Tumor suppressive miR-99b-5p as an epigenomic regulator mediating mTOR/AR/SMARCD1 signaling axis in aggressive prostate cancer.
Tumor suppressive miR-99b-5p as an epigenomic regulator mediating mTOR/AR/SMARCD1 signaling axis in aggressive prostate cancer.
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DOI：
10.3389/fonc.2023.1184186
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发表时间：
2023
影响因子：
4.7
通讯作者：
Wang, Bi-Dar
中科院分区：
文献类型：
--
作者：
Waseem, Mohammad;Gujrati, Himali;Wang, Bi-Dar
关键词：
与欧洲裔美国人（EA）男性相比，非洲裔美国人（AA）男性的PCa发病率高2.3倍，PCa死亡率高1.7倍。除了社会经济因素外，新出现的证据强调，生物风险因素可能在AA PCa差异中发挥关键作用。先前，我们已经表明下调的miR-99 b-5 p和上调的mTOR协同促进AA PCa侵袭性和耐药性。 在这项研究中，我们的目的是探索AA PCa侵袭性中的miR-99 b-5 p/mTOR/AR/SMACD 1信号传导轴。研究中使用的分析包括EA PCa和AA PCa细胞系的2D和/或3D培养模型中的免疫荧光、蛋白质印迹、体外功能测定（TUNEL、集落形成和MTT）和染色质免疫沉淀（ChIP）-qPCR测定。具体地，免疫荧光染色和蛋白质印迹分析已经揭示，与EA PCa（LNCaP）细胞系相比，核mTOR、AR和SMARD 1在AA PCa（MDA PCa 2b）中高度表达。Western blot分析进一步显示miR-99 b-5 p抑制EA和AA PCa细胞质和细胞核中mTOR、AR/AR-V7和SMARD 1的蛋白水平。体外功能（MTT、TUNEL和克隆形成）测定已经证明miR-99 b-5 p有效地抑制EA和AA PCa细胞中的细胞增殖/存活并诱导细胞凋亡。此外，miR-99 b-5 p和恩杂鲁胺（Enz）的组合协同增强针对侵袭性AA PCa和去势抵抗性前列腺癌（CRPC）的细胞毒性。mTOR ChIP-qPCR分析进一步证明miR-99 b-5 p或miR-99 b-5 p/Enz显著减少了mTOR向参与CRPC代谢重编程的基因的募集。总之，miR-99 b-5 p可能作为表观基因组驱动因子调节AA PCa和耐药CRPC中的mTOR/AR/SMARD 1信号传导轴。
African American (AA) men exhibited 2.3-fold higher PCa incidence and 1.7-fold higher PCa mortality rates when compared to the European American (EA) men. Besides the socioeconomic factors, emerging evidence has highlighted that biological risk factors may play critical roles in the AA PCa disparities. Previously, we have shown that downregulated miR-99b-5p and upregulated mTOR cooperatively promotes the AA PCa aggressiveness and drug resistance. In this study, we aimed to explore the miR-99b-5p/mTOR/AR/SMARCD1 signaling axis in AA PCa aggressiveness. The analyses used in the study included immunofluorescence, western blot, in-vitro functional assays (TUNEL, colony forming, and MTT), and chromatin immunoprecipitation (ChIP)-qPCR assays in 2D and/or 3D culture model of EA PCa and AA PCa cell lines. Specifically, the immunofluorescence staining, and western blot analysis has revealed that nuclear mTOR, AR, and SMARCD1 were highly expressed in AA PCa (MDA PCa 2b) compared to EA PCa (LNCaP) cell line. Western blot analysis further revealed that miR-99b-5p inhibited protein levels of mTOR, AR/AR-V7 and SMARCD1 in cytoplasm and nuclei of EA and AA PCa. The in-vitro functional (MTT, TUNEL, and clonogenic) assays have demonstrated that miR-99b-5p effectively inhibited cell proliferation/survival and induced cell apoptosis in EA and AA PCa cells. Moreover, combination of miR-99b-5p and enzalutamide (Enz) synergistically enhances the cytotoxicity against aggressive AA PCa and castration-resistant prostate cancer (CRPC). mTOR ChIP-qPCR assays further demonstrated that miR-99b-5p or miR-99b-5p/Enz significantly reduces the recruitment of mTOR to the genes involved in the metabolic reprogramming in CRPC. Taken together, miR-99b-5p may function as an epigenomic driver to modulate the mTOR/AR/SMARCD1 signaling axis in AA PCa and resistant CRPC.
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影响因子：
4.6
作者：
Matin F;Jeet V;Moya L;Selth LA;Chambers S;Australian Prostate Cancer BioResource;Clements JA;Batra J
通讯作者：
Batra J
影响因子：
50.3
作者：
Cato, Laura;de Tribolet-Hardy, Jonas;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
11.1
作者：
Hung, Chiu-Lien;Liu, Hao-Hsuan;Fu, Chih-Wei;Yeh, Hsun-Hao;Hu, Tsan-Lin;Kuo, Zong-Keng;Lin, Yu-Chin;Jhang, Mei-Ru;Hwang, Chrong-Shiong;Hsu, Hung-Chih;Kung, Hsing-Jien;Wang, Ling-Yu
通讯作者：
Wang, Ling-Yu
影响因子：
3.7
作者：
Devaney, J. M.;Wang, S.;Kwabi-Addo, B.
通讯作者：
Kwabi-Addo, B.