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前列腺癌细胞来源的外泌体 ZNF667-AS1 通过与 U2AF1 结合减少 TGFBR1 mRNA 的稳定性，从而抑制 Treg 扩增和 DTX 耐药。

Prostate cancer cell-derived exosomes ZNF667-AS1 reduces TGFBR1 mRNA stability to inhibit Treg expansion and DTX resistance by binding to U2AF1.

机构信息

Department of Urology Surgery Center, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830002, Xinjiang Uygur Autonomous Region, People's Republic of China.

Department of Pathology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, 830002, Xinjiang Uygur Autonomous Region, People's Republic of China.

出版信息

Mol Med. 2024 Oct 18;30(1):179. doi: 10.1186/s10020-024-00947-z.

DOI:10.1186/s10020-024-00947-z
PMID:39425009
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11488200/
Abstract

BACKGROUND

Docetaxel (DTX) resistance attenuates anti-tumor effects of DTX on prostate cancer (mCRPC) and drug resistance was related to Treg expansion in tumors. ZNF667-AS1 played a suppressing role in various tumors and tumor-derived exosomes carry lncRNAs to participate in tumor progression. Here, the effects of ZNF667-AS1 on malignant characteristics and DTX resistance in PC and the effect and its underlying molecular mechanism of tumor-derived exosomes carrying ZNF667-AS1 on Treg expansion were investigated.

METHODS

The identification of exosomes were determined using TEM, NTA and western blot. The abundance of genes and proteins were evaluated using IHC, RT-qPCR, western blot and FISH. Malignant phenotypes of PC cells were evaluated by means of Edu, scratch test, transwell, CCK-8 and flow cytometry. The percentage of CD4CD25Foxp Tregs was detected using flow cytometry. The location of ZNF667-AS1 was detected using nuclear-cytoplasmic fractionation. The co-location of ZNF667-AS1 and U2AF1 protein was detected using IF-FISH assay. The interactions among ZNF667-AS1, TGFBR1 and U2AF1 were verified using RNA pull-down, RIP and dual luciferase activity.

RESULTS

ZNF667-AS1 expression in PC samples was lowered, which was negatively relative to poor prognosis and DTX resistance. ZNF667-AS1 overexpression inhibited malignant phenotypes of PC cells, tumor growth and DTX resistance. Besides, DTX resistant cell-derived exosomes expressed lower ZNF667-AS1 expression. Exosomes carrying exogenously high ZNF667-AS1 expression derived PC cells or serum of mice suppressed Treg expansion. On the mechanism, ZNF667-AS1 interacted with U2AF1 to destabilize TGFBR1 mRNA and reduce TGFBR1 expression in CD4T cells.

CONCLUSION

ZNF667-AS1 suppressed cell growth of PC cells, tumor growth of mice and DTX resistance to PC cells and exogenously high ZNF667-AS1 expression in tumor-derived exosomes destabilized TGFBR1 mRNA and reduce TGFBR1 expression through interacting with U2AF1, thus resulting in attenuated Treg expansion, which was related to DTX resistance.

摘要

背景

多西紫杉醇（DTX）耐药会减弱 DTX 对前列腺癌（mCRPC）的抗肿瘤作用，且耐药与肿瘤中 Treg 的扩增有关。ZNF667-AS1 在各种肿瘤中发挥抑制作用，肿瘤衍生的外泌体携带 lncRNA 参与肿瘤进展。本研究旨在探讨 ZNF667-AS1 对 PC 恶性特征和 DTX 耐药的影响，以及携带 ZNF667-AS1 的肿瘤衍生外泌体对 Treg 扩增的影响及其潜在的分子机制。

方法

通过 TEM、NTA 和 Western blot 确定外泌体的鉴定。使用 IHC、RT-qPCR、Western blot 和 FISH 评估基因和蛋白质的丰度。通过 Edu、划痕试验、Transwell、CCK-8 和流式细胞术评估 PC 细胞的恶性表型。通过流式细胞术检测 CD4CD25Foxp Tregs 的百分比。通过核质分离检测 ZNF667-AS1 的位置。通过 IF-FISH 测定检测 ZNF667-AS1 和 U2AF1 蛋白的共定位。使用 RNA 下拉、RIP 和双荧光素酶活性验证 ZNF667-AS1、TGFBR1 和 U2AF1 之间的相互作用。

结果

PC 样本中 ZNF667-AS1 的表达降低，与不良预后和 DTX 耐药呈负相关。ZNF667-AS1 过表达抑制 PC 细胞的恶性表型、肿瘤生长和 DTX 耐药。此外，DTX 耐药细胞衍生的外泌体表达较低的 ZNF667-AS1 表达。携带高表达外源性 ZNF667-AS1 的 PC 细胞衍生的外泌体或小鼠血清抑制 Treg 扩增。在机制上，ZNF667-AS1 与 U2AF1 相互作用，使 TGFBR1 mRNA 不稳定，降低 CD4T 细胞中的 TGFBR1 表达。

结论

ZNF667-AS1 抑制 PC 细胞的生长、小鼠肿瘤的生长和 PC 细胞的 DTX 耐药，肿瘤衍生的外泌体中外源性高表达的 ZNF667-AS1 通过与 U2AF1 相互作用使 TGFBR1 mRNA 不稳定，降低 TGFBR1 表达，从而导致 Treg 扩增减弱，与 DTX 耐药有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f71/11488200/d6c464400386/10020_2024_947_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f71/11488200/d6c464400386/10020_2024_947_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f71/11488200/58efd397b8ea/10020_2024_947_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f71/11488200/238a5305d27c/10020_2024_947_Fig6_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7f71/11488200/d6c464400386/10020_2024_947_Fig8_HTML.jpg

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