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工程化外泌体靶向抑制 SIRT6 可抑制前列腺癌的肿瘤发生和转移。

Targeted inhibition of SIRT6 via engineered exosomes impairs tumorigenesis and metastasis in prostate cancer.

机构信息

State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.

School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.

出版信息

Theranostics. 2021 Apr 26;11(13):6526-6541. doi: 10.7150/thno.53886. eCollection 2021.

DOI:10.7150/thno.53886
PMID:33995674
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8120217/
Abstract

The treatment for metastatic castration-resistant prostate cancer patients remains a great challenge in the clinic and continuously demands discoveries of new targets and therapies. Here, we assess the function and therapeutic value of SIRT6 in metastatic castration-resistant prostate cancer. The expression of SIRT6 was examined in prostate cancer tissue microarray by immunohistochemistry staining. The functions of SIRT6 and underlying mechanisms were elucidated by and experiments. We also developed an efficient method to silence SIRT6 by aptamer-modified exosomes carrying small interfering RNA and tested the therapeutic effect in the xenograft mice models. SIRT6 expression is positively correlated with prostate cancer progression. Loss of SIRT6 significantly suppressed proliferation and metastasis of prostate cancer cell lines both and . SIRT6-driven prostate cancer displays activation of multiple cancer-related signaling pathways, especially the Notch pathway. Silencing SIRT6 by siRNA delivered through engineered exosomes inhibited tumor growth and metastasis. SIRT6 is identified as a driver and therapeutic target for metastatic prostate cancer in our findings, and inhibition of SIRT6 by engineered exosomes can serve as a promising therapeutic tool for clinical application.

摘要

在临床上，转移性去势抵抗性前列腺癌患者的治疗仍然是一个巨大的挑战，不断需要发现新的靶点和治疗方法。在这里，我们评估了 SIRT6 在转移性去势抵抗性前列腺癌中的功能和治疗价值。通过免疫组织化学染色，在前列腺癌组织微阵列中检测 SIRT6 的表达。通过 和 实验阐明了 SIRT6 的功能和潜在机制。我们还开发了一种通过携带小干扰 RNA 的适配体修饰的外泌体沉默 SIRT6 的有效方法，并在异种移植小鼠模型中测试了治疗效果。SIRT6 的表达与前列腺癌的进展呈正相关。SIRT6 的缺失显著抑制了前列腺癌细胞系的增殖和转移。SIRT6 驱动的前列腺癌显示出多种与癌症相关的信号通路的激活，特别是 Notch 通路。通过工程化外泌体递送的 siRNA 沉默 SIRT6 抑制了肿瘤生长和转移。在我们的研究中，SIRT6 被确定为转移性前列腺癌的驱动因子和治疗靶点，工程化外泌体抑制 SIRT6 可作为一种有前途的临床应用治疗工具。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15d2/8120217/3da3c5561526/thnov11p6526g007.jpg
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