LncRNA IGFBP4-1 promotes tumor development by activating Janus kinase-signal transducer and activator of transcription pathway in bladder urothelial carcinoma

Chunjing Li^1,2#, Yu Cao^3#, Li Zhang^1,2#, Jierong Li^1,2#, Huayan Wu¹, Fengsheng Ling¹, Jintao Zheng¹, Jianfeng Wang¹, Bowei Li¹, Jun He¹, Xumin Xie¹, Zhilin Li¹, Yiping Chen¹, Xuemei He¹, Mingjuan Guo¹, Huiling Wei¹, Jing Ye¹, Yun Guo¹, Shilin Zhang^1,2✉, Liang Liu^3✉, Guoqing Liu^1,2✉, Chunxiao Liu^4✉

1. Department of Urology, Affiliated Foshan Maternal and Child Healthcare Hospital, Southern Medical University, Foshan, China.
2. The second school of Clinical Medicine, Southern Medical University, Foshan, China.
3. Ningxiang People's Hospital, The Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Ningxiang, China.
4. Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
#These authors contributed equally to this work.
✉ Corresponding authors: Shilin Zhang (E-mail: zhang_40_1@163.com); Liang Liu (E-mail: 40881892@qq.com); Guoqing Liu (E-mail: 13929974636@163.com) and Chunxiao Liu (E-mail: liuchx888@163.com).

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Citation:
Li C, Cao Y, Zhang L, Li J, Wu H, Ling F, Zheng J, Wang J, Li B, He J, Xie X, Li Z, Chen Y, He X, Guo M, Wei H, Ye J, Guo Y, Zhang S, Liu L, Liu G, Liu C. LncRNA IGFBP4-1 promotes tumor development by activating Janus kinase-signal transducer and activator of transcription pathway in bladder urothelial carcinoma. Int J Biol Sci 2020; 16(13):2271-2282. doi:10.7150/ijbs.46986. Available from http://www.ijbs.com/v16p2271.htm

Abstract

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.

Keywords: bladder cancer, IGFBP4-1, prognosis, proliferation, JAK/STAT