MicroRNA-375 is a therapeutic target for castration-resistant prostate cancer through the PTPN4/STAT3 axis

作者：Gan, Junqing; Liu, Shan; Zhang, Yu; He, Liangzi; Bai, Lu; Liao, Ran; Zhao, Juan; Guo, Madi; Jiang, Wei; Li, Jiade; Li, Qi; Mu, Guannan; Wu, Yangjiazi; Wang, Xinling; Zhang, Xingli; Zhou, Dan; Lv, Huimin; Wang, Zhengfeng; Zhang, Yanqiao; Qian, Cheng; Feng, MeiYan; Chen, Hui; Meng, Qingwei; Huang, Xiaoyi^*

来源：Experimental and Molecular Medicine, 2022, 54(8): 1290-1305.

DOI：10.1038/s12276-022-00837-6

• SQUAMOUS-CELL CARCINOMA
• ANDROGEN-RECEPTOR
• INHIBITION
• EXPRESSION
• PROLIFERATION
• MIR-375
• PATHWAY

The functional role of microRNA-375 (miR-375) in the development of prostate cancer (PCa) remains controversial. Previously, we found that plasma exosomal miR-375 is significantly elevated in castration-resistant PCa (CRPC) patients compared with castration-sensitive PCa patients. Here, we aimed to determine how miR-375 modulates CRPC progression and thereafter to evaluate the therapeutic potential of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes loaded with miR-375 antisense oligonucleotides (e-375i). We used miRNA in situ hybridization technique to evaluate miR-375 expression in PCa tissues, gain- and loss-of-function experiments to determine miR-375 function, and bioinformatic methods, dual-luciferase reporter assay, qPCR, IHC and western blotting to determine and validate the target as well as the effects of miR-375 at the molecular level. Then, e-375i complexes were assessed for their antagonizing effects against miR-375. We found that the expression of miR-375 was elevated in PCa tissues and cancer exosomes, correlating with the Gleason score. Forced expression of miR-375 enhanced the expression of EMT markers and AR but suppressed apoptosis markers, leading to enhanced proliferation, migration, invasion, and enzalutamide resistance and decreased apoptosis of PCa cells. These effects could be reversed by miR-375 silencing. Mechanistically, miR-375 directly interfered with the expression of phosphatase nonreceptor type 4 (PTPN4), which in turn stabilized phosphorylated STAT3. Application of e-375i could inhibit miR-375, upregulate PTPN4 and downregulate p-STAT3, eventually repressing the growth of PCa. Collectively, we identified a novel miR-375 target, PTPN4, that functions upstream of STAT3, and targeting miR-375 may be an alternative therapeutic for PCa, especially for CRPC with high AR levels. @@@ Prostate cancer: stem cell treatment targets microRNA A microRNA shown to promote prostate cancer growth can be targeted through a treatment derived from stem cells. Prostate cancer is lethal for many men, and its growth is promoted by testosterone. However, some "castration-resistant" strains keep growing even after treatments that reduce testosterone levels. Xiaoyi Huang at Harbin Medical University Cancer Hospital, China, and co-workers examined the role of microRNA-375 in the progression of castration-resistant prostate cancer. They found that microRNA-375 was over-expressed in cancer tissue samples and promoted tumor growth by interfering with a specific signaling pathway. The team applied a treatment comprising extracellular vesicles called exosomes that are derived from human stem cells and loaded with molecules that suppress microRNA-375. The treatment inhibited microRNA-375 and thereby repressed the cancer growth, while also reducing the cancer's resistance to the testosterone-blocking drug enzalutamide.

• 单位
  哈尔滨医科大学; 郑州大学; 1