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

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 30; no. 1; pp. 179 - 16
• Main Authors: Shi, Zhenfeng, Pu, Wenjing, Li, Min, Aihemaitijiang, Mierzhayiti, Li, Shuo, Zhang, Xiaoan, Liu, Bide, Sun, Min, Li, Jiuzhi, Li, Zhiwei
• Format: Journal Article
• Language: English
• Published: England BioMed Central 18.10.2024; BMC
• Subjects: Androgens; Animals; Apoptosis; Cancer therapies; Cell growth; Cell Line, Tumor; Cell Proliferation; Chemotherapy; Docetaxel; Docetaxel - pharmacology; Drug Resistance, Neoplasm - genetics; Exosomes; Exosomes - metabolism; Flow cytometry; Gene Expression Regulation, Neoplastic; Humans; Lymphocytes; Male; Mice; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptor, Transforming Growth Factor-beta Type I - genetics; Receptor, Transforming Growth Factor-beta Type I - metabolism; RNA Stability; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tregs; ZNF667-AS1; United States > US; China; Xinjiang China; Exosomes; Prostate cancer; Tregs; Docetaxel; ZNF667-AS1
• DOI: 10.1186/s10020-024-00947-z
• ISSN: 1528-3658; 1076-1551

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. 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 CD4 CD25 Foxp 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. 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 CD4 T cells. 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.