Patel Girijesh Kumar, Dutta Sayanika, Syed Mosharaf Mahmud, Ramachandran Sabarish, Sharma Monica, Rajamanickam Venkatesh, Ganapathy Vadivel, DeGraff David J, Pruitt Kevin, Tripathi Manisha, Nandana Srinivas
Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Cancers (Basel). 2021 Oct 7;13(19):5020. doi: 10.3390/cancers13195020.
Deciphering the mechanisms that drive transdifferentiation to neuroendocrine prostate cancer (NEPC) is crucial to identifying novel therapeutic strategies against this lethal and aggressive subtype of advanced prostate cancer (PCa). Further, the role played by exosomal microRNAs (miRs) in mediating signaling mechanisms that propagate the NEPC phenotype remains largely elusive. The unbiased differential miR expression profiling of human PCa cells genetically modulated for TBX2 expression led to the identification of miR-200c-3p. Our findings have unraveled the TBX2/miR-200c-3p/SOX2/N-MYC signaling axis in NEPC transdifferentiation. Mechanistically, we found that: (1) TBX2 binds to the promoter and represses the expression of miR-200c-3p, a miR reported to be lost in castrate resistant prostate cancer (CRPC), and (2) the repression of miR-200c-3p results in the increased expression of its targets SOX2 and N-MYC. In addition, the rescue of mir-200c-3p in the context of TBX2 blockade revealed that miR-200c-3p is the critical intermediary effector in TBX2 regulation of SOX2 and N-MYC. Further, our studies show that in addition to the intracellular mode, TBX2/miR-200c-3p/SOX2/N-MYC signaling can promote NEPC transdifferentiation via exosome-mediated intercellular mechanism, an increasingly recognized and key mode of propagation of the NEPC phenotype.
破译驱动向神经内分泌前列腺癌（NEPC）转分化的机制对于确定针对这种致命且侵袭性强的晚期前列腺癌（PCa）亚型的新治疗策略至关重要。此外，外泌体微小RNA（miR）在介导传播NEPC表型的信号机制中所起的作用在很大程度上仍不清楚。对经基因调控TBX2表达的人PCa细胞进行无偏倚的差异miR表达谱分析，鉴定出了miR-200c-3p。我们的研究结果揭示了NEPC转分化中的TBX2/miR-200c-3p/SOX2/N-MYC信号轴。从机制上讲，我们发现：（1）TBX2与启动子结合并抑制miR-200c-3p的表达，据报道该miR在去势抵抗性前列腺癌（CRPC）中缺失，以及（2）miR-200c-3p的抑制导致其靶标SOX2和N-MYC的表达增加。此外，在TBX2阻断的情况下挽救miR-200c-3p表明，miR-200c-3p是TBX2调节SOX2和N-MYC的关键中间效应因子。此外，我们的研究表明，除了细胞内模式外，TBX2/miR-200c-3p/SOX2/N-MYC信号还可以通过外泌体介导的细胞间机制促进NEPC转分化，这是一种越来越被认可的NEPC表型传播的关键模式。
