Insulin-like growth factor binding protein 4-1 (IGFBP4-1), a new long noncoding RNA (lncRNA), has been reported to contribute to tumorigenesis and has been suggested to be a poor prognostic marker in human lung cancer. However, there still lacks basic studies that investigated the biological role of IGFBP4-1 in bladder urothelial carcinoma to date. In this study, we investigated the relationship between IGFBP4-1 expression and prognosis in patients with bladder cancer. Cell proliferation, cell cycle and cell apoptosis assays were performed to assess IGFBP4-1 function by up-regulating or down-regulating IGFBP4-1 in bladder cancer cells. A xenograft mice model was used to validate the in vitro results. Blockade of Janus kinase-signal transducer and activator of transcription pathway (JAK/STAT) was used to evaluate JAK/STAT signaling activity. The results showed that IGFBP4-1 was overexpressed in bladder cancer tissues compared with that in normal bladder tissues, and its expression level was positively correlated with poor prognosis in bladder cancer patients. Overexpression of IGFBP4-1 markedly promoted cell proliferation and cell cycle progression, and inhibited cell apoptosis, while knockdown of IGFBP4-1 notably suppressed the proliferation, promoted cell apoptosis, and induced cell cycle arrest at the G0/G1 phase. Mechanistically, we revealed that IGFBP4-1 promotes the activation of the JAK/STAT pathway in bladder cancer cells. Moreover, the JAK/STAT inhibitor dramatically blocked the tumor-promoting activity of IGFBP4-1. Tumor growth in vivo was also suppressed by knocking down of IGFBP4-1. In conclusion, IGFBP4-1 promoted bladder cancer progression by activating the JAK/STAT signaling pathway. These findings suggest that IGFBP4-1 exhibits an oncogenic role in the development of human bladder cancer.

中文翻译：

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LncRNA IGFBP4-1 通过激活 Janus 激酶信号转导器和膀胱尿路上皮癌转录途径激活剂促进肿瘤发展。

胰岛素样生长因子结合蛋白 4-1 (IGFBP4-1) 是一种新的长非编码 RNA (lncRNA)，据报道有助于肿瘤发生，并被认为是人类肺癌的不良预后标志物。然而，迄今为止仍缺乏探讨IGFBP4-1在膀胱尿路上皮癌中生物学作用的基础研究。在本研究中，我们探讨了IGFBP4-1表达与膀胱癌患者预后的关系。进行细胞增殖、细胞周期和细胞凋亡测定，通过上调或下调膀胱癌细胞中的 IGFBP4-1 来评估 IGFBP4-1 功能。使用异种移植小鼠模型来验证体外结果。使用 Janus 激酶信号转导器和转录通路激活剂 (JAK/STAT) 的阻断来评估 JAK/STAT 信号传导活性。结果显示，与正常膀胱组织相比，IGFBP4-1在膀胱癌组织中过表达，其表达水平与膀胱癌患者不良预后呈正相关。IGFBP4-1的过表达显着促进细胞增殖和细胞周期进程，并抑制细胞凋亡，而IGFBP4-1的敲低则显着抑制增殖，促进细胞凋亡，并诱导细胞周期停滞在G0/G1期。从机制上讲，我们揭示了 IGFBP4-1 促进膀胱癌细胞中 JAK/STAT 通路的激活。此外，JAK/STAT 抑制剂显着阻断了 IGFBP4-1 的促肿瘤活性。IGFBP4-1 的敲低也抑制了体内肿瘤的生长。总之，IGFBP4-1通过激活JAK/STAT信号通路促进膀胱癌进展。这些发现表明 IGFBP4-1 在人类膀胱癌的发展中表现出致癌作用。