Ai Jianzhong, Li Jia, Su Qin, Ma Hong, Wei Qiang, Li Hong, Gao Guangping
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, 88 South Keyuan Road, Chengdu 610041, China.
Horae Gene Therapy Center, University of Massachusetts Medical School, 368 Plantation Street, Worcester, MA 01605, USA.
Mol Ther Nucleic Acids. 2021 Nov 29;27:122-132. doi: 10.1016/j.omtn.2021.11.018. eCollection 2022 Mar 8.
Effective treatments for prostate cancer (PCa) require further development, and previous studies have reported that PTEN and its downstream target CDKN1B are significantly downregulated in PCa cells compared with normal cells. Therefore, modulation of PTEN and CDKN1B expression might be a promising therapeutic approach for PCa treatment. Expression of PTEN and CDKN1B was verified in specimens from PCa patients and transgenic adenocarcinoma mouse prostate (TRAMP) mice. The effect of PTEN on PCa cell migration, apoptosis, and the cell cycle was analyzed using a wound-healing assay and flow cytometry. We assessed the ability of intraprostatic and intratumoral injections of recombinant adeno-associated virus (rAAV) 9 expressing Pten or Cdkn1b into TRAMP mice and a subcutaneous tumor xenograft mouse model, respectively, to inhibit PCa progression. PTEN and CDKN1B were significantly downregulated in human and mouse PCa samples, and CDKN1B expression correlated positively with PTEN expression. PTEN overexpression significantly inhibited cell migration and cell-cycle progression and promoted apoptosis in PCa cells by decreasing Ccnd1 expression and increasing that of Cdkn1b. Importantly, treatment with the rAAV9.Pten or rAAV9.Cdkn1b extended the lifespan of TRAMP mice and inhibited the growth rate of tumor xenografts by regulating downstream gene expression. Moreover, neoplasia in treated prostates was significantly diminished compared with that in control prostates, and apoptosis was markedly observed in xenografts treated with Pten or Cdkn1b. These data indicate that rAAV-based PTEN/CDKN1B delivery is promising for the development of novel therapeutics for PCa.
前列腺癌（PCa）的有效治疗方法仍需进一步研发，此前的研究报道，与正常细胞相比，PTEN及其下游靶点CDKN1B在PCa细胞中显著下调。因此，调节PTEN和CDKN1B的表达可能是一种有前景的PCa治疗方法。在PCa患者和转基因腺癌小鼠前列腺（TRAMP）小鼠的标本中验证了PTEN和CDKN1B的表达。采用划痕愈合试验和流式细胞术分析了PTEN对PCa细胞迁移、凋亡和细胞周期的影响。我们分别评估了向TRAMP小鼠前列腺内和肿瘤内注射表达Pten或Cdkn1b的重组腺相关病毒（rAAV）9，以及向皮下肿瘤异种移植小鼠模型中注射该病毒，对抑制PCa进展的能力。在人和小鼠的PCa样本中，PTEN和CDKN1B均显著下调，且CDKN1B的表达与PTEN的表达呈正相关。PTEN的过表达通过降低Ccnd1的表达和增加Cdkn1b的表达，显著抑制了PCa细胞的迁移和细胞周期进程，并促进了细胞凋亡。重要的是，用rAAV9.Pten或rAAV9.Cdkn1b进行治疗可延长TRAMP小鼠的寿命，并通过调节下游基因表达抑制肿瘤异种移植的生长速度。此外，与对照前列腺相比，治疗后的前列腺肿瘤明显减少，在用Pten或Cdkn1b治疗的异种移植瘤中明显观察到凋亡现象。这些数据表明，基于rAAV的PTEN/CDKN1B递送对于开发PCa的新型治疗方法具有前景。
