使用 Malat1 小干扰 RNA 或雄激素受体剪接变体 7 降解增强剂 ASC-J9 进行临床前研究以抑制恩杂鲁胺耐药前列腺癌的进展。
Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9 to Suppress Enzalutamide-resistant Prostate Cancer Progression.
机构信息
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA; Chawnshang Chang Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
出版信息
Eur Urol. 2017 Nov;72(5):835-844. doi: 10.1016/j.eururo.2017.04.005. Epub 2017 May 18.
BACKGROUND
While androgen-deprivation-therapy with the recently developed antiandrogen enzalutamide (Enz) shows promising therapeutic benefits in men with metastatic castration-resistant prostate cancer (PCa), many patients develop resistance to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7 (AR-v7).
OBJECTIVE
Our aim is to identify the mechanisms responsible for AR-v7 production and to develop novel preclinical approaches to suppress the Enz-resistant (EnzR) PCa.
DESIGN, SETTING, AND PARTICIPANTS: We established EnzR-PCa cell lines and examined the long noncoding RNA Malat1 (Malat1) function in conferring Enz resistance. We also examined the in vivo effects of Malat1 short interfering RNA and the AR-v7 degradation enhancer, ASC-J9.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Enz resistance and expression of Malat1 and AR-v7. All statistical comparisons were analyzed with a t-test or one way analysis of variance followed by t-test.
RESULTS AND LIMITATIONS
We demonstrated that Malat1 is indispensable for Enz-induced AR-v7 production in VCaP and EnzR-C4-2 cells. We observed increased AR-v7 and Malat1 expression in our established EnzR-PCa cell lines and in some PCa patients who received Enz treatment. Targeting the Malat1/AR-v7 axis resulted in altering the PCa resistance to androgen deprivation therapy with Enz. The limitation of this study includes the small sample size from the same human patients before and after receiving Enz treatment.
CONCLUSIONS
Targeting the Malat1/AR-v7 axis via Malat1-short interfering RNA or AR-v7 degradation enhancer ASC-J9 in EnzR-PCa cell lines and mouse models suppressed EnzR-PCa progression.
PATIENT SUMMARY
Androgen deprivation therapy-enzalutamide treatment may not be the best choice for prostate cancer patients who have higher expression of the Malat1/androgen receptor splicing variant 7 axis, and new therapies using Malat1-short interfering RNA or ASC-J9 may be developed in the future to better suppress enzalutamide-resistant prostate cancer.
背景
虽然最近开发的抗雄激素恩扎卢胺（Enz）的雄激素剥夺疗法在转移性去势抵抗性前列腺癌（PCa）男性中显示出有希望的治疗益处，但许多患者对 Enz 产生耐药性，这可能涉及雄激素受体（AR）剪接变体 7（AR-v7）的诱导。
目的
我们的目的是确定导致 AR-v7 产生的机制，并开发抑制恩扎卢胺耐药（EnzR）PCa 的新临床前方法。
设计、地点和参与者：我们建立了 EnzR-PCa 细胞系，并研究了长链非编码 RNA Malat1（Malat1）在赋予 Enz 耐药性方面的作用。我们还研究了 Malat1 短发夹 RNA 和 AR-v7 降解增强剂 ASC-J9 的体内作用。
结果测量和统计分析
Enz 耐药性以及 Malat1 和 AR-v7 的表达。所有统计比较均通过 t 检验或单因素方差分析 followed by t-test 进行分析。
结果和局限性
我们证明了 Malat1 对于 VCaP 和 EnzR-C4-2 细胞中 Enz 诱导的 AR-v7 产生是必不可少的。我们在我们建立的 EnzR-PCa 细胞系和一些接受 Enz 治疗的 PCa 患者中观察到 AR-v7 和 Malat1 表达增加。靶向 Malat1/AR-v7 轴导致改变了 Enz 治疗去势抵抗性前列腺癌的耐药性。本研究的局限性包括接受 Enz 治疗前后来自同一人类患者的样本量较小。
结论
通过 Malat1-short interfering RNA 或 AR-v7 降解增强剂 ASC-J9 在 EnzR-PCa 细胞系和小鼠模型中靶向 Malat1/AR-v7 轴抑制了 EnzR-PCa 的进展。
患者总结
雄激素剥夺疗法-恩扎卢胺治疗可能不是 Malat1/雄激素受体剪接变体 7 轴表达较高的前列腺癌患者的最佳选择，未来可能会开发使用 Malat1-short interfering RNA 或 ASC-J9 的新疗法，以更好地抑制恩扎卢胺耐药性前列腺癌。
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