN) metastasis is poor, and it is not improved by current treatments. Long noncoding RNAs (lncRNAs) are involved in the pathology of various tumors, including BCa. However, the role of Differentiation antagonizing non-protein coding RNA (DANCR) in BCa LN metastasis remains unclear. In this study, we discover that DANCR was significantly upregulated in BCa tissues and cases with LN metastasis. DANCR expression was positively correlated with LN metastasis status, tumor stage, histological grade, and poor patient prognosis. Functional assays demonstrated that DANCR promoted BCa cell migration, invasion, and proliferation in vitro and enhanced tumor LN metastasis and growth in vivo. Mechanistic investigations revealed that DANCR activated IL-11-STAT3 signaling and increased cyclin D1 and PLAU expression via guiding leucine-rich pentatricopeptide repeat containing (LRPPRC) to stabilize mRNA. Moreover, oncogenesis facilitated by DANCR was attenuated by anti-IL-11 antibody or a STAT3 inhibitor (BP-1-102). In conclusion, our findings indicate that DANCR induces BCa LN metastasis and proliferation via an LRPPRC-mediated mRNA stabilization mechanism. DANCR may serve as a multi-potency target for clinical intervention in LN-metastatic BCa.
膀胱癌（BCa）伴淋巴结（LN）转移患者的预后较差，目前的治疗方法并不能改善这种情况。长链非编码 RNA（lncRNA）参与了包括 BCa 在内的各种肿瘤的病理学过程。然而，分化拮抗非蛋白编码 RNA（DANCR）在 BCa LN 转移中的作用尚不清楚。在本研究中，我们发现 DANCR 在 BCa 组织和伴 LN 转移的病例中显著上调。DANCR 的表达与 LN 转移状态、肿瘤分期、组织学分级和患者预后不良呈正相关。功能分析表明，DANCR 促进了 BCa 细胞在体外的迁移、侵袭和增殖，并增强了肿瘤 LN 转移和生长。机制研究表明，DANCR 通过引导富含亮氨酸重复五肽重复蛋白（LRPPRC）稳定 mRNA 来激活 IL-11-STAT3 信号通路，并增加 cyclin D1 和 PLAU 的表达。此外，DANCR 促进的致癌作用可被抗 IL-11 抗体或 STAT3 抑制剂（BP-1-102）减弱。总之，我们的研究结果表明，DANCR 通过 LRPPRC 介导的 mRNA 稳定机制诱导 BCa LN 转移和增殖。DANCR 可能成为 LN 转移性 BCa 临床干预的多效性靶点。
