Wang Can, Li Wenchao, Hu Qiang, Feng Ninghan, Liu Chunhui, Shi Naipeng, Chen Shuqiu, Chen Ming, Guan Han, You Zonghao, Xu Bin
Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
Surgical Research Center, Institute of Urology, Medical School of Southeast University, Nanjing, 210009, China.
Oncogene. 2022 Oct;41(41):4645-4657. doi: 10.1038/s41388-022-02461-0. Epub 2022 Sep 10.
Although miR-7 suppresses the initiation and progression in cancers, little is known about its role in prostate cancer, especially in transgenic mouse models. In present study, we found that expression of miR-7, regulated by p53, was lower in prostate cancer tissues, and miR-7 overexpression significantly mitigated prostate cancer cells growth both in vitro, in organoids and in vivo regardless of p53 status. After we generated miR-7 overexpression transgenic mice and miR-7/TRAMP mice, we found that transgenic overexpression of miR-7 in mice is safe and miR-7/TRAMP mice have a preferred overall survival. Moreover, in vivo treatment of miR-7 inhibited subcutaneous tumour growth in mice and prolonged the survival of mice harboring prostate cancer lung metastasis when co-injection with PD-1 antibody. In addition, miR-7 downregulated glycolysis of prostate cancer cells by inhibiting several key pathways including HIF-1α, and subsequently remodeled acidic tumour microenvironment, PanKLa level and T cell infiltration. In summary, our findings highlighted a promising target for development of miRNA-based therapeutics for prostate cancer patients regardless of p53 status.
尽管miR-7抑制癌症的发生和发展，但其在前列腺癌中的作用，尤其是在转基因小鼠模型中的作用，仍知之甚少。在本研究中，我们发现受p53调控的miR-7在前列腺癌组织中的表达较低，并且无论p53状态如何，miR-7过表达均能显著减轻前列腺癌细胞在体外、类器官和体内的生长。在我们构建了miR-7过表达转基因小鼠和miR-7/TRAMP小鼠后，我们发现小鼠中miR-7的转基因过表达是安全的，并且miR-7/TRAMP小鼠具有更好的总体生存率。此外，在体内，miR-7治疗可抑制小鼠皮下肿瘤生长，并且在与PD-1抗体共同注射时可延长患有前列腺癌肺转移小鼠的生存期。此外，miR-7通过抑制包括HIF-1α在内的几种关键途径下调前列腺癌细胞的糖酵解，随后重塑酸性肿瘤微环境、泛素激酶La水平和T细胞浸润。总之，我们的研究结果突出了一个有望用于开发针对前列腺癌患者的基于miRNA的治疗方法的靶点，而无论其p53状态如何。
