Exosomes transferring long non-coding RNA FAL1 to regulate ovarian cancer metastasis through the PTEN/AKT signaling pathway
Authors: S-X Zhang
Q Zhang
T-Y Len
L-H Yang
Q-H Zhao
Journal: European review for medical and pharmacological sciences (2020)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Tumor-derived exosomes; Long non-coding RNAs (lncRNAs); Ovarian cancer (OC); Tumorigenesis; Metastasis
Affiliations: Department of Gynaecology, The Second Affiliated Hospital of Kunming Medical University, Kunming, P.R. China. .

Abstract:  Objective: Tumor-derived exosomes have been repeatedly studied as tumor antigens, suppressing T-cell signaling molecules and promoting apoptosis in ovarian cancer (OC). Long non-coding RNAs (lncRNAs) have been recognized as major regulators in tumorigenesis, including OC. For this study, we try to find out the mechanism of exosomes and lncRNA FAL1 in OC. Materials and methods: After the extraction and identification of exosomes, the internalization of exosomes was observed. Invasion and migration experiments were conducted to investigate the effect of SKOV3 cells-secreted exosomes on OC tumorigenesis and metastasis. Furthermore, the in vivo findings were verified via xenograft tumors in nude mice. FAL1 was knocked out on exosomes. OC cells treated with exosomes were co-cultured with lncRNA FAL1 or/and PTEN to measure cell invasion and migration. Results: SKOV3-secreted exosomes were absorbed and internalized by OC cells. After exosome treatment, the migration and invasion of OC cells were enhanced, tumors in nude mice were larger and heavier, metastasis was increased, and lncRNA FAL1 expression was increased. When lncRNA FAL1 was knocked out, the promoting effects of SKOV3 cells-secreted exosomes on OC cell metastasis were weakened, along with increased PTEN level and decreased AKT phosphorylation level. In HO-8910PM cells treated with siRNA-FAL1 exosomes and siRNA-PTEN, cell invasion and migration, and AKT phosphorylation were restored. Conclusions: SKOV3-secreted exosomes inhibited the PTEN/AKT signaling pathway by transferring lncRNA FAL1, thus inhibiting OC cell metastasis in vitro and in vivo. 

Retracted: Yes

PubPeer comments:
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 Withdrawn. https: www.europeanreview.org article 23560 *The article u201cExosomes transferring long non-coding RNA FAL1 to regulate ovarian cancer metastasis through the PTEN AKT signaling pathway, by Q. Zhang, T.-Y. Len, S.-X. Zhang, Q.-H. Zhao, L.-H. Yang, published in Eur Rev Med Pharmacol Sci 2020; 24 (1): 43-54u2013DOI: 10.26355 eurrev_202001_19894u2013PMID: 31957817u201d has been withdrawn from the authors stating that u201cafter the manuscript has been accepted, we are ready to continue to study the exosomes and their mechanism of action. Before the research, we read the latest guideline of exosomes research, MISEV2018. This guideline first suggests that extracellular vesicles should be used to refer to these cell-derived noncellular membrane structures, while exosomes are only applicable to those vesicles released from intracellular sources to extracellular cells by special means. Secondly, the guidelines suggest that when performing key functional verification experiments with extracellular vesicles, methods such as density gradient centrifugation should be used to purify the vesicles. Thirdly, strict negative control should be set up in the functional study of cells, such as cell-conditioned medium treated with extracellular vesicle production inhibitor (GW4869), so as to exclude the false positive of other non-extracellular vesicle components in functional analysis. In our published manuscripts, we called extracellular vesicles as exosomes, and used exosomes separation kit with low purity to separate the exosomes. No appropriate negative control is used in the functional analysis. Most importantly, the conclusion we made in our study is u201cSKOV3-secreted exosomes inhibited the PTEN AKT signaling pathway by transferring lncRNA FAL1, thus inhibiting OC cell metastasis in vitro and in vivou201d. However, the study did not confirm whether lncRNA FAL1 was encapsulated by extracellular vesicles and transferred to OC cells or induced by extracellular vesicles to upregulate its expression in OC cells. Based on the above reasons, we believe that our understanding of extracellular vesicles is not deep enough, which leads to the inaccuracy and over-interpretation of the experimental results. In order to avoid the readersu2019 misunderstanding of extracellular vesicles and ensure the preciseness of scientific research, all of our authors decided to withdraw this article. We will conduct our research again according to MISEV2018, interpret the experimental results and write articles again, and will submit to ERMPS in the near futureu201d.* *The Publisher apologizes for any inconvenience this may cause.* ,