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SIRT3 和 SIRT6 通过抑制坏死性凋亡介导的固有免疫反应促进前列腺癌进展。

The SIRT3 and SIRT6 Promote Prostate Cancer Progression by Inhibiting Necroptosis-Mediated Innate Immune Response.

机构信息

Department of Pathology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.

出版信息

J Immunol Res. 2020 Nov 17;2020:8820355. doi: 10.1155/2020/8820355. eCollection 2020.

DOI:10.1155/2020/8820355
PMID:33282964
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7685829/
Abstract

The sirtuins (SIRTs), including seven family members, belong to class III histone deacetylase (HDAC) enzymes, which have been intensively investigated in cancers. Although the function of SIRTs in the cancer immunology is explored, SIRT-specific mechanisms regulating necroptosis-related innate immune response are not clear. In our present study, we found that both the mRNA and protein expression levels of SIRT3 and SIRT6 are significantly increased in the PCa tissues (HR, CI = 3.30 - 03; HR, CI = 2.35 - 08; and HR, CI = 9.20 - 08) and were associated with patients' Gleason score and nodal metastasis. Furthermore, multivariate analysis showed that the PCa patients with higher expression levels of SIRT3 and SIRT6 had shorter overall survival (OS). Mechanistically, we found that SIRT3 and SIRT6 promote prostate cancer progress by inhibiting RIPK3-mediated necroptosis and innate immune response. Knockdown of both SIRT3 and SIRT6 not only activates TNF-induced necroptosis but also refreshes the corresponding recruitment of macrophages and neutrophils. Overall, our study identified that SIRT3 and SIRT6 are key regulators of necroptosis during prostate cancer progression.

摘要

沉默调节蛋白（Sirtuins，SIRTs）包括 7 个家族成员，属于 III 类组蛋白去乙酰化酶（HDAC）酶，已在癌症中进行了深入研究。虽然 SIRTs 在癌症免疫学中的功能已被探索，但 SIRT 特异性调节坏死性凋亡相关固有免疫反应的机制尚不清楚。在本研究中，我们发现 SIRT3 和 SIRT6 的 mRNA 和蛋白表达水平在前列腺癌组织中均显著升高（HR，CI = 3.30-03；HR，CI = 2.35-08；和 HR，CI = 9.20-08），并与患者的 Gleason 评分和淋巴结转移有关。此外，多变量分析表明，SIRT3 和 SIRT6 表达水平较高的前列腺癌患者总生存期（OS）更短。机制上，我们发现 SIRT3 和 SIRT6 通过抑制 RIPK3 介导的坏死性凋亡和固有免疫反应促进前列腺癌的进展。敲低 SIRT3 和 SIRT6 不仅激活了 TNF 诱导的坏死性凋亡，还刷新了相应的巨噬细胞和中性粒细胞的募集。总之，本研究确定 SIRT3 和 SIRT6 是前列腺癌进展过程中坏死性凋亡的关键调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/c956d11bf3ac/JIR2020-8820355.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/dae1e86649fc/JIR2020-8820355.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/d589dc59fdc2/JIR2020-8820355.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/fcba864f3651/JIR2020-8820355.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/c956d11bf3ac/JIR2020-8820355.004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/dae1e86649fc/JIR2020-8820355.001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/d589dc59fdc2/JIR2020-8820355.002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/fcba864f3651/JIR2020-8820355.003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98a4/7685829/c956d11bf3ac/JIR2020-8820355.004.jpg

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