Mechanism of Tumor-derived Extracellular Vesicles in Prostatic Cancer Progression Through the CircFMN2/KLF2/RNF128 Axis

Overview

Journal Apoptosis

Publisher Springer

Date 2023 Jul 14

PMID 37452271

Authors

Shuang Huang

Jianming Zhao

Hongkai Yu

Guangfu Chen

Affiliations

Soon will be listed here.

Abstract

Circular RNAs (circRNAs) are a major type of cargos encapsulated in extracellular vesicles (EVs) and regulate the progression of prostatic cancer (PC). This study was conducted to explore the role of tumor-derived EVs in PC cell proliferation, invasion, and migration via shuttle of circRNA formin 2 (circFMN2). RT-qPCR or Western blot assay showed that circFMN2 was upregulated while KLF2 and RNF128 were downregulated in PC tissues and cells. EVs were separated from PC cells and characterized and its internalization in PC cells was examined, which suggested that PC-EVs mediated the shuttle of circFMN2 to upregulate circFMN2 expression in PC cells. PC cell functions were determined by cell counting kit-8, colony formation and Transwell assays, which suggested that PC-EVs fueled the proliferation, invasion, and migration of PC cells. At cellular level, PC-EVs mediated the shuttle of circFMN2 to upregulate circFMN2 expression in PC cells, and circFMN2 binding to HuR decreased the HuR-KLF2 interaction and repressed KLF2 expression, which further reduced the KLF2-RNF128 promoter binding and repressed RNF128 transcription. Overexpression of KLF2/RNF128 ablated the effects of PC-EVs on the proliferation, invasion, and migration of PC cells. The xenograft tumor models and lung/liver metastasis models were established and revealed that PC-EVs accelerated tumorigenesis and metastasis in vivo via delivery of circFMN2 and repression of KLF2/RNF128.

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References

De Nunzio C, Lombardo R . Best of 2022 in prostate cancer and prostatic diseases. Prostate Cancer Prostatic Dis. 2023; 26(1):5-7. DOI: 10.1038/s41391-023-00652-8. View

Achard V, Putora P, Omlin A, Zilli T, Fischer S . Metastatic Prostate Cancer: Treatment Options. Oncology. 2021; 100(1):48-59. DOI: 10.1159/000519861. View

Uhr A, Glick L, Gomella L . An overview of biomarkers in the diagnosis and management of prostate cancer. Can J Urol. 2020; 27(S3):24-27. View

Bebelman M, Smit M, Pegtel D, Baglio S . Biogenesis and function of extracellular vesicles in cancer. Pharmacol Ther. 2018; 188:1-11. DOI: 10.1016/j.pharmthera.2018.02.013. View

Urabe F, Kosaka N, Ito K, Kimura T, Egawa S, Ochiya T . Extracellular vesicles as biomarkers and therapeutic targets for cancer. Am J Physiol Cell Physiol. 2019; 318(1):C29-C39. DOI: 10.1152/ajpcell.00280.2019. View

Giovannelli P, Di Donato M, Galasso G, Monaco A, Licitra F, Perillo B . Communication between cells: exosomes as a delivery system in prostate cancer. Cell Commun Signal. 2021; 19(1):110. PMC: 8586841. DOI: 10.1186/s12964-021-00792-1. View

Chen L, Shan G . CircRNA in cancer: Fundamental mechanism and clinical potential. Cancer Lett. 2021; 505:49-57. DOI: 10.1016/j.canlet.2021.02.004. View

Hua J, Chen S, He H . Landscape of Noncoding RNA in Prostate Cancer. Trends Genet. 2019; 35(11):840-851. DOI: 10.1016/j.tig.2019.08.004. View

Jin L, Zhang Z . Serum miR-3180-3p and miR-124-3p may Function as Noninvasive Biomarkers of Cisplatin Resistance in Gastric Cancer. Clin Lab. 2020; 66(12). DOI: 10.7754/Clin.Lab.2020.200302. View

10.

Shan G, Shao B, Liu Q, Zeng Y, Fu C, Chen A . circFMN2 Sponges miR-1238 to Promote the Expression of LIM-Homeobox Gene 2 in Prostate Cancer Cells. Mol Ther Nucleic Acids. 2020; 21:133-146. PMC: 7286986. DOI: 10.1016/j.omtn.2020.05.008. View

11.

Fan C, Zhu X, Zhou Q, Wang W . CircFMN2 Boosts Sorafenib Resistance in Hepatocellular Carcinoma Cells via Upregulating CNBP by Restraining Ubiquitination. J Oncol. 2022; 2022:2674163. PMC: 9334069. DOI: 10.1155/2022/2674163. View

12.

Liu H, Lan T, Li H, Xu L, Chen X, Liao H . Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR. Theranostics. 2021; 11(3):1396-1411. PMC: 7738888. DOI: 10.7150/thno.53227. View

13.

Chen J, Wu Y, Luo X, Jin D, Zhou W, Ju Z . Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer. Theranostics. 2021; 11(15):7507-7526. PMC: 8210600. DOI: 10.7150/thno.59546. View

14.

Wang Q, He Y, Kan W, Li F, Ji X, Wu X . microRNA-32-5p targets KLF2 to promote gastric cancer by activating PI3K/AKT signaling pathway. Am J Transl Res. 2019; 11(8):4895-4908. PMC: 6731418. View

15.

Li Y, Tu S, Zeng Y, Zhang C, Deng T, Luo W . KLF2 inhibits TGF-β-mediated cancer cell motility in hepatocellular carcinoma. Acta Biochim Biophys Sin (Shanghai). 2020; 52(5):485-494. DOI: 10.1093/abbs/gmaa024. View

16.

Li R, Chen J, Gao X, Jiang G . Transcription factor KLF2 enhances the sensitivity of breast cancer cells to cisplatin by suppressing kinase WEE1. Cancer Biol Ther. 2021; 22(7-9):465-477. PMC: 8489924. DOI: 10.1080/15384047.2021.1949228. View

17.

Zhu Y, Tong Y, Wu J, Liu Y, Zhao M . Knockdown of LncRNA GHET1 suppresses prostate cancer cell proliferation by inhibiting HIF-1α/Notch-1 signaling pathway via KLF2. Biofactors. 2019; 45(3):364-373. DOI: 10.1002/biof.1486. View

18.

Wang B, Liu M, Song Y, Li C, Zhang S, Ma L . KLF2 Inhibits the Migration and Invasion of Prostate Cancer Cells by Downregulating MMP2. Am J Mens Health. 2018; 13(1):1557988318816907. PMC: 6775556. DOI: 10.1177/1557988318816907. View

19.

Bialkowska A, Yang V, Mallipattu S . Krüppel-like factors in mammalian stem cells and development. Development. 2017; 144(5):737-754. PMC: 5374354. DOI: 10.1242/dev.145441. View

20.

Haymaker C, Yang Y, Wang J, Zou Q, Sahoo A, Alekseev A . Absence of Grail promotes CD8 T cell anti-tumour activity. Nat Commun. 2017; 8(1):239. PMC: 5552797. DOI: 10.1038/s41467-017-00252-w. View